Olefin Metathesis in Confined Geometries: A Biomimetic Approach toward Selective Macrocyclization

Article abstract of DOI:10.1021/jacs.9b08776

The synthesis of macrocycles is severely impeded by concomitant oligomer formation. Here, we present a biomimetic approach that utilizes spatial confinement to increase macrocyclization selectivity in the ring-closing metathesis of various dienes at elevated substrate concentration up to 25 mM using an olefin metathesis catalyst selectively immobilized inside ordered mesoporous silicas with defined pore diameters. By this approach, the ratio between macro(mono)cyclization (MMC) product and all undesired oligomerization products (O) resulting from acyclic diene metathesis polymerization was increased from 0.55, corresponding to 35% MMC product obtained with the homogeneous catalyst, up to 1.49, corresponding to 60% MMC product. A correlation between the MMC/O ratio and the substrate-to-pore-size ratio was successfully established. Modification of the inner pore surface with dimethoxydimethylsilane allowed fine-tuning the effective pore size and reversing surface polarity, which resulted in a further increase of the MMC/O ratio up to 2.2, corresponding to >68% MMC product. Molecular-level simulations in model pore geometries help to rationalize the complex interplay between spatial confinement, specific (substrate and product) interaction with the pore surface, and diffusive transport. These effects can be synergistically adjusted for optimum selectivity by suitable surface modification.

Full text of DOI:10.1021/jacs.9b08776

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Article
Olefin Metathesis in Confined Geometries: A Biomimetic
Approach Towards Selective Macrocyclization
Felix Ziegler, Johannes Teske, Iris Elser, Michael Dyballa, Wolfgang Frey, Hamzeh
Kraus, Niels Hansen, Julia Rybka, Ulrich Tallarek, and Michael R Buchmeiser
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08776 • Publication Date (Web): 07 Nov 2019
Downloaded from pubs.acs.org on November 7, 2019
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Olefin Metathesis in Confined Geometries: A Biomimetic Approach
Towards Selective Macrocyclization
Felix Ziegler†, Johannes Teske†, Iris Elser†, Michael Dyballa‡, Wolfgang Frey§, Hamzeh
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†
∥
∥
⊥
⊥
Kraus , Niels Hansen , Julia Rybka , Ulrich Tallarek , Michael R. Buchmeiser*
†Institute of Polymer Chemistry, ‡Institute of Chemical Technology, §Institute of Organic Chemistry, Uni-
versity of Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
∥
Institute of Thermodynamics and Thermal Process Engineering, University of Stuttgart, Pfaffenwaldring
9, D-70569 Stuttgart, Germany
⊥
Department of Chemistry, Philipps-University of Marburg, Hans-Meerwein-Strasse 4, D-35032 Marburg,
Germany
ABSTRACT:
The synthesis of macrocycles is severely impeded by concomitant oligomer formation. Here, we
present a biomimetic approach that utilizes spatial confinement to increase macrocyclization selectivity in the
ring closing metathesis of various dienes at elevated substrate concentration up to 25 mM using an olefin me-
tathesis catalyst selectively immobilized inside ordered mesoporous silicas with defined pore diameters. By this
approach, the ratio between macro(mono)cyclization (MMC) product and all undesired oligomerization products
(O) resulting from acyclic diene metathesis polymerization was increased from 0.55, corresponding to 35% MMC
product obtained with the homogeneous catalyst, up to 1.49, corresponding to 60% MMC product. A correlation
between the MMC/O ratio and the substrate-to-pore-size ratio was successfully established. Modification of the
inner pore surface with dimethyldimethoxysilane allowed to fine-tune the effective pore size and to reverse
surface polarity, which resulted in a further increase of the MMC/O ratio up to 2.2, corresponding to > 68% MMC
product. Molecular-level simulations in model pore geometries help to rationalize the complex interplay between
spatial confinement, specific (substrate and product) interaction with the pore surface, and diffusive transport.
These effects can be synergistically adjusted for optimum selectivity by suitable surface modification.
clization (MMC) yields because of the ring-chain equi-
INTRODUCTION
librium (Scheme 1).16-17 This is particularly unfavora-
Macrocyclic compounds play an important role in
ble in case the starting diene has been prepared
through a multi-step, possibly stereoselective synthe-
sis, as is often the case with many progenitors for bi-
ologically and pharmaceutically active compounds.
