Alternating chiral selectivity of aldol reactions under the confined space of mesoporous silica

Article abstract of DOI:10.1039/c5cc07255g

The chiral selectivities were altered and high diastereo- and enantio-selectivities of the products were obtained in water medium without adding acid co-catalysts when a primary-tertiary diamine catalyst was immobilized on mesoporous SBA-15 to form a recyclable catalyst for the direct asymmetric aldol reaction of cyclohexanone with p-nitrobenzaldehyde.

Full text of DOI:10.1039/c5cc07255g

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Alternating Chiral Selectivity of Aldol Reactions under the
Confined Space of Mesoporous Silica
Chewei Yeh,a Yan-Ru Sun,a Shing-Jong Huang,b Yeun-Min Tsai aand Soofin Chenga*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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alternation of enantioselectivity of the products in aldol reaction
through immobilization of a specific organic catalyst on solid
supports has never been observed.
The chiral selectivities were altered and high diastereo- and
enantio-selectivities of the products were obtained in water
medium without adding acid co-catalysts when a primary-tertiary
diamine catalyst was immobilized on mesoporous SBA-15 to form
a recyclable catalyst for the direct asymmetric aldol reaction of
cyclohexanone with p-nitrobenzaldehyde.
In 2007, Luo et al.7 reported that chiral trans-N,N-dialkyl
diaminocyclohexanes with the aid of strong acids such as
trifluoromethanesulfonic acid and trifluoroacetic acid (TFA) in 1:1
molar ratio could nicely catalyze direct aldol reactions with high
efficiency and chiral selectivity. The same group reported the first
The aldol reaction provides an atom-economic route to synthesize
β-hydroxy carbonyl compounds,1 which have a broad range of
applications in areas such as pharmaceuticals production,2 along
with the formation of new carbon-carbon bonds. L-proline was
found by List and coworkers3 in 2000 as an effective asymmetric
catalyst in intermolecular aldol reactions. Since then much progress
has been made in the development of organocatalysis for aldol
reaction. 4
example of grafting
a diamine chiral catalyst on magnetic
nanoparticles and demonstrated high activity, stereoselectivity, and
recyclability in direct aldol reactions.8 However, the
enantioselectivities were retained as those in homogeneous system.
In the present study,
a primary-tertiary diamine (trans-N,N-
dialkylateddiaminocyclohexane, DDAC) catalyst was covalent
bonded on mesoporous SBA-15 to form a recyclable catalyst. A
remarkable alternation in chiral selectivities of the products in
direct asymmetric aldol reaction of cyclohexanone with p-
nitrobenzaldehyde was observed. Moreover, water can take the
place of strong acid additives in the immobilized system to give high
diastereo- and enantio-selectivities of the products.
The chiral diaminocyclohexane catalyst (trans-N,N-diallyl
diaminocyclohexane, abbreviated DDAC) was anchored on the thiol-
functionalized mesoporous SBA-15 (SH-SBA-15) through AIBN-
mediated thiol-ene reaction (Scheme 1).9 The resultant material is
termed DDAC-SH-SBA-15. SH-SBA-15 was synthesized by one-pot
co-condensation of tetraethyl orthosilicate (TEOS) and 3-
mercaptopropyltrimethoxysilane (MPTMS) in 2 M HCl containing
Pluronic P123 as the pore-directing agent, following the procedures
reported in Reference 10 to achieve homogeneous distribution of
the catalytic sites.10 The reactant molar compositions were 0.017
P123: 1 TEOS: 0.1 MPTMS: 7.9 HCl: 220 H2O.
