Proline Functionalized UiO-67 and UiO-68 Type Metal-Organic Frameworks Showing Reversed Diastereoselectivity in Aldol Addition Reactions

Article abstract of DOI:10.1021/acs.chemmater.5b04575

Functionalization of dicarboxylate linkers with proline was used to generate catalytically active metal-organic frameworks (MOFs) for diastereoselective aldol addition. Due to high robustness and chemical stability, zirconium based MOFs, namely UiO-67 and

Full text of DOI:10.1021/acs.chemmater.5b04575

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Article
Proline functionalized UiO-67 and UiO-68 type Metal-Organic Frameworks
Showing Reversed Diastereoselectivity in Aldol Addition Reactions.
Christel Kutzscher, Georg Nickerl, Irena Senkovska, Volodymyr Bon, and Stefan Kaskel
Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.5b04575 • Publication Date (Web): 21 Mar 2016
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Chemistry of Materials
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Proline functionalized UiO-67 and UiO-68 type Metal-Organic
Frameworks Showing Reversed Diastereoselectivity in Aldol
Addition Reactions
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Christel Kutzscher, Georg Nickerl, Irena Senkovska, Volodymyr Bon, and Stefan Kaskel*
Department of Inorganic Chemistry, Technische Universität Dresden, Bergstraße 66, Dꢀ01069 Dresden, Germany.
ABSTRACT: Functionalization of dicarboxylate linkers with proline was used to generate catalytically active metalꢀorganic
frameworks (MOFs) for diastereoselective aldol addition. Due to high robustness and chemical stability, zirconium based MOFs,
namely UiOꢀ67, and UiOꢀ68 were chosen as catalyst hosts. During the MOF synthesis, utilizing Boc protected proline functionalꢀ
ized linkers H2bpdcꢀNHProBoc and H2tpdcꢀNHProBoc, in situ deprotection of the Boc groups without racemization is achieved,
enabling direct application of the enantiopure, homochiral MOFs in catalytic reaction, without further postꢀsynthetic treatment.
Solvent screenings, kinetic studies as well as cycling tests were used to evaluate the conditions for diastereoselective aldol addition
using a model reaction of 4ꢀnitrobenzaldehyde and cyclohexanone. High yields (up to 97%) were achieved in reasonable reaction
time using ethanol as solvent. In comparison to homocatalytic reactions catalyzed by Lꢀproline and its derivatives, MOFs showed
opposite diastereoselectivity attributed to the catalytic sites in confined pore space rendering this class of materials as promising
catalysts for fine chemical production.
I
NTRODUCTION
the porous DUTꢀ32 structure, containing pores up to 4 nm in
diameter.12 However, thermal treatment during MOF synthesis
and especially during thermal postꢀsynthetic deprotection of
DUTꢀ32ꢀNHProBoc leads to undesirable racemization and
simultaneous elimination of stereoselectivity in catalysis.10
Other methods, such as postsynthetic peptide functionalization
of MOFs minimize the negative impact of thermal treatment
on chiral information, but imply low functionalization degree
and require additional synthetic steps.9 A crucial issue for the
use of proline functionalized MOFs in asymmetric aldol addiꢀ
tion is to overcome low yields and/or low
(dia)stereoselectivity in connection with long reaction time.
Noteworthy, in most reported asymmetric aldol addition reacꢀ
tions of 4ꢀnitrobenzaldehyde and cyclohexanone catalyzed by
The application and research on the use of organocatalysts is
the prevailing field in asymmetric synthesis, and has attracted
tremendous attention since 2000. The development of efficient
organocatalysts is significant for synthesis procedures in the
drug, dye, and polymer industry and furthermore attractive for
the chemical synthesis of natural products.1,2 The αꢀamino acid
L
ꢀproline is one of the known “privileged chiral catalysts”,
which is a group of organocatalysts with outstanding catalytic
properties over a wide range of reaction types.3 Proline and its
derivatives are enamineꢀ or imine catalysts for asymmetric
reactions, namely Mannich, Michael, MoritaꢀBaylisꢀHillman
reactions and the aldol addition, which is the oldest and most
important CꢀC coupling reaction in organic chemistry.1 Beꢀ
yond the application of proline in homogeneous catalysis, the
interest in heterogeneous reactions, catalyzed by functionalꢀ
ized polymers or porous materials, is growing. One promising
material class for these applications are metalꢀorganic frameꢀ
works (MOFs), since the modular structure of these materials
allows well defined functionalization by linker design, post
synthetic functionalization or infiltration of active species.
Lꢀproline and its derivatives as homogeneous or heterogeneous
catalysts results in formation of antiꢀadduct, favored over the
syn configuration.13
In this work we report for the first time on reversed diastereoꢀ
meric selectivity as compared to homogeneous catalysts,
achieved using new Lꢀproline functionalized MOFs as catalyst.
Moreover, a high activity and good recyclability of the reacꢀ
tion could be verified. Proline functionalization of highly
stable UiOꢀ67 and UiOꢀ68 compounds is even accompanied
by in situ deprotection of the ProꢀBoc group (needed for the
MOF formation) reducing synthetic demands. The result is an
enantiomerically pure catalytically active material directly
obtained in the MOF synthesis.