One approach to improve macrocyclization yields en-
tails highly dilute conditions, typically ≤ 5 mM in sub-
strate.18-20 Furthermore, the slow addition of the sub-
strate to a catalyst solution promotes RCM.3, 15 With
cyclic ethers this problem can be alleviated by the use
of Li-ions,21-23 which form cyclic chelates and thus fa-
vor macrocyclization over oligomerization. Recently,
Fogg et al.24 outlined the use of an N,N-chelated Ru-
alkylidene, which allowed for high macrocyclization
yields, albeit still at 1 mol-% catalyst and 0.5 mM sub-
strate levels. Grela et al.25 used the back-biting reac-
tion in combination with a tailored distillation appa-
ratus to constantly remove the macrocyclic product.
This way it was possible to work at higher substrate
concentration (up to 0.2 M) at a 1 mol-% catalyst
pharmaceutical chemistry, e.g., as fragrances and
drugs.1-2 Macrocyclization can be accomplished by
different means,3 however, catalytic reactions such as
olefin metathesis have moved into the focus,4-11 the
more since these reactions can nowadays be realized
with high stereoselectivity.12-15 An unsolved problem
in macrocyclization is related to the efficiency of this
type of reaction. Mostly for entropic reasons, oli-
gomerization often dominates over macrocyclization.
In fact, Fogg et al.16 clearly demonstrated that ring-
closing metathesis (RCM) does not selectively proceed
via cyclization of the substrate as such, but also in-
volves oligomerization followed by back-biting and
concomitant RCM. In other words, if olefin metathesis
is used for macrocyclization, RCM and acyclic diene
metathesis (ADMET) oligomerization compete to a
substantial extent, leading to low macro(mono)cy-
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level. However, this strategy is obviously restricted to Importantly, this concept can only be expected to
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macrocyclization products that can be readily distilled
and also requires significant differences in the boiling
points of the starting compound and the product. Im-
mobilization strategies26 have been used, too, to im-
prove macrocyclization yields.27-28 Unfortunately,
these again required low substrate concentrations (0.5
mM) as well as high catalyst loadings (5 mol-%). Also,
immobilization has often been accomplished via the
alkylidene moiety, which releases the catalyst during
the first catalytic cycle, impedes permanent immobi-
lization and makes continuous flow experiments im-
possible.29 Similar accounts for physisorbed cata-
lysts.30 Consequently, compared to the homogeneous
catalyst, improved macrocyclization selectivity was
only achieved in very few cases. Finally, cavitands
have been reported to favor RCM-based macrocy-
clization, though again at low substrate concentration
and high catalyst loading (3 mol-%).31
Here, we present a new biomimetic approach that
uses a biological concept to eliminate the drawbacks
related to macrocyclization to a great extent and
which allows running macrocyclization reactions at
low catalyst loading and higher substrate concentra-
tion. Similar to enzymes, which can create highly sub-
strate specific reaction sites, our concept is based on
the idea to synergistically use both a well-defined or-
ganometallic catalyst and a defined pore shape and
size to create chemoselective reaction sites through
spatial confinement. The underlying concept entails
the pore size selective immobilization of a ruthenium-
based olefin metathesis catalyst inside the pores of a
support, here SBA-15-type silica, which is a mesopo-
rous silica consisting of ordered, hexagonally ar-
ranged, cylindrical pores.32-33 Similar to an enzyme or
a metalloenzyme,34-36 this particular approach pro-
vides a confined space for the macrocyclization reac-
tion. If the pore diameter is tuned such that only one
substrate can approach the catalyst inside the pore at
the same time, MMC must prevail and oligomerization
be suppressed (Scheme 1).
work if the catalyst is selectively fixed inside but not
outside the mesopores and the hydrodynamic diame-
ter of the substrate fits the pore diameter. This, in
turn, requires a pore size-selective functionalization
and careful tuning of the pore diameter. According to
the study of hindered diffusion in similar ordered mes-
oporous silicas by Tallarek et al.37 the hydrodynamic
diameter of both the catalyst and the substrate should
be less than ca. one third of the nominal pore diame-
ter, since otherwise diffusion into the pores becomes
severely obstructed.
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RESULTS AND DISCUSSION
Scheme 2 illustrates the synthesis of the homogene-
ous catalyst bearing a trimethoxysilyl-tether at the
NHC, which was used for its immobilization on the
silica support. Mesitylimidazole was reacted with (3-
iodopropyl)trimethoxysilane to yield the 1,3-disubsti-
tuted imidazolium salt, which was then deprotonated
with potassium hexamethyldisilazide (HMDS). The re-
sulting free carbene was finally reacted with the 1st-
generation Grubbs-Hoveyda catalyst to yield catalyst
3
.
Scheme 2. Synthesis of catalyst 3.
