Creation of monomeric La complexes on apatite surfaces and their application as heterogeneous catalysts for Michael reactions

Article abstract of DOI:10.1039/b512030f

Using a cation-exchange method, an equimolar substitution of La ³⁺ for Ca²⁺ occurred by the treatment of stoichiometric hydroxyapatite (HAP: Ca₁₀(PO₄)₆(OH) ₂) with an aqueous solution of La(OTf)₃, affording a monomeric hydroxyapatite-bound La complex (LaHAP). Physicochemical characterization by means of XRD, XPS, IR, and La K-edge XAFS analyses proved that a monomeric La³⁺ phosphate complex was generated on its surface. Such monomeric La³⁺ species function as an efficient heterogeneous catalyst for the Michael reaction of 1,3-dicarbonyls with enones under aqueous or solvent-free conditions. The work-up procedure is straightforward and the spent catalyst could be recycled without any loss of the catalytic activity. Further application to an asymmetric version was also investigated using various apatite catalysts modified with chiral organic ligands. Enantioselectivity was found to depend on the chiral ligand, solvent, and rare earth metal triflate precursor (RE(OTf)₃) for the reaction of methyl 1-oxoindan-2- carboxylate with methyl vinyl ketone. Under optimized reaction conditions, a monomeric fluoroapatite-bound La complex catalyst modified with (R,R)-tartaric acid (TA-LaFAP) provided the Michael adduct quantitatively in up to 60% ee. the Royal Society of Chemistry the Centre National de la Recherche Scientifique 2006.

Full text of DOI:10.1039/b512030f

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PAPER
www.rsc.org/njc | New Journal of Chemistry
Creation of monomeric La complexes on apatite surfaces and their
application as heterogeneous catalysts for Michael reactions
Kohsuke Mori, Michitaka Oshiba, Takayoshi Hara, Tomoo Mizugaki, Kohki
Ebitani and Kiyotomi Kaneda*
Received (in Montpellier, France) 24th August 2005, Accepted 24th October 2005
First published as an Advance Article on the web 9th November 2005
DOI: 10.1039/b512030f
Using a cation-exchange method, an equimolar substitution of La3+ for Ca2+ occurred by the
treatment of stoichiometric hydroxyapatite (HAP: Ca10(PO4)6(OH)2) with an aqueous solution of
La(OTf)3, affording a monomeric hydroxyapatite-bound La complex (LaHAP). Physicochemical
characterization by means of XRD, XPS, IR, and La K-edge XAFS analyses proved that a
monomeric La3+ phosphate complex was generated on its surface. Such monomeric La3+ species
function as an efficient heterogeneous catalyst for the Michael reaction of 1,3-dicarbonyls with
enones under aqueous or solvent-free conditions. The work-up procedure is straightforward and
the spent catalyst could be recycled without any loss of the catalytic activity. Further application
to an asymmetric version was also investigated using various apatite catalysts modified with chiral
organic ligands. Enantioselectivity was found to depend on the chiral ligand, solvent, and rare
earth metal triflate precursor (RE(OTf)3) for the reaction of methyl 1-oxoindan-2-carboxylate
with methyl vinyl ketone. Under optimized reaction conditions, a monomeric fluoroapatite-bound
La complex catalyst modified with (R,R)-tartaric acid (TA-LaFAP) provided the Michael adduct
quantitatively in up to 60% ee.
owing to their multiple functionalities.4 Our strategy for the
Introduction
design of nanostructured heterogeneous catalysts focuses on
In the drive toward environmentally friendly organic synthesis
the utilization of promising ability of HAP, which can be
routes, the development of nanostructured heterogeneous
considered as a rigid macroligand for catalytically active
centers.5 The cation-exchange ability of the HAP enables an
catalysts is one of the most exciting challenges in modern
chemistry.1 A general principle for the design of these hetero-
equimolar substitution of transition metal cations, e.g. Ru3+
or Zn2+, for Ca2+ on its surface, which gave monomeric metal
geneous catalysts requires precise control of the coordination
species stabilized by phosphate ligands.5a,k Such transition
sphere at which the elementary catalytic steps proceed while
maintaining robust stabilization of the catalytically active
metal-substituted HAPs exhibit remarkably high catalytic acti-
species on the solid surface. To date, most attempts have
vities for various aerobic oxidation reactions and carbon–
focused on the encapsulation of efficient soluble systems with-
carbon bond-forming reactions with high reusability. The
in a zeolite cavity or anchoring on an insoluble matrix via
covalent bond formation.2 It is also possible to immobilize
use of apatite surfaces is a powerful method of creating stable
active sites, and also provides unexpected novel functions
cationic or anionic complexes by ion paring with anionic or
including site isolation of well-defined active species, steric
cationic solids, respectively. These hybrid catalysts, however,
control of the reaction pathway, and specific performances in
often have encountered serious disadvantages such as tedious
aqueous media.