The XRD patterns of SH-SBA-15 displayed three well-resolved
peaks in the region of 2θ = 0.9-1.8o indexed to the (100), (110), and
(200) diffraction planes of the 2D hexagonal p6mm mesostructure
(Figure S1, ESI). Slight shifts toward higher angles and decreases in
intensity were observed after the chiral amine was anchored onto
the SH-SBA-15 support. The SEM and TEM images of SH-SBA-15 and
DDAC-SH-SBA-15 showed no changes in rod-shaped morphology
and the retaining of cylindrical mesoporous channels of the 2D-
hexagonal structures. N2 adsorption-desorption isotherms of both
SH-SBA-15 and DDAC-SH-SBA-15 samples show type IV isotherms
and H1 hysteresis loops (Figure S2, ESI), characteristics of the large
tubular pores of SBA-15 materials. The steep capillary
Homogeneous aldol reactions often require tedious processes
for product purification. Moreover, it is not economical that the
elaborated chiral organocatalysts, which sometimes are prepared
by long and troublesome processes, cannot be reused. Thus,
catalysts of easy separation, recovery and recycling remain a
scientific challenge of economic and environmental relevance.5
A
recent review summarized the results of about 360 catalysts
studied from the beginning (2000) on asymmetric direct aldol
reactions taking place in the presence of immobilized chiral
organocatalysts.6 The immobilization methods include covalent
bonding, ligand grafting, microencapsulation, ion exchange, and
electrostatic interactions. Various supports have been used,
including organic polymers, such as polystyrene, poly(ethylene
glycol), tentagel resin, chitosan, ionic liquids, etc. and inorganic
solids, such as zirconium phosphonate, graphene oxide, clays, silica
gel, and mesoporous silica. However, the most active catalysts are
those already showed good performance under homogeneous
conditions. The immobilized catalysts are usually emphasized on
their regenerability and reusability. To the best of our knowledge,
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The disappearances of allyl carbons at 120 and 135 ppm and C
atoms on cyclohexane at 40-80 ppm are also evident. These results
demonstrate again that DDAC derivatives are successfully anchored
onto SH-SBA-15 through thiol-ene addition reaction.
To set a reference, DDAC was used as a homogeneous catalyst
for the cross-aldol condensation between p-nitrobenzaldhyde (NBA)
and cyclohexanone (CH) (1NBA: 10CH: 0.1DDAC equiv ratio) under
ambient temperature. Four products of two anti-isomers and two
syn-isomers were obtained, as shown in Scheme 2. The catalytic
results are summarised as Entries 1’ and 2’ in Table 1. In consistence
with the literature reports, the anti/syn ratio of the 2-(Hydroxy(4-
nitrophenyl)methyl) cyclohexan-1-one products is 76/24 obtained
with trifluoroacetic acid (TFA) as the additive (entry 1’). The role of
the acidic additive was suggested to be related to its possible
function in facilitating the enamine catalytic cycle.11 When a weak
acid such as terephthalic acid (pTPA) was added, the conversion
Scheme
1
The
preparation
route
of
trans-N,N-
dialkylateddiaminocyclohexanes functionalized mesoporous silica.
condensations at P/P0 around 0.40-0.70 indicate a uniform pore size
distribution. The pore diameters, estimated by BJH method on the
adsorption branches of the isotherms, decrease from 4.9 nm for SH-
SBA-15 to 4.1 nm for DDAC-SH-SBA-15 (Table S1, ESI). Moreover, the
BET surface area and pore volume were remarkably decreased from
615 to 265 m2/g and 0.59 to 0.29 cm3/g, respectively. These results
suggest that DDAC was successfully immobilized on SBA-15. The
elemental analysis showed that the N loading on DDAC-SH-SBA-15
was about 1.08 mmol/g and S loading of 1.17 mmol/g. The N/S
atomic ratio of around 1 indicates that the divinyl-substituted chiral
DDAC is probably attached to SH-SBA-15 through a di-substitution
reaction.
Scheme
2 Direct aldol reaction between p-nitrobenzaldhyde and
cyclohexanone and the four isomer products.
Table 1 Direct aldol reactions over DDAC and that immobilized on SBA-15
Entry Additive Conv. [a] Anti : syn[b]
Selectivity [%][c]
The thermogravimetric (TG) analyses have been carried out to
compare the thermal stabilities of the SH-SBA-15 materials before
and after anchoring of DDAC. The TG profiles show that the total
weight losses of SH-SBA-15 and DDAC-SH-SBA-15 are 11.8 and 30.1
wt%, respectively (Figure S3, ESI). SH-SBA-15 has only a one-step
weight loss appeared at 250-420 oC, due to the decomposition of
thiol group, while DDAC-SH-SBA-15 has another weight loss at
higher temperatures of 520-700 oC. Moreover, the weight loss in the
lower temperature region is also increased after DDAC is anchored.