Scheme 1. Concept of macrocyclization in confined
geometries.
blocked outer surface
catalyst-containing inner pore surface
Si
Si
O
O
O
O
O
O
Si catalyst
O
Si
catalyst
ADMET
O
Si catalyst
X
X
n
m
O
O
O
MeO
Si
catalyst
RCM
O
X
M
n
m
y
back biting RCM
n
m
Figure 1. Single crystal X-ray structure of
3
. Selected
bond lengths [pm] and angles [°]: Ru(1)-C(19) 182.9(5);
Ru(1)-C(1) 199.8(5); Ru(1)-O(1) 225.8(3); Ru(1)-Cl(1)
233.13(13); Ru(1)-Cl(2) 233.21(13); C(19)-Ru(1)-Cl(2)
SBA-15 with different pore sizes
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104.98(14); C(19)-Ru(1)-O(1), 101.0(2); C(1)-Ru(1)-Cl(1)
3 @ SBA-15
3 @ SBA-15
62Å, respec-
µmol/g for
and
tively. To confirm pore5-0sÅelective catalyst immobiliza-
90.18(13); C(1)-Ru(1)-Cl(2) 92.29(13); C(1)-Ru(1)-O(1)
2
3
4
5
6
7
8
9
178.33(15); O(1)-Ru(1)-Cl(1) 88.15(9); O(1)-Ru(1)-Cl(2)
89.21(9); Cl(1)-Ru(1)-Cl(2) 152.52(5).
3
tion, we also immobilized on both unmodified SBA
SBA-1550Å unmodified
1550Å and SBA-1562Å, referred to as
SBA-1562Å 3 @
unmodified. A comparison between
3
and
Notably, catalyst is stable under air. Figure 1 shows
SBA 1550Å/SBA 1562Å
3 @ SBA 1550Å unmodified/SBA-
and
its single crystal X-ray structure along with selected
1562Å
3
revealed Ru-loadings of 2.0/3.4 and
bond lengths and angles.
crystallizes in a mono-
unmodified
40.5/56.0 µmol/g, respectively. The low Ru-loading in
clinic system in the space group P21/c (a = 1268.39(7)
pm, b = 2797.40(14) pm, c = 952.88(5) pm; α = γ =
90° and β = 108.741(2)). All bond lengths and angles
are unsuspicious; all methoxy-groups are distorted.
3
modified SBA-15 suggests that the majority of is in-
deed located inside but not outside the mesopores.
Energy-dispersive X-ray (EDX) spectroscopy measure-
ments were carried out and proved the existence of
catalyst on unmodified SBA-15 (Figure S6 and Figure
S7); however, the Ru-loading on modified SBA-15 was
too low to be measured. We make a diffusion-con-
trolled immobilization accountable for the compara-
tively low catalyst loadings in the modified SBAs.
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Two different silica materials with defined average
pore diameters of 50 Å and 62 Å, respectively, re-
SBA-15
SBA-15
62Å, were modified
ferred to as
and
50Å
to allow for a selective catalyst immobilization inside
the mesopores (Scheme 3). Ruthenium, i.e., catalyst
loadings determined by ICP-OES were 2.0 and 3.4
Scheme 3. Multi-step modification38 of SBA-15 for pore-selective immobilization of the catalyst inside the meso-
pores.
SBA-15: 48, 63 Å
outside
inside
OH
Si
Si
Si
Si
O
O
HO
O
O
OH
OH
OH
HMDS
neat, r.t., 3 h
Soxhlet extraction
solvent, 120 °C, 216 h
OH
OH
OH
Si
Si
OH
OH
OH
HO
HO
O
O
OH
OH
OH
OH
OH
OH
OH
O
O
OH
Si
Si
OH
3,
O
Pluronic® P-123
ethanol, r.t., 24 h
CH2Cl2,
r.t., 168 h
catalyst =
O
Si
N
N
O
Si
Si
O
O
Cl
Ru
O
O
O
Si catalyst
Pluronic® P-123
SBA-15
Si
Cl
O
O
O
OH
O
O
Si catalyst
Si
MeO
By contrast, the higher loadings observed with un-
modified SBA stem from catalyst immobilization both
outside and inside the pores.
around 5.520 ppm and the signals for both the E- and
Z-monomacrocycle (MMC) at 5.457 ppm and 5.429
ppm (see Figure S9). Generally, a higher macrocy-
clization selectivity was observed with larger sub-
3 @ SBA-1550Å
We then evaluated the selectivity of
3 @
strates, at similar conversion, when using
3 @ SBA-15
and
along with the homogeneous cat-
62Å
SBA-1550Å
3 @ SBA-1562Å
(Figure 3). This
instead of
alyst for a number of substrates characterized by dif-
ferent hydrodynamic diameters and functional groups
(Figure 2 and Scheme 4). Using 0.1 mol-% catalyst,
conversion was between 15 and 55%. Compared to
the homogeneous catalyst, macrocyclization selectiv-
ity was substantially improved for all substrates with
strongly suggests that a confinement effect based on
the size of the substrate and of the pore is effective.