The combination of the catalytically active
Lꢀproline with
MOFs to create a heterogeneous catalyst and their activity in
asymmetric catalysis was already reported by several groups.4–
11 Proline functionalization by incorporation of proline derived
linkers was published by the group of Telfer.5 Coupling of
Lꢀ
proline and linear 4,4′ꢀbiphenyldicarboxylic acid (H2bpdc)
afforded the chiral linker chirꢀH2bpdc capable to form
IRMOFꢀProꢀBoc [Boc: Nꢀ(tertꢀbutyloxycarbonyl)] structure.
Postsynthetic deprotection of the thermolabile Bocꢀgroup
resulted in chiral IRMOFꢀPro with free amine group of proꢀ
line. The obtained homochiral material, with enantiomeric
excess (ee) value of 80% for chiral proline group, was applied
in stereoselective aldol reactions showing moderate eeꢀvalues
up to 14% and good diastereomeric excess of 25 : 75
(syn : anti). The same linker could be also incorporated into
R
ESULTS AND DISCUSSION
Material synthesis and Characterization
The zirconium based MOFs UiOꢀ67 and UiOꢀ68 are isoreticuꢀ
lar compounds containing Zr6O4(OH)4ꢀclusters as octahedral
nodes, connected by linear linkers (bpdc2ꢀ and terphenylꢀ4,4’ꢀ
dicarboxylate (tpdc2ꢀ), respectively) forming a 12ꢀconnected
framework with fcu topology.14 The latter implies the presence
of octahedral and tetrahedral pores. The dimensions and acꢀ
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cessibility of the pores increases with the length of the organic seven days in absence of metal salt showed no Boc eliminaꢀ
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linker, used in the synthesis. To obtain homochiral MOFs of
UiO type with proline functionality, the linkers were coupled
tion. Therefore neither thermal treatment nor DMF and its
degradation derivatives are responsible for Boc deprotection.
To rule out the influence of hydrochloric acid generated in the
solvothermal ZrCl4 treatment, defined amount of HCl was
added to H2bpdcꢀNHProBoc solution in DMF in a control
experiment. After thermal treatment at 120 °C for 4 days, (in
analogy to UiO synthesis) no decomposition of the Boc group
was observed. Finally, the influence of zirconium salt on the
deprotection was investigated. To prevent MOF formation
during these tests, the ester of the linker (Me2bpdcꢀNHProBoc)
was used instead of dicarboxylic acid. Equal equivalents of
Me2bpdcꢀNHProBoc and ZrCl4 dissolved in DMF were heated
at 120 °C for 4 days, whereas after each 24 h reaction mixture
was investigated by HPLC. In addition to the signal of pure
Me2bpdcꢀNHProBoc at 16.8 min, the chromatogram shows a
distinct signal at 29.8 min originating from Boc deprotected
Me2bpdcꢀNHPro, already after 24 h (see Figure 2a). Further
temperature treatment (up to 4 days), however, leads to the
significant decrease of this signal (from 41% to 4%, see Figꢀ
ure 2b) and simultaneously to increasing turbidity of the soluꢀ
tion, indicating a precipitation of a linkerꢀzirconium adduct.
to Boc protected Lꢀproline following the recently published
procedure,10 whereas the precursors were synthesized using
the literature known protocol (see Figure 1).5,15 The resulting
chiral linkers H2bpdcꢀNHProBoc and H2tpdcꢀNHProBoc were
applied in the MOF synthesis (following reaction conditions
reported by Schaate et al.15 for UiOꢀ67 and UiOꢀ68) using
benzoic acid as modulator (for more details see ESI, chapter
2).
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Figure 1. Synthesis of a) UiOꢀ67ꢀNHPro and b) UiOꢀ68ꢀ
NHPro with proline functionalized linkers H2bpdcꢀNHProBoc
and H2tpdcꢀNHProBoc by thermal heating with ZrCl4 and
benzoic acid as modulator in DMF.
Figure 2. Investigations on deprotection with Zr4+: a) HPLC
chromatograms of Me2bpdcꢀNHProBoc (bottom), fully deproꢀ
tected Me2bpdcꢀNHPro (middle) and Me2bpdcꢀNHProBoc
after treatment in DMF with ZrCl4 for 1 day at 120 °C (top).
Grey marked signal could not be assigned. (The formation of
second enantiomer can be ruled out.) b) Areaꢀpercent of the
peak assigned to deprotected Me2bpdcꢀNHPro in comparison
to Me2bpdcꢀNHProBoc signal after treatment in DMF at
120 °C with ZrCl4 after defined time.