These additional weight losses are all attributed to the
decomposition of the DDAC moiety.
(2R,1’S) (2S,1’R) (2S,1’S) (2R,1’R)
[%]
1 ‘[d] TFA
95
43
41
76
76 : 24
42 : 58
56 : 44
27 : 73
24 : 76
60 : 40
76 : 24
85 : 15
─
74.9(97) 1.1
39.9(90) 2.1
54.0(93) 2.0
23.6(75) 3.4
17.0(42) 7.0
57.6{92} 2.4
73.7(94) 2.3
81.6(92) 3.4
22.0(83) 2.0
50.6(75) 7.4
31.2(42) 12.8
2 ‘[d] pTPA
3
4
5
6
7
8
─
Solid state 13C CP-MAS NMR spectra of the SH-SBA-15 and
DDAC-SBA-15 samples are shown in Figure 1. The 13C CP-MAS NMR
spectrum reveals three intense peaks at 11, 19, and 25 ppm,
corresponding to the C atoms on the O3Si-CH2-CH2-CH2-SH or O3Si-
CH2-CH2-CH2-S-CH2- tethers displayed in sequence from left to right.
TFA
35.4
37.2
37.6(3)
(CF2COOH)2 79
38.8(2)
CH3COOH
pTPA
61
24.4(22) 15.6
63
7.6
2.9
─
16.4(37)
H2O
70
12.1(61)
9[e] H2O
trace
─
─
─
The reactions were carried out with cyclohexanone (0.2 mL, 2 mmol),
aldehyde (0.20 mmol, 1 equiv), the catalyst DDAC and additive (0.02 mmol,
0.1 equiv) without solvent at RT for 24 h. [a] Conversion of p-
nitrobenzaldhyde determined by HPLC analysis with external standard. [b]
Determined by 1H NMR. [c] The products’ configurations determined by chiral-
phase HPLC analysis and comparing with reported data; values in parenthesis
are e.e. selectivities. [d] Homogeneous system. [e] Me3Si-DDAC-SH-SBA-15
catalyst.
Figure 1 Solid-state 13C CP-MAS NMR spectra of SH-SBA-15 and DDAC-SH-
SBA-15. DDAC-SH-SBA-15.
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decreased and the anti/syn ratio of the product was inversed (entry for the high anti/syn ratio of 85/15 and enantioselectivity of 92%
2’). Moreover, the reaction became very sluggish, affording only obtained when water was used as additive (Table 1, entry 8). The
trace products if no acids were added. Similar result was observed importance of the nitro-group on p-nitrobenzaldehyde in hydrogen-
when water was added as the additive. That indicates that water is bonding was examined by using benzaldehyde to take the place of
too weak as an acid to assist the direct aldol reaction. The p-nitrobenzaldehyde as the reactant, and it was found that both the
transition-state model of the protonated catalytic center was aldehyde conversion and enantioselectivity decreased markedly
proposed by Luo et al.,7 showing that E-isomer of the enamine and (Table S2, ESI).
steric hindrance between the cyclohexene and benzene rings were
the main factors for formation of anti-isomer with (2R,1’S) enantio- DDAC-SH-SBA-15 was refluxed in a toluene solution containing
selectivity in this reaction (Scheme S1). trimethylsilyl chloride for 24 h to convert the surface silanol to
In order to provide evidence of the roles of the silanol groups,
When immobilized DDAC-SH-SBA-15 was used as the catalyst trimethylsilyl ether. The catalytic performance of resultant Me3Si-
(10 mol%), the aldol reaction is markedly accelerated even without DDAC-SH-SBA-15 in the aldol reaction of CH and NBA is poor and
any additive (entry 3), in contrast to the trace conversion over only trace amount of aldehyde conversion is obtained (Table 1,
pristine organocatalyst. With TFA as the additive, the reaction rate is entry 9). This result confirms the importance of the hydrogen-
increased but is slightly slower than that of the pristine bonding provided by the silanol groups on the silica wall in the
organocatalyst (entry 4). However, it is surprising to find that the catalytic reaction.
anti/syn ratio of the products is reversed from 76/24 obtained in
homogeneous system to 27/73 after the chiral diamines DDAC were
immobilized on SBA-15. Products of similar reversed anti/syn ratio
are observed with 2,2,3,3-tetrafluoro succinic acid as the additive
(entry 5). Nevertheless, the enantioselectivities of syn-isomers are
rather low with these strong acid additives.