5
3
By upscaling the RCM reaction of substrate with
@ SBA-1550Å
(MMC/O = 1.97) by a factor of 25 it
could be shown that it is also possible to work with
larger quantities (Table S8).
3 @ SBA-1550Å
both materials.
exhibited the highest
5
selectivity of 66% (MMC/O = 1.94 for substrate ) at
substantially elevated substrate concentration of
25 mM (Figure 3). The determination of the MMC:O
5
ratios by NMR is exemplified for substrate . One
needs to integrate the signal of the oligomer (O)
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esters-based α,ω-dienes
modification further increased selectivity as demon-
4 6 8 10
1
2
O
O
O
strated for substrates ‒ and ‒
(Figure 4). In the
9
case of , macrocyclization selectivity increased from
O
O
O
8
5
3
4
8
8
8
3 @ SBA-15
MMC/O = 0.55 to 1.80 for
50Å-DMDMS as com-
4
8.81 Å
5
10.64 Å
3
pared to operating in solution. This corresponds to
an increase in macrocyclization selectivity of 29%
5
6
7
8
O
O
O
O
3
with respect to operating in solution (Figure 5). In-
12
8
8
deed, with the macrocyclization selectivity for the ho-
6
11.71 Å
3
mogeneous catalyst as reference (100%), a plot of
9
selectivity changes for the individual substrates
against their hydrodynamic diameter reveals a clear
α,ω-dienes with various functional groups
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OAc
OMe
SBA-15
trend for
(Figure 5). Up to a hydrodynamic
50Å
diameter of ~0.9 nm the selectivity increases irrespec-
tive of the functional group of the substrate, while
above ~0.9 nm MMC selectivity drops quickly.
7
7
7
7
8
8.52 Å
7
8.45 Å
OTBDMS
O
7
7
7
7
9
9.05 Å
10
7.73 Å
Figure 2. Various α,ω-dienes used in macrocyclization.
Hydrodynamic diameter (in red) as determined via
DOSY-NMR in deuterated benzene using the Stokes-Ein-
stein equation.
Scheme 4. Examples for the reaction of substrates
5 and 9 with 3 @ SBA-1550Å, 3 @ SBA-1550Å-DMDMS, 3
@ SBA-1562Å, and 3 @ SBA-1562Å-DMDMS, and with the
homogeneous catalyst 3 to the macro(mono)cycliza-
tion products 11 and 12.
Figure 3. MMC/O ratios obtained in the RCM of sub-
strates 4‒10 using 3 @ SBA-1550Å or SBA-1562Å and with
the homogeneous catalyst 3. Reactions were run for 24
hours in C6D6 at 50 °C, using 0.1 mol-% catalyst with
respect to substrate and a 25 mM substrate concentra-
tion.
O
O
OTBDMS
O
O
5
7
7
8
8
9
5
DMDMS
modification
=
homogeneous
O
O
OTBDMS
O
O
27
17
11
Figure 4. MMC/O ratios for the reaction of 3 @ SBA-
12
, , ,
1550Å 3 @ SBA-1550Å-DMDMS 3 @ SBA-1562Å 3 @ SBA-1562Å-
To reduce the pore size and reverse the pore surface
polarity, we additionally modified the inner surface of
the SBA-15 materials after immobilization of the cat-
alyst with dimethoxydimethylsilane (DMDMS). This
and the homogeneous catalyst
3
obtained in the
DMDMS
RCM of substrates
4
‒
6
and
8
‒
10 in C6D6 after 24 hours
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at 50 °C using 0.1 mol-% of catalyst with respect to sub-
5
12
amounts of substrate and product , which are dis-
tributing between the two pore-flanking reservoirs
and the pore (Figure 6b). The radial profiles of sub-
strate and product (density distributions) in the un-
modified (Figure 6c) and the DMDMS-modified pore
(Figure 6d) reveal substantial differences that are en-
gendered by the surface modification: In the unmodi-
fied pore, both substrate and product molecules
strongly enrich near the surface due to localized ad-
sorption with their carbonyl oxygen onto the silanol
groups of the bare silica surface via hydrogen bond-
ing. This is reflected by the yellow and orange lines
in Figure 6c, which peak close to the surface. The hy-
drophobic tails of the molecules are oriented towards
the pore center, away from the polar surface (blue and
green lines). In the DMDMS-modified pore (Figure
6d), by contrast, the enrichment of substrate and
product molecules along the surface with its now re-
versed polarity is essentially suppressed (note the or-
der of magnitude difference in the density scales in
Figure 6c and d and, consequently, the molecules are
more uniformly distributed over the pore cross-sec-
tion. To verify the impact of the strikingly different
adsorption behavior on pore-level transport of sub-
strate and product molecules, we first recorded their
diffusion profiles in the unmodified and the DMDMS-
modified pore (Figure 6e). Due to the lack of adsorp-
tion onto (or even partitioning into) the DMDMS layer,
diffusion near the nonpolar surface is enhanced com-
pared to the unmodified bare-silica pore, where the
localized adsorption onto the silanol groups signifi-
cantly slows down molecular transport near the sur-
face. Together with the radial density distributions
r(r) shown in Figure 6c,d, the radial profiles of the
1
2
3
4
5
6
7
8
strate and 25 mM substrate concentration.