multi-step preparations and limited stability against metal
We envisaged that the accommodation of rare earth metals,
leaching. Another approach involves the doping of reactive
which prefer high coordination numbers from 6–12 due to
species into sol–gel materials.3 Unfortunately, this method
their large ionic radii,6 into the apatite framework could
usually causes a decrease in the structural ordering and
generate a heterogeneous catalyst that combines potential
inferior activity compared with homogeneous analogues be-
vacant coordination sites as well as robust stability. These
cause a large proportion of metal centers is buried within the
characteristics could allow further binding of organic modi-
pore walls.
fiers, e.g., chiral ligands, to form an enantioselective sphere on
Apatites and related compounds, most notably hydroxya-
a solid surface. Herein we describe our detailed studies con-
patite (HAP: Ca10(PO4)6(OH)2) and fluoroapatite (FAP:
cerning the synthesis and characterization of a hydroxyapa-
Ca10(PO4)6F2), are of considerable interest in many areas
tite-bound La complex (LaHAP) and its evaluation as a
recyclable heterogeneous catalyst for the Michael reaction of
1,3-dicarbonyls with enones under aqueous or solvent-free
Department of Materials Engineering Science, Graduate School of
Engineering Science, Osaka University, 1-3 Machikaneyama,
Toyonaka, Osaka 560-8531, Japan. E-mail: kaneda@cheng.es.
osaka-u.ac.jp; Fax: +81-6-6850-6260; Tel: +81-6-6850-6260
conditions. Conducting the reactions by heterogeneous cata-
lysts under aqueous7 or solvent-free8 conditions instead of
using harmful organic solvents could make a contribution to
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Fig. 2 La K-edge XANES spectra of (A) LaHAP, (B) LaFAP, (C)
TA-LaFAP, and (D) La2O3.
Fig. 1 Structure of apatite.
site surrounded by both OHꢁ and PO4 tetrahedra.9 No
3–
improve environmental outcomes and simplify organic synth-
eses. We also describe the extension to an asymmetric version
by a fluoroapatite-bound La complex catalyst modified with
(R,R)-tartaric acid (TA-LaFAP).
signals assignable to n(C–F) band could be observed in the
infrared spectra (IR), suggesting that OTf ligands originating
from the La precursor were not present. The absence of OTf
groups was also supported by X-ray photoelectron spectro-
scopy (XPS) and elemental analyses. The XPS spectra of the
LaHAP and La2O3 showed identical binding energy values of
836.2 and 835.8 eV for La 3d5/2, respectively. Formation of a
trivalent La species was also indicated by the edge position of
the La K-edge X-ray absorption near-edge structure (XANES)
spectrum of the LaHAP, which was identical to that of La2O3
(A and D in Fig. 2).10 The Fourier transforms (FT) of k3-
weighted extended X-ray absorption fine structure (EXAFS)
data are depicted in Fig. 3. There were no peaks suggestive of
contiguous La–O–La bonds in the LaHAP (A), detectable in
that of La2O3 (D) at around 3.7 A. The inverse FT of the main
peaks of the LaHAP was well fitted using five short (2.52 A)
and three longer (2.59 A) La–O bonds. The La–O distances
were slightly longer than the value of 2.43 A in the La–Na–
BINOL complex.11 We therefore propose a monomeric LaIII
complex surrounded by hydroxyl, phosphate, and weakly
coordinated aqua ligands on the HAP surface, as illustrated
in Fig. 4. In the case of the LaFAP prepared by the same
method with FAP in place of HAP, the shape and edge
position of the XANES spectra resembled those of the LaHAP
(B and A in Fig. 2). Additionally, comparing analogous
FT-EXAFS spectra of the LaFAP with the LaHAP (B and
A in Fig. 3) shows that the La species are supported on FAP in
a monomeric form having +3 oxidation state and that the
local structure around the La species is quiet similar to that of
LaHAP.
Results and discussion
Catalyst preparation and characterization
The hexagonal apatite structure comprises Ca2+ sites sur-
rounded by PO4 tetrahedral; OHꢁ or Fꢁ ions occupy
3–
columns parallel to the hexagonal axis, as illustrated in Fig.