Obviously, the hard Lewisꢀacidity of Zr4+ is responsible for the
in situ deprotection of H2bpdcꢀNHProBoc and H2tpdcꢀ
NHProBoc, whereas the acidity of Zn2+ is too low and the
deprotection does not take place during the synthesis of Znꢀ
based MOFs, such as DUTꢀ32ꢀNHProBoc10 and IRMOFꢀProꢀ
Boc.5
According to the powder Xꢀray diffraction (PXRD) patterns of
the crystalline MOF products, the obtained compounds UiOꢀ
67ꢀNHPro and UiOꢀ68ꢀNHPro are isostructural to the targeted
UiOꢀ67 and UiOꢀ68 frameworks (Figure 3). The XRD pattern
of UiOꢀ67ꢀNHPro was subjected to Pawley refinement (Figꢀ
ure S.18, ESI) which resulted in lattice parameter
a = 26.8663(1) Å, which is slightly smaller than that for UiOꢀ
Liquid phase 1HꢀNMR analysis of the MOFs after digestion in
DCl and DMSOꢀd6 indicated intact proline side group at the
linker backbones, but the initial Boc protecting group could
not be detected. Further investigations of as synthetized mateꢀ
rials by TGA confirm the absence of the Boc protecting group
(see ESI, Figure S.4). Astonishingly, MOF synthesis under the
above mentioned conditions lead to the advantageous in situ
decomposition of the thermal labile Boc group. This is an
outstanding finding as it stays in stark contrast to the observaꢀ
tions made during the synthesis of Zn based MOFs with
H2bpdcꢀNHProBoc, such as DUTꢀ32ꢀNHProBoc10 and
IRMOFꢀProꢀBoc,5 investigated earlier. In the latter cases,
postꢀsynthetic deprotection was always a necessary postꢀ
synthetic step, achieved only under harsh conditions and thus
posing limitations in terms of wide applicability.
To get insights into the in situ deprotection process, further
investigations were performed using pure H2bpdcꢀNHProBoc
linker as model system (see ESI, chapter 4). Thermal treatꢀ
ment of H2bpdcꢀNHProBoc in DMF (p.a.) at 120 °C for up to
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Chemistry of Materials
67.16 UiOꢀ68ꢀNHPro could be obtained in the form of single
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crystals of diffraction quality. However, as frequently obꢀ
served for other chiral MOFs (DUTꢀ32ꢀNHProBoc10, chirꢀ
UMCMꢀ117) the synchrotron single crystal Xꢀray diffraction
study reveals only the structure of the main skeleton of the
framework (see ESI, chapter 6). The high symmetry of the
structure as well as disorder in the large pores of the MOFs do
not allow to localize the chiral Lꢀproline groups. In order to
estimate the favorable positions of catalytic active groups
inside the framework, proline groups were modeled using
Material Studio 5.0.18 Further the geometry optimization was
performed in the same program using universal force field.
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Figure 4. Structures of UiOꢀ67ꢀNHPro (top) and UiOꢀ68ꢀ
NHPro (bottom): a) Simplified representation of octahedral
pore, highlighting linker backbone and proline side group, b)
Crystal structure of the MOFs, highlighting the two pore types
by grey spheres, c) Simplified representation of tetrahedral
pore, highlighting linker backbone and proline side group.
(Hydrogen atoms are omitted for clarity.)
All these observations are reflected in the pore size distribuꢀ
tions obtained from the theoretical calculations (Figure 5).
Thus, in case of UiOꢀ67, the chiral modification of the frameꢀ
work leads to the drastic decrease of the pore diameter from
10.0 and 12.8 Å to ca. 8.8 Å, making pore size very similar to
the size of the envisioned product molecule (Figure 5). In case
of UiOꢀ68 materials the size of the tetrahedral pore is strongly
affected by substituents, but the diameter of the large octaheꢀ
dral pore changes from 17.7 to 16.4 Å only. The accurate
crystallographic estimation of pore sizes is difficult due to the
low rotation barrier of proline side groups of bpdcꢀNHPro2ꢀ
and tpdcꢀNHPro2ꢀ. Nevertheless, the calculation results are
strongly supported by the catalytic activity of the materials,
discussed below.
After activation of UiOꢀ67ꢀNHPro in high vacuum from ethaꢀ
nol, the material shows permanent porosity (according to N2
physisorption measurement at 77 K, Figure 6) with total pore
volume of 0.51 cm3 gꢀ1. The conventional thermal drying of
UiOꢀ68ꢀNHPro compound results in low nitrogen uptake in
physisorption measurements, therefore supercritical drying by
exchange of ethanol with CO2 was applied. The nitrogen phyꢀ
sisorption shows, as expected, significant increase in the pore
volume of UiOꢀ68ꢀNHPro up to 0.93 cm3 gꢀ1 (Figure 6). The
values of the total pore volume are comparable with the geoꢀ
metrically calculated values obtained for the simulated strucꢀ
ture models using Poreblazer 3.0.2.19 These amount to
0.56 cm3 gꢀ1 for UiOꢀ67ꢀNHPro and 1.15 cm3 gꢀ1 for UiOꢀ68ꢀ
NHPro.
Figure 3. PXRD patterns of as synthesized UiOꢀ67ꢀNHPro (a)
and UiOꢀ68ꢀNHPro (b) soaked in DMF (black curves) in
comparison to theoretical PXRD (grey curve) patterns calcuꢀ
lated from the crystal structures of UiOꢀ67 and UiOꢀ68, reꢀ
spectively.