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Figure 5. Results in Figure 3 and Figure 4 for 3 @ SBA-
1550Å were plotted against the hydrodynamic diameter of
substrates ‒ and ‒
4 6 8 10 (black). The results for 3 @ SBA-
1550Å-DMDMS are plotted against the hydrodynamic diameter
of substrates , and
10 (red). Arrows indicate the
increase in macrocyclization selectivity between 3 @
SBA-1550Å and 3 @ SBA-1550Å-DMDMS
4
‒
6
8
‒
.
In that regards, macrocyclization efficiency serves as
probe for the confinement effect. Indeed, it highlights
the enzyme-like sensitivity, with which the spatial
confinement affects macrocyclization, identifying just
a narrow operational window for optimum MMC se-
lectivity. Furthermore, the systematically higher se-
3 @ SBA-15
lectivity observed for
50Å-DMDMS is attributed
to both the reduced pore diameter and the weakened
interaction between the nonpolar surface and the es-
ter, ether, or carbonyl groups of the products, which
supposedly results in shorter residence times at and
near the catalytic centers and, thus, in a reduced
probability of the macrocycles to experience ring re-
opening (cf. Scheme 1). Indeed, the DMDMS-
modification actually reverses the surface polarity
from polar to nonpolar. Since most substrates are
highly nonpolar, pore polarity must play an important
role in substrate transport into and out of the pores.
This effect is clearly mirrored by the results. Thus, the
increase in macrocyclization selectivity (Figure 5, ar-
( )
diffusion coefficients parallel to the pore axis ꢀ|| ꢁ in
Figure 6e can, in turn, be used to calculate average
pore diffusivities of substrate and product molecules
according to
( ) ( )
ꢂ ꢃ ꢄ ꢃ ꢃꢅꢃ
∫
||
〈
ꢀ||
〉
=
(1)
( )
ꢂ ꢃ ꢃꢅꢃ
∫
in which r is the radial distance from the pore center. In
the unmodified pore, we obtained diffusivities according
to eq. (1) of 0.23 ´ 10-9 m2s-1 (substrate) and 0.25 ´ 10-9
m2s-1 (product). For the DMDMS-modified pore, they
strongly increase to 0.71 ´ 10-9 m2s-1 (substrate) and 0.73
´ 10-9 m2s-1 (product), that is, by a factor of three.
6
rows) is stronger for the more nonpolar substrates
10
9
4
and than for the more polar ones (e.g., and
).
To better understand the important fine-tuning effects
of the chemical surface modification, which add to
the basic morphological properties of the underlying
SBA-15 support (pore size, shape, and connectivity),
we utilized molecular dynamics simulations employ-
ing cylindrical model pore geometries with and with-
out DMDMS-modification. Figure 6a,b depict front
and side view, respectively, onto the ~4.8 nm-diame-
ter, 10 nm-long model silica pore with DMDMS
There are several implications emerging from the re-
sults in Figure 6. Local enrichment of substrate and
product molecules near the catalytic centers is unfa-
vorable since it increases the risk of both oligomeri-
zation (proximity of substrate molecules) and back-
biting (proximity of product molecules). Suitable sur-
face modification suppresses the adsorption and local
enrichment, leading to higher pore-level diffusivities
that guarantee faster transport of substrate molecules
3
groups and two catalytic centers at its inner surface
(Figure 6a). The solvent benzene contains equimolar
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1550Å
3 @ SBA-15
to (and product molecules from) the catalytic centers,
and furthermore enhances the confinement effect.
This interplay of effects introduced by the surface
modification rationalizes the improved MMC selectiv-
ity seen in the experiments and can also form the ba-
sis for optimizing the conversion by reducing
transport limitations.