If weak acid additives were introduced, the diastereo-
selectivities over DDAC-SH-SBA-15 were found to be also reversed
from that observed in homogeneous system (entries 6-7).
Moreover, (2R,1’S) isomer is the main product, similar to that
observed in the homogeneous system with strong acid additives. To
our delight, an extremely high anti/syn ratio of 85/15 and (2R,1’S)
enantioselectivity of 92% were obtained when water was used as
the additive (entry 8). This finding is unique since water is not an
effective additive in the homogeneous system.
Changes in stereoselectivity with supported catalysts were
previously reported in enantioselective reactions promoted by
immobilized metallic complexes.12 A complete reversion in anti/syn
Scheme 3 Proposed transition states for syn- and anti-aldoladducts in the
confined space of DDAC-SH-SBA-15.
ratio and an increase in the enantioselectivity of the major product
were described in the Mukaiyama-aldol reaction of 1-phenyl-1-
trimethylsilyloxyethene with α-ketoesters catalyzed by clay
supported bis(oxazoline)–copper complexes. It is attributed to a
change in the symmetry of the complex when it is placed in the
vicinity of the clay surface. That reason however is not applicable to
our case with the organic catalyst.
The opposite catalytic performance and different product
selectivities observed on SBA-15 immobilized catalyst is obviously
attributed to the confined space in the mesoporous silica. With
strong acid additives, the gegen ion may adhere to protonated
catalytic center in the confined space (Scheme 3A). It repels the
aldehyde substrate from approaching the catalytic center and the
unfavorable syn isomers are formed as the main products. The low
enantioselectivities of syn products confirm this proposal. More
interestingly, high enantioselectivities of anti-aldol (2R,1’S) product
were obtained when less acidic additives or even water were added
(Table 1, entries 6-8). These results were totally contrary to that
observed under homogeneous condition.
The recyclability of the catalyst was examined by separating the
spent catalysts from the liquid products by simple filtration, and the
recovered catalyst was used in the next run. Entries 1-3 in Table S3
(ESI) show the results under the same reaction condition as that of
Entry 8, Table 1 but using 0.2 mL water as the solvent without acid
additive. The recycled catalyst shows only slight decrease in
conversions, diastereoselectivities and enantioselectivities. Another
series of experiments were carried out to see if the changes in
stereoselectivity over the supported DDAC catalyst was permanent.
The same sample of solid catalyst using water additive was
recovered by filtration, washing with acetylacetone and methanol,
and used with TFA additive for second run, and finally recovered
and reused again with water. The results were shown in Entries 2-4
in Table S2 (ESI). The recyclability of the catalyst and the
dependence of anti/syn ratios and enantioselectivities on the
additives were clearly demonstrated.
In conclusion, SBA-15 immobilized primary-tertiary diamine
catalyst developed in this work demonstrated unprecedented
alternation of the diastereoselectivity of the products in asymmetric
direct aldol reactions, attributing to the confined space of
mesopores and the interaction of the surface silanol groups with
the intermediate species in the transition state. High anti-
diastereoselectivities of the products were obtained when water
was added in direct aldol reaction of cyclohexanone with p-
nitrobenzaldehyde, providing a green route for organic synthesis.
To achieve the anti-aldol product, some forces should be
present to keep the aldehyde and cyclohexene in E-geometry under
the catalytic transition-state. One of the possible forces is the
hydrogen-bonding between the nitro-group at the para-position of
the benzaldehyde and surface silanol group, as shown in Scheme
3B. This kind of interaction is probably more drastic if the less acidic
additive or water is present. In addition, water may also contribute
the cage effect and trap the reactants and the organic moieties
around catalytic centers. These two roles of water probably account
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This work was financially supported by the Ministry of Science
and Technology, Taiwan. Acknowledgements are extended to C.-W.
Lu and C.-Y. Lin of Instrumentation Center, College of Science, NTU
for elemental analyses and EM experiments.
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