The analysis of the UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro strucꢀ
tures shows significant differences between them in terms of
the location of the chiral groups. Thus, in UiOꢀ67ꢀNHPro the
Lꢀproline substituents are directed toward the large octahedral
pores causing an almost complete blocking of the latter. On
the contrary, UiOꢀ68ꢀNHPro is characterized by completely
different position of the middle phenyl ring, where the
Lꢀ
proline is coordinated. The side groups are located in the tetꢀ
rahedral pores or in the proximity to the pore windows, conꢀ
necting tetrahedral and octahedral pores (see Figure 4).
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HPLC on a commercial reversed phase column RPꢀ18 (see
ESI, chapter 5.2).
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Scheme 1. Asymmetric aldol addition of 4ꢀnitrobenzaldehyde
and cyclohexanone yielding two possible diastereomers: synꢀ
and antiꢀadduct.
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In general, the stereoselectivity of this proline catalyzed reacꢀ
tion is based on the cyclic intermediate state between the aldeꢀ
hyde and enamine species formed by hydrogen bonding. Typiꢀ
cally, antiꢀadduct formation by direct aldol addition of 4ꢀ
Figure 5. Pore size distribution calculated by Poreblazer
3.0.219 for UiOꢀ67, UiOꢀ67ꢀNHPro, UiOꢀ68, and UiOꢀ68ꢀ
NHPro. The size of the aldol product of 4ꢀnitrobenzaldehyde
and cyclohexanone addition was estimated from the crystal
structure reported by Wu et al.20
nitrobenzaldehyde and cyclohexanone catalyzed by Lꢀproline
is favored. The reaction is usually performed in DMSO at low
temperatures (typically at room temperature) with 20 mol% of
catalyst.20–23 For investigation of catalytic performance of the
MOFs several parameters were modified to optimize the reacꢀ
tion conditions with regard to conversion, yield, reaction time,
and diastereoselectivity. The reactions were performed using
UiOꢀ67ꢀNHPro, UiOꢀ68ꢀNHPro, and Me2bpdcꢀNHPro as
catalysts using 1 eq. 4ꢀnitrobenzaldehyde and 10 eq. cyclohexꢀ
anone in 5 ml solvent (see Table 1).
The ester Me2bpdcꢀNHPro was used as reference homogeneꢀ
ous catalyst, proving the general catalytic activity of the proꢀ
line side group coupled to the phenyl ring backbone. It showed
moderate yields up to 60% by stirring at 24 °C for 7 days in
nꢀheptane. Solvents with higher polarity, such as DCM or
DMSO decrease the reaction yield. Concerning the diastereꢀ
oselectivity, the antiꢀadduct formation is preferred in this
homogeneous reaction with diastereomeric ratio (dr) up to
23 : 77 (syn : anti) (Table 1, entries 1ꢀ3).
The use of MOF based catalyst UiOꢀ67ꢀNHPro in the same
reaction results in drastically reduced yield (11 ꢀ 17%) despite
slightly increased reaction temperature of 40 °C (see Table 1,
entries 4ꢀ6). Henschel et al. already demonstrated by liquid
phase adsorption experiments, that the solvent has significant
impact on the adsorption behavior of substrates depending
strongly on the polarity of MOFs.24 Therefore several solvents
were tested in catalytic screening. The lowest conversion was
observed for the reaction in pure cyclohexanone (additionally
5 ml were added to the initial amount) giving a yield of about
10% (Table 1, entry 8). The best performance was achieved
using ethanol as solvent with a yield up to 39%. Obviously,
ethanol enables the best substrate/product transport and might
have the lowest affinity to the amine group of proline.
Using the isoreticular structure UiOꢀ68ꢀNHPro as catalyst
results in a significantly increased yield up to 97% for the
reaction in ethanol (Table 1, entry 12). This observation is
clearly related to the increased pore and pore window sizes,
resulting in better kinetics for adsorption of substrates and
desorption of products.
Figure 6. Nitrogen physisorption isotherms for UiOꢀ67ꢀ
NHPro and UiOꢀ68ꢀNHPro at 77 K. Adsorption ꢀ filled cirꢀ
cles, desorption ꢀ open circles.
Asymmetric Aldol Addition
Due to the in situ deprotection of the proline group during the
MOF synthesis, the materials UiOꢀ67ꢀNHPro and UiOꢀ68ꢀ
NHPro are directly applicable as catalysts for asymmetric
catalysis based on prolineꢀdriven reactions.