However, due to catalyst decomposition and diffusion
limitations in the SBA-15 particles under the experi-
mental conditions, conversions are generally lower
and
(MMC/O = 1.63, 2.26, 1.15,
62Å
1
2
3
4
5
6
7
8
3 @ SBA-15
@
3 @ SBA-15
10 °C,
@
and 1.64 for
70 °C,
50Å
3 @ SBA-15
@
3 @ SBA-1550Å
@
10 °C, and
70 °C, respectively)6.2TÅ he higher temperatures result in
lower viscosities of the reaction mixture and thus in
faster diffusion to and from the catalyst, which ex-
plains the higher conversion. In addition, the reaction
should be accelerated due to a reduced stability of all
ruthenacyclobutane intermediates.39-42 On the other
hand, higher temperatures reduce the extent of sub-
strate and product adsorption onto the surface (an is-
sue highlighted in Figure 6) and therefore also ac-
count for the increased MMC selectivity. When per-
forming the RCM reaction at different substrate con-
centrations and catalyst:substrate ratios (Figure 7c,d),
62Å
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3
for immobilized on any SBA-15 material than for the
3 @ SBA-15
homogeneous catalyst. Accordingly,
50Å al-
ways showed the lowest conversion for all substrates.
5
However, the reaction kinetics of substrate recorded
3 @ SBA-1550Å 3 @ SBA-1562Å
with
and
and for the
(Figure 7a) revealed that
3
it becomes evident that even small amounts of im-
3
homogeneous catalyst
mobilized at the pore entrances to the SBA-15 parti-
cles suffice to adversely affect selectivity such that the
spatial confinement effect offered by the mesopores
macrocyclization selectivity remained virtually inde-
pendent of conversion with MMC/O = 1.91, 1.41, and
3 @ SBA-1550Å 3 @ SBA-15
62Å, and the ho-
0.83 for
,
3 @ SBA-15
cannot be fully exploited. In principle,
3 @ SBA-1562Å
should not show any decrease 5i0nÅ
3
mogeneous catalyst , respectively. The diffusion-lim-
ited intraparticle transport and catalyst decomposi-
tion also caused the substrate conversion to deviate
from a 1st-order reaction kinetics. In view of these re-
sults, different reaction temperatures were investi-
gated (Figure 7b). With increasing temperature, both
or
selectivity with higher substrate concentration (Figure
7c, right panel) provided that all catalysts experience
a perfect confinement effect.
3 @ SBA-
conversion and selectivity increased for
Figure 6. a) Front view onto the silica block with DMDMS-modified cylindrical pore of 4.8 nm diameter. The purple
structures represent two catalysts attached to the inner pore surface. b) Side view of the simulation box with equimo-
lar amounts of substrate
3
5
(green) and product 12 molecules (orange). The pierced silica block is flanked by two solvent
reservoirs. Benzene as the solvent is indicated by the grey dots. c) Radial number density profiles of the carbonyl
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oxygen (yellow/orange) and vinylic carbon (blue/green) in the substrate (solid lines) and product (dashed lines), respec-
tively, in the unmodified pore. The shaded area indicates the configurational space accessible by the ruthenium atom
of the catalyst. d) Distributions corresponding to panel c, but in the DMDMS-modified pore. e) Radial dependence of
the axial self-diffusion coefficient of substrate (solid lines) and product molecules (dashed lines) in the unmodified (pink
and gray) and the DMDMS-modified pore (brown and cyan). The radial distance r from the pore center (where r = 0)
is normalized by the effective pore radius, representing the region accessible to the substrate and product molecules.
1
2
3
4
5
6
7
8
9
3
However, once even small amounts of are located
likely that catalysts located further inside the pore
(and particle) react. While these findings are con-
sistent with the proposed confinement effect, they do
not adversely affect the practical implementation of
this approach, since RCM reactions are usually car-
ried out with the lowest possible catalyst:substrate ra-
tio. In line with our findings and explanations, the ho-
close to the entrance of a pore leading into an SBA-
15 particle, the fraction of substrate molecules that
react with the catalyst at the pore entrance must be
higher at low catalyst:substrate ratio. Indeed, an al-
most exponential loss in macrocyclization selectivity
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3 @ SBA-1550Å
3 @ SBA-1562Å
was observed for
and
3
showed (within experimental
with increasing
catalyst:substrate
ratio
mogeneous catalyst
3 @ SBA-
(MMC/O = 2.12, 1.48, 1.76, and 1.05 for
error) the expected, slightly increasing macrocycliza-
tion selectivity over the investigated range of cata-
1550Å
SBA-1562Å
3
SBA-15
3
@ 0.4 mol-%,
@ 0.05 mol-%,
@
@
@
@ 0.05 mol-%, and 50Å
@
lyst:substrate ratios with respect to substrate
3
SBA-1562Å
5
0.4 mol-%) (Figure 7d). Clearly, with a maximum turn-
over number for each catalytic center prior to decom-
position, low catalyst:substrate ratios make it more
(MMC/O = 0.85 and 0.88 for 0.05 and 0.4 mol-% of
3
, cf. Figure 7d).
Figure 7. Macrocyclization reaction of substrate
catalyst:substrate ratios. a) Macrocyclization kinetics for
geneous catalyst at 25 mM substrate concentration and 0.1 mol-% catalyst:substrate ratio. In the case of 3 @ SBA-
1550Å and 3 @ SBA-1562Å, each point represents a new reaction terminated at different times. Macrocyclization of
with
at b) different temperatures (10, 24, 50, and
5
in C6D6 at different temperatures, substrate concentrations, and
5
with 3 @ SBA-1550Å and 3 @ SBA-1562Å and with the homo-
3
5
3 @ SBA-1550Å and 3 @ SBA-1562Å and with the homogeneous catalyst
3
70 °C; catalyst:substrate ratio: 0.1 mol-%; substrate concentration: 25 mM), c) different substrate concentrations (5, 10,
20, and 25 mM; catalyst:substrate ratio: 0.1 mol-%; temperature: 50 °C), and d) different catalyst:substrate ratios (0.05,
0.1, 0.2, 0.3, and 0.4 mol-%; substrate concentration: 25 mM; 50 °C).
chloride (21.0 mmol) in CH2Cl2 (40 mL) was subse-
EXPERIMENTAL SECTION
quently added pyridine (1.7 mL, 21.0 mmol) and the
General procedure for the synthesis of esters-based
corresponding alcohol (9.5 mmol/19 mmol) at 0 °C.
a,w-dienes (GP-1).
To a stirred solution of the acid
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After stirring for 4 hours at room temperature, the re- the removal of nitrogen in the pores, vacuum was ap-
1
2
3
4
5
6
7
8
action mixture was washed with 1.0 M aq. HCl solu-
tion (40 mL), sat. aq. NaHCO3 solution (40 mL), brine
(40 mL), dried over anhydrous Na2SO4, filtered, and
evaporated. The obtained crude product was purified
via column chromatography on SiO2 to obtain the cor-
responding ester.
plied. The suspension was stirred for 7 days at room
temperature. Then, the suspension was filtered and
the resulting silica containing the immobilized cata-
lyst was washed with CH2Cl2 (1000 mL), dried in
vacuo at 50 °C for 24 hours, and stored under inert
atmosphere at -35 °C.
General Procedure for the RCM of a,w-dienes (GP-
Pore characterization of the unmodified and modified
SBA-15 were carried out via Ar sorption measure-
ments (Figures S1-S5), EDX measurements (Figures
S6-S7) and solid-state NMR (Figure S8).
2).
To a stirred solution of the diene (0.75 mmol) in
9
CH2Cl2 (200 mL) was added the 2nd-generation Grubbs
catalyst (31.8 mg, 0.0375 mmol, 5 mol-%) at room
temperature. After stirring for 14 hours under reflux
and under N2, the reaction mixture was cooled to
room temperature and ethyl vinyl ether (5 mL, 70 eq)
was added. The mixture was stirred for further 2
hours at room temperature. All volatiles were re-
moved under reduced pressure, the obtained crude
product was purified via column chromatography on
SiO2 to obtain the corresponding macrocyclic prod-
uct, whose (E)/(Z) isomers were separated by semi-
preparative HPLC.
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Molecular dynamics simulations.
The cylindrical
mesopore model consisted of a 4.8 nm-diameter pore
carved through the (111) face of a b-cristobalite block
(8.096 nm × 7.893 nm × 10 nm (x × y × z)) along the
z-direction, following procedures reported previ-
ously,43-44 resulting in 5.55 silanol groups/nm2 on the
inner pore surface. The cylindrical pore was flanked
by two solvent reservoirs with the outer surfaces bear-
ing 4.52 silanol groups/nm². They were grafted uni-
formly random with 2.70 trimethylsilyl groups/nm² to
mimic experimental conditions, where the silanols on
the external surface of the SBA-15 silica particles have
been shielded. Two systems were simulated, which
differed in the surface modification inside the pore:
the bare silica surface bearing 5.55 silanol groups/nm2
and a DMDMS-modified silica surface with 3.34
DMDMS groups/nm² (leaving 2.21 residual silanol
groups/nm2). Each cylindrical pore was then grafted
General procedure for the RCM of a,w-dienes with
3 (GP-3).
The substrate was dissolved in C6D6 (990.5
3
µL ) and the catalyst
(stock solution 9.5 µL) was
1
added. After 24 hours, H NMR data were acquired.
The conversion and the ratio of macro(mono)cycliza-
tion (MMC) to oligomerization (O) were determined
by integration of the corresponding signals.
General procedure for the RCM of a,w-dienes with
3
with two catalysts . Both systems were equilibrated
3 @ SBA-15 (GP-4).