Investigations of enantiomeric purity of the H2bpdcꢀ
NHProBoc linker during the thermal treatment were perꢀ
formed and are reported earlier. As a result of these investigaꢀ
tions only low changes in eeꢀvalue (max. 4%) up to 120 °C
were observed.10 Therefore, the racemization of the H2bpdcꢀ
NHProBoc linker at the temperature of MOFꢀsynthesis
(120 °C in DMF) is not expected and the UiOꢀ67ꢀNHPro and
UiOꢀ68ꢀNHPro are expected to be homochiral, containing (S)ꢀ
proline side groups (for more details see ESI, chapter 3). The
aldol addition of cyclohexanone with 4ꢀnitrobenzaldehyde was
selected as model reaction for estimation of catalytic perforꢀ
mance of the new MOFs (Scheme 1). Four different isomers
of aldol adduct can be produced in the reaction: two of them
are synꢀoriented and two are antiꢀoriented. Consequently,
there are two possible pairs of diastereomers, synꢀ and antiꢀ
adduct, which can be quantitatively examined by nonꢀchiral
Surprisingly, investigations on diastereoselectivity of the
reactions showed a preferred synꢀadduct formation by both
MOFs. The highest stereoselectivity was achieved using UiOꢀ
68ꢀNHPro catalyst in ethanol with good drꢀvalues up to
88 : 12 (syn : anti) and desynꢀvalue (diastereomeric excess
comparing to synꢀadduct) of 76% (Table 1, entry 12). In the
homogeneously catalyzed direct aldol addition, according to
Mlynarski et al., the addition of water improves the stereoseꢀ
lectivity.25 Therefore catalytic performance of UiOꢀ67ꢀNHPro
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in a solvent mixture of ethanol/water (4/1) was examined.
However, in our MOF catalyzed reaction the diastereoselectivꢀ
ity significantly decreased from desyn = 58% in pure ethanol to
desyn = 26% in ethanol/waterꢀmixture (see Table 1, entry 10).
proved diastereoselectivities by application of ZnCl2, FeCl3,
HgCl2 or CdCl2 in combination with ꢀproline in contrast to
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L
typical reaction modes. They assume an in situ formation of a
catalytically active complex based on Lewis acids coordinated
by functional groups of proline, affecting the stereoselectivity
of the aldol reaction, however, resulting in preferred antiꢀ
adduct formation. In principle in UiO catalyzed reactions, the
Zr cluster can also participate and influence the diastereoselecꢀ
tivity, and should correspond to missing linker defects, which
can be estimated to a limited extent by physisorption and
elemental analysis. However, within this work the influence of
defects on stereoselectivity was not further investigated.
Further enantioselectivity studies showed no enantiomeric
excess (ee) in any catalytic conversions using UiOꢀ67ꢀNHPro
or UiOꢀ68ꢀNHPro (see ESI, chapter 5.4). However, an imꢀ
portant selectivity feature is the pronounced diastereoselectiviꢀ
ty, as it is remarkably reversed by applying our new chiral
MOF catalysts.
Table 1. Catalysis studies for aldol addition of
4ꢀnitrobenzaldehyde and cyclohexanone.a
drb
(syn:anti)
Yield
(%)b
desyn
(%)c
Nr.
Catalyst
Solvent
9
Me2bpdcꢀ
NHPro[d]
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1
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3
DMSO
nꢀheptane
DCM
28
60
38
36 : 64
29 : 71
23 : 77
ꢀ 28
ꢀ 40
ꢀ 53
Me2bpdcꢀ
NHPro[d]
Me2bpdcꢀ
NHPro[d]
4
5
6
UiOꢀ67ꢀNHPro*
UiOꢀ67ꢀNHPro*
UiOꢀ67ꢀNHPro*
DMSO
nꢀheptane
DCM
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11
17
72 : 28
57 : 43
62 : 38
44
13
23
All further investigations were performed using optimized
reaction
parameters:
20 mol%
MOF,
1 eq.
4ꢀnitrobenzaldehyde, 10 eq. cyclohexanone, 5 ml ethanol,
40 °C. Both MOFs, UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro, conꢀ
taining ethanol in pores, were used without additional activaꢀ
tion. For constant stirring of the reaction mixtures two differꢀ
ent stirring conditions were used (see ESI, chapter 5.5). For
cycling tests, as well as parameter screenings indirect stirring
was applied to prevent mechanical stress on the materials. For
kinetic investigations direct stirring was used.
UiOꢀ67ꢀ
7
DCM
5
71 : 29
41
NHPro*,[e]
cyclohexan
one
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UiOꢀ67ꢀNHPro*
UiOꢀ67ꢀNHPro
UiOꢀ67ꢀNHPro
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39
34
80
77 : 23
79 : 21
63 : 37
55
58
26
EtOH
EtOH:H2O
(4:1)
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12
UiOꢀ68ꢀNHPro*
UiOꢀ68ꢀNHPro
DCM
EtOH
78 : 22
88 : 12
56
76
97
[a]
* Dried material was used as catalyst; Reaction conditions:
40 °C, 10 days, 1 mmol 4ꢀnitrobenzaldehyde, 10 mmol cyclohexꢀ
anone, 5 ml solvent, 20 mol% catalyst (related to the active proꢀ
[b]
line amount in the material);
chapter 5.2);
Determined by HPLC (see ESI,
[c]
De based on synꢀamount (see ESI, chapter 5.2);
[d] Reaction conditions: room temperature, 7 days;
catalyst.
5 mol%
[e]
As an outstanding observation, diastereomeric selectivity of
UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro is reversed in comparison
to homogeneously catalyzed reactions. Using an analogous
linkerꢀester Me2bpdcꢀNHPro as a homogeneous catalyst, antiꢀ
adduct was preferred with drꢀvalues up to 23 : 77 (syn : anti).
Furthermore in the majority of other published catalytic reacꢀ
tions with
Lꢀproline or other Lꢀproline derivatives as catalyst,
also the antiꢀadduct is preferably formed.21,22,25,26 Also other
Figure 7. Kinetic curves of aldol reaction (performed under
direct stirring) catalyzed by UiOꢀ68ꢀNHPro (◒) and UiOꢀ67ꢀ
NHPro (•) in ethanol at 40 °C.
MOFs functionalized by Lꢀproline, like CMILꢀ1 published by
Banerjee et al .6, showed antiꢀselectivity in this reaction.
Confined space in the pores might be a possible explanation
for this observation, affecting the formation of the cyclic tranꢀ
sition state in the aldol addition. In contrast, the enlargement
of the pores from UiOꢀ67ꢀNHPro to UiOꢀ68ꢀNHPro does not
reduce the preferred synꢀproduct formation. Due to the high
concentration of proline groups (each pore is surrounded by at
least six linkers with proline side groups, see Figure 4), the
participation of several prolines in the transition state could
also explain the reversed selectivity. Theoretical calculations
could be very helpful to attain further insights in the selectivity
reversal mechanism but are beyond the scope of this work.
Kinetic progress of the catalysis can be evaluated by the kinetꢀ
ic curves for UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro in Figure 7.
They show significant differences in catalyst performance.
The kinetic curve for UiOꢀ68ꢀNHPro has a steep increase and
ends up in a plateau, indicating maximum yield of 97% after
six days. In contrast to this, the kinetic curve for UiOꢀ67ꢀ
NHPro shows no plateau and permanent increase of the yield
for up to eleven days. Consequently, the reaction in UiOꢀ67ꢀ
NHPro pores is more kinetically hindered (slow adꢀ and deꢀ
sorption kinetics of substrates and products, respectively) due
to smaller pores and pore windows in comparison to UiOꢀ68ꢀ
NHPro (as discussed above), resulting in low yield and exꢀ
tended reaction time. The catalyst performance in this case can
Previous research on the stereoselectivity of Lꢀproline driven
aldol addition demonstrated also the high influence of Lewis
acids in aldol addition catalysis.27 The authors describe imꢀ
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Chemistry of Materials
be improved by widening pores and pore windows, using UiOꢀ
68ꢀNHPro instead of UiOꢀ67ꢀNHPro. The maximum yield of
97% is reached after six days with UiOꢀ68ꢀNHPro, whereas
the yield of reaction catalyzed by UiOꢀ67ꢀNHPro is only 30%
after same reaction time.
Page 6 of 9
with reversed stereoselectivity, obtaining drꢀvalues of 88 : 12
(syn : anti). Remarkably, UiOꢀ68ꢀNHPro and UiOꢀ67ꢀNHPro
are the first published ꢀproline functionalized MOFs with
preferred synꢀadduct formation in this reaction type.
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L
To test the stability and recyclability of the MOF catalysts,
cycling studies were performed. Therefore, the same samples
of UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro were utilized for severꢀ
al catalytic runs of asymmetric aldol addition of cyclohexaꢀ
none and 4ꢀnitrobenzaldehyde (Figure 8).
Reactions catalyzed by UiOꢀ67ꢀNHPro show significant deꢀ
crease in yield from 39% to 26% after three cycles. Furtherꢀ
more desyn slightly decreases. In contrast to UiOꢀ67ꢀNHPro,
the UiOꢀ68ꢀNHPro shows low variation in yields ranging from
81% up to 92% after three cycles. Additionally, the desynꢀvalue
is only marginally affected.
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C
ONCLUSIONS
In situ deprotection of chiral Boc protected linkers during the
synthesis of zirconium based MOFs is of great advantage and
represents an important progress in proline based MOF catalyꢀ
sis. Catalytic in situ deprotection facilitates the formation of
catalysts with high enantiomeric purity due to the dispensable
and often disruptive thermal treatment usually needed for
deprotection. In direct aldol addition reactions very high yields
could be achieved within reasonable reaction time. The influꢀ
ence of reaction solvent and the pore size on the reaction rate
could be clearly demonstrated by comparing two isoreticular
compounds, UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro with different
window sizes. Both MOFs showed reversed diastereoselectiviꢀ
ty in aldol addition, preferring synꢀaldol adduct formation for
reaction of cyclohexanone with 4ꢀnitrobenzaldehyde, in conꢀ
trast to homogeneous catalysis preferring the antiꢀaldol adꢀ
duct, but the aldol adducts obtained are racemic in this case.