The substrate was dissolved in
5
with an equimolar mixture of substrate and its MMC
12
C6D6 (1.0 mL) and the corresponding SBA-15 contain-
product
in benzene at 50°C. The number of ben-
zene molecules in the simulation box was Nbenzene
3
ing the homogeneous catalyst (approx. 7-50 mg, de-
=
pending on the Ru-content and substrate:catalyst ra-
tio) was added. After 24 hours, 1H NMR data were ac-
quired. The conversion and the ratio of
macro(mono)cyclization (MMC) to oligomerization (O)
were determined by integration of the corresponding
signals.
4872 for the bare-silica pore and Nbenzene = 4620 for
the DMDMS-modified pore. Each simulation system
contained 10 substrate and 10 product molecules cor-
responding to a 20 mM solution of substrate and prod-
uct, respectively. Force-field parameters for Si, O, and
H atoms of the silica surface were taken from Gulmen
and Thompson.45-46 The GAFF force field was used for
General procedure for the multi-step modification
of SBA-15 (GP-5). Refilling:
SBA-15 (approx. 10 g)
substrate, product, and benzene molecules as well as
was added to a solution of P123 (40 g) in ethanol (150
mL). The mixture was stirred for 24 hours at room
temperature. The suspension was filtered and dried in
47
3
for the surface groups. Catalyst was modeled in its
precursor state, using structural parameters from the
single-crystal X-ray structure (Figure 2b) and GAFF
force field parameters combined with force constants
reported by Ahmadi et al.;48 partial atomic charges
were calculated with the DDEC approach.49 Simula-
tions were run using GROMACS 2016.5.50 Equilibra-
tion was carried out for 50 ns and the spatially-de-
pendent density and diffusion profiles were generated
from a 600 ns trajectory.
Selective protection of
vacuo at 80 °C for 24 hours.
silanol groups outside the mesopores:
The refilled
SBA-15 (approx. 15 g) was treated with hexamethyl-
disilazane (HMDS, 200 mL) for three hours at room
temperature. The mixture was filtered and the selec-
tively protected silica was washed with hexane (500
Removal of the surfactant:
mL).
removed by Soxhlet extraction with ethanol at 140 °C
Immobilization of the catalyst:
The surfactant was
for seven days.
Re-
CONCLUSIONS
filled, selectively protected, and extracted silica (2 g)
3
was added to a solution of (200 mg) in CH2Cl2. For
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We thank the Plietker group (Department of Organic
We successfully established a biomimetic approach to
1
2
3
4
5
6
7
8
Chemistry, University of Stuttgart) for the access to their
prep-scale HPLC equipment. We thank Viola Duppel,
MPI-FKF, Stuttgart, for the EDX measurements.
improve macrocyclization and suppress oligomeriza-
tion in the RCM-based synthesis of macrocyclic com-
pounds. The method presented here allows for a re-
silient and generally valid correlation between the
size of a substrate (as well as subtle changes thereof)
and its propensity to undergo macro(mono)cyclization
with a catalyst located inside a silica mesopore of de-
fined shape and size (cylinder diameter). Both pore
diameter and hydrodynamic radius of the substrate
have been shown to influence macrocyclization selec-
tivity. The extension to a nonpolar inner surface ad-
ditionally increases macrocyclization selectivity by re-
ducing the pore diameter and facilitating diffusion via
decreased adsorption of substrate molecules onto the
modified surface. Also, the importance of a pore-se-
lective catalyst immobilization with all catalysts im-
mobilized inside the pores ‒ sufficiently far away from
the pore entrances ‒ has been demonstrated. The pre-
sented approach allows for substantially higher mac-
rocyclization selectivity and higher substrate concen-
trations compared to existing procedures. Further im-
provements can be expected from tailored surface
modifications of the pore morphologies, which will
help to explore and utilize the full potential of the syn-
ergistic effects on macrocyclization selectivity arising
from the intrinsic spatial confinement, specific inter-
actions with the surface, local residence times, and
average transport rates.
ABBREVIATIONS
MMC, macro(mono)cyclization product; O, oligomeriza-
tion product; DMDMS, dimethyldimethoxysilane; RCM,
ring-closing metathesis; ADMET, acyclic diene metathe-
sis; SBA, Santa Barbara Amorphous.
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AUTHOR INFORMATION
Corresponding Author
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Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.,
*michael.buchmeiser@ipoc.uni-stuttgart.de
Palladium-Catalyzed Cross-Coupling Reactions in Total
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Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs,
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schaft DFG (grant numbers TA 268/11-1 and 358283783
‒ CRC 1333) and the Ministry of Science, Research, and
the Arts Baden-Württemberg is gratefully acknowledged.
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