This indicates mechanistic differences controlling the heteroꢀ
geneous reaction induced either by pore wall interactions with
the substrate, the additional Lewis acidity of Zr4+ of the MOF
clusters or additional (multiple) interactions of the neighboring
proline groups due to the high concentration of the latter in the
pore. Despite catalysis with UiOꢀ67ꢀNHPro and UiOꢀ68ꢀ
NHPro showed no enantiomeric selectivity in product forꢀ
mation, an even more valuable feature of our new chiral
MOFs is the ability to target the rational synthesis of synꢀ
adducts, which is generally nonꢀpreferred in homogeneous
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The decomposition of the framework could be ruled out by
PXRD measurements (see ESI, Figure S.16). Nitrogen phyꢀ
sisorption investigations of the MOFs after the cycling test
showed decreasing porosity, indicating possible pore blocking
(see ESI, Figure S.15). Further side product formation, based
on proline derivatization, as described by several groups27,28
,
can also influence the porosity and the yield of the reaction.
Coupling of aldehyde species with proline resulting in a oxaꢀ
zolidinone or oxapyrrolydizine species could reduce the
amount of catalytically active sites and reduce the pore volꢀ
ume of the frameworks.27,28 Further evidence for this side
product formation in case of UiO catalyzed reactions could not
be found (see ESI, chapter 5.5).
catalysis with Lꢀproline species itself. Thus we believe our
new findings to be a valuable platform for synthetic chemists.
Moreover, we hope our findings will trigger theoretical invesꢀ
tigations to improve the mechanistic understanding of space
confined catalytic conversions in the fine chemical production
portfolio.
EXPERIMENTAL SECTION
Synthesis of Me2tpdc-NHProBoc: Dimethyl 2’ꢀaminoꢀ
1,1’:4,1’’ꢀterphenylꢀ4,4’’ꢀdicarboxylate (723 mg, 2.0 mmol),
1ꢀhydroxybenzotriazole (HOBt, 297 mg, 2.2 mmol, 1.1 eq.)
and
Nꢀ(tertꢀbutyloxycarbonyl)ꢀ
Lꢀproline
(BocꢀProꢀOH,
475 mg, 2.2 mmol, 1.1 eq.) were suspended in 14 ml anhyꢀ
drous DCM and stirred at room temperature for 30 minutes in
argonꢀflow. Afterwards the suspension was cooled down to
0 °C. Separately a solution of N,N'ꢀdicyclohexylꢀcarbodiimide
(DCC, 454 mg, 2.2 mmol, 1.1 eq.) in 5 ml anhydrous DCM
was prepared and added slowly to the cooled reaction mixture
within one hour. The reaction mixture was heated up to room
temperature and stirred for 4 days under argon atmosphere.
The resulting suspension was filtered to obtain an orange
solution. The solvent was removed by evaporation under reꢀ
duced pressure. Flash chromatography of the raw product in
ethyl acetate and hexane (1 : 1) and drying under high vacuum
afforded a pale yellow solid. Yield: 761 mg (1.36 mmol,
68%).
Figure 8. Yield and desynꢀvalue development using same samꢀ
ple of UiOꢀ67ꢀNHPro and UiOꢀ68ꢀNHPro for three cycles of
asymmetric aldol addition of cyclohexanone and
4ꢀnitrobenzaldehyde at 40 °C for 10 days.
Up to now several proline functionalized MOFs were reported
and used in different types of asymmetric aldol addition.5,6,9,11
High yields up to 95% could be obtained especially using
MILꢀ101 species, which also provides high porosity.9,6 The
applied materials showed good stereoselectivity, whereas
direct comparison is restricted due to varying aldol reaction
types. Banerjee et al.6 also presented aldol addition of cycloꢀ
hexanone with 4ꢀnitrobenzaldehyde catalyzed by chirꢀMILꢀ
101 achieving drꢀvalues up to 20 : 80 (syn : anti) with preꢀ
ferred antiꢀadduct formation and yields up to 81%. In comparꢀ
ison, UiOꢀ68ꢀNHPro shows even increased yields of 97% but
Synthesis of H2tpdc-NHProBoc: Me2tpdcꢀNHProBoc
(619 mg, 1.11 mmol) was dissolved in 10 ml of tetrahydrofuꢀ
ran (THF) and 10 ml of an aqueous 1 M KOH solution was
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Chemistry of Materials
added. The resulting emulsion was stirred at 50 °C overnight. screwed glass tube with direct mixing of the stirring bar in the
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The organic solvent was removed under reduced pressure, and
the resulting aqueous solution was cooled down to 0 °C. By
addition of aqueous 1 M HCl, the pH value was set to 4, which
afforded a pale yellow precipitate, which was filtered and
washed with water and ethanol. The product was dried in high
vacuum. Yield: 479 mg (0.90 mmol, 81%).
MOF.
Crystal Structure:
Crystal data for UiO-68-NHPro: C120H48N6O32Zr6, M =
2632.96 g molꢀ1, cubic, F23, a = 32.880(4) Ǻ, V = 35546(7)
Å3, Z = 4, ρcalc= 0.492 g cmꢀ3, λ = 0.88561 Å, T = 296 K,
reflections collected/unique 41593/ 6782, R1 = 0.0571, wR2 =
0.2780, S = 2.754, largest diff. peak 2.162 e Åꢀ3 and hole ꢀ
1.308 e Åꢀ3. CCDCꢀ1419929 contains the supplementary crysꢀ
tallographic data for UiOꢀ68ꢀNHPro. These data can be obꢀ
tained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Proline
groups were modeled in both compounds using Material Stuꢀ
dio 5.0 in P213 space group.[17]
Synthesis of UiO-67-NHPro: A solution of ZrCl4 (30 mg,
0.13 mmol) and benzoic acid (235 mg, 1.92 mmol, 15 eq.) in
DMF (5 ml) was prepared. To this solution H2bpdcꢀNHProBoc
(58 mg, 0.13 mmol) was added and the resulting mixture was
thermally treated at 120 °C for 4 days. The obtained colorless,
crystalline precipitate was washed with DMF (3 x 5 ml). For
activation of the material, solvent exchange with ethanol
(5 x 5 ml) was performed, followed by solvent evaporation
and final activation in high vacuum for 24 h at room temperaꢀ
ture. Yield: 54 mg (90%).
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ASSOCIATED CONTENT
Synthesis of UiO-68-NHPro: Benzoic acid (471 mg,
3.86 mmol, 30 eq.) and ZrCl4 (30 mg, 0.13 mmol) were solved
in 5 ml DMF (dry). Afterwards H2tpdcꢀNHProBoc (68 mg,
0.13 mmol) and deionized water (5 µl) were added to the
solution. The mixture was thermally treated in an oven at
120 °C for 4 days. The resulting colorless crystals were
washed with DMF (3 x 5 ml). For additional drying and actiꢀ
vation of the material solvent exchange with ethanol (3 x 5 ml)
and finally with liquid CO2 was performed, followed by suꢀ
percritical drying from CO2. The dry material was stored in
argonꢀatmosphere. Yield: 23 mg (33%).
Supporting Information Available. Detailed synthetic proceꢀ
dures and analytics of synthesized linkers and materials, as well as
further results from deprotection study and catalysis, including
HPLC spectra, PXRD, NMR spectra and nitrogen physisorption
isotherms. This material is available free of charge via the Internet
at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: stefan.kaskel@chemie.tuꢀdresden.de.
Catalysis with UiO-67-NHPro: Two batches of UiOꢀ67ꢀ
NHPro (approximately 100 mg, 0.21 mmol regarding to
amount of proline groups) were combined and washed with
ethanol (3 x 5 ml) and the supernatant solvent was removed.
The material was transferred in a screwed glass vial
Phone: +49 351463ꢀ33632. Fax: +49 351 463ꢀ37287.
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support from the
Deutsche Forschungsgemeinschaft within the priority program
SPP 1362 “Poröse metallorganische Gerüstverbindungen”. Furꢀ
thermore, we acknowledge chiral HPLC measurements by Anton
Keßberg from Organic Chemistry I Department at Technische
Universität Dresden.
(32 x 11.6 mm), which was placed in
a culture tube
(16 x 100 mm). On top of the small glass tube, a stirring bar
was placed. A solution of 4ꢀnitrobenzaldehyde (151 mg,
1 mmol) in ethanol (dry, 5 ml) was added to UiOꢀ67ꢀNHPro.
After short mixing time, cyclohexanone (982 mg, 10 mmol)
was added dropwise. The solution was stirred at 40 °C (unless
declared otherwise) for 7 to 11 days. Conversion, yield, and
diastereomeric selectivity were determined using HPLC using
a RPꢀ18 column. For catalytic tests using dried sample, UiOꢀ
67ꢀNHPro (93 mg, 0.20 mmol regarding to amount of proline
in UiOꢀ67ꢀNHPro) was directly soaked with mixture of startꢀ
ing materials. For each reaction 5 ml of solvent were used.
Catalyst used with direct stirring were placed directly in a
culture tube and stirred with a stirring bar.
Catalysis with UiO-68-NHPro: Three batches of UiOꢀ68ꢀ
NHPro (approximately 70 mg, 0.13 mmol regarding to the
amount of proline) were combined and washed with ethanol (3
x 5 ml). Analogue to catalytic tests performed with UiOꢀ67ꢀ
NHPro, the material was transferred in a glass tube with a
stirring bar on top, which was placed in a culture tube. 4ꢀ
Nitrobenzaldehyde (98.2 mg, 0.65 mmol) were solved in ethaꢀ
nol (5.0 mol) and mixed with the MOF. Cyclohexanone (638
mg, 6.50 mmol) was added dropwise and the reaction was
stirred at 40 °C for 7ꢀ11 days. Conversion, yield and diastereꢀ
omeric selectivity were determined using HPLC and a RPꢀ18
column. For catalysis with dried material UiOꢀ68ꢀNHPro
(70 mg, 0.13 mmol) was soaked in mixture of starting materiꢀ
als in 5 ml solvent. Direct stirring was performed without
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Exceptional Stability. J. Am. Chem. Soc. 2008, 130, 13850–
13851.
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