1.4 The crystal structure presents two nonequivalent Ca2+
sites: one set of Ca2+ ions is aligned in columns (site I: CaI),
while the other set forms equilateral triangles centered on the
screw axes (site II, CaII). As mentioned above, various kinds of
transition metal cations can readily be accommodated into the
apatite framework by taking advantage of their cation-ex-
change ability.5a,k Using this approach, various rare earth
metal-exchanged HAPs were synthesized by treatment of
stoichiometric HAP, Ca10(PO4)6(OH)2, with an aqueous solu-
tion of the corresponding rare earth metal triflates (RE(OTf)3)
at room temperature for 9 h. In this way, the LaHAP was
obtained from La(OTf)3 as a white powder (La content: 0.16
mmol gꢁ1).
To gain insight into the structure around La species of the
LaHAP, characterization by means of physicochemical meth-
ods was carried out. Retention of the crystal structure of the
LaHAP was confirmed by X-ray diffraction (XRD). Elemental
analysis determined that both the Ca/P ratio of the parent
HAP and the (La + Ca)/P ratio of the LaHAP were 1.67,
demonstrating that the substitution of La3+ for Ca2+ was
isomorphic in the above preparation sequence. It has been well
documented that larger cations compared to Ca2+ (ionic
radius: r = 1.14 A) replace Ca2+ at site II, whereas smaller
ones occupy site I.4 Due to its larger ionic radius, the La3+
cations (1.22 A) is thought to be accommodated into the CaII
Michael reaction by LaHAP catalyst
Michael reaction is widely recognized as one of the most
important carbon–carbon bond-forming reactions, leading to
functionalized adducts of high synthetic value.12 In particular,
1,5-dioxo synthons, which are available from the reaction of
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Fig. 4 A proposed surface structure of apatite-bound La complexes.
The LaHAP catalyzed-Michael reactions could be extended
to other 1,3-dicarbonyl compounds and enones under solvent-
free (method A) or aqueous conditions (method B), as demon-
strated in Tables 2 and 3. In all cases, the desired 1,4-addition
products were obtained exclusively without the formation of
aldol-type compounds. Acyclic and cyclic enones were found
to be good acceptors for the reaction with 1a (Table 2). It is
said that the solvent-free Michael reactions with cyclic enones
using FeCl3 ꢂ 6H2O18 and Cu(OAc)2 ꢂ 6H2O19 hardly occur.
Moreover, the LaHAP catalyst was applicable to a less
reactive acceptor methyl acrylate (2e) under solvent-free con-
ditions (entry 9). 2a also successfully reacted with a variety of
b-keto esters and 1,3-diketones (Table 3). The reaction rate in
an aqueous medium was largely dependent on the solubility of
the substrate, but a 25 mmol-scale experiment for the reaction
of 1a with 2a under biphasic conditions was performed to give
90% isolated yield of Michael adduct after 12 h, in which the
corresponding turnover number (TON) and turnover fre-
quency (TOF) approached up to 4500 and 375 hꢁ1, respec-
tively.
Fig. 3 Fourier-transforms of k3-weighted La K-edge EXAFS experi-
mental data for (A) LaHAP, (B) LaFAP, (C) TA-LaFAP, and (D)
La2O3.
1,3-dicarbonyl compounds with enones, can be transformed
into cyclohexenone derivatives for use as paramount building
blocks in steroid and terpenoid synthesis.13 In the quest to
improve the reaction, various transition metal complexes,
including chiral versions have been developed instead of
traditional strong bases.14 Among them, RE(OTf)3 com-
pounds are considered to be effective for aqueous Michael
reactions.15
In an effort to evaluate the potential catalytic activity of the
LaHAP, the Michael reaction of 2-oxocyclopentanecarboxy-
late (1a) with methyl vinyl ketone (2a) was carried out under
several sets of reaction conditions. As can be seen from Table
1, the LaHAP gave the highest yield of 2-oxo-1-(3-oxobutyl)-
cyclopentanecarboxylate under solvent-free conditions (entry
1), and also showed higher catalytic activity than the homo-
geneous La(OTf)3 precursor (entry 5). The activity of rare
earth metal-exchanged HAPs decreased in the order LaHAP
(>99%) > ScHAP (90%) >YHAP (67%) > YbHAP (39%)
(entries 2, 3 and 6), which is not the order of decreasing Lewis
acidity of the metal center: the Sc3+ ion is the smallest rare
earth metal and is hence the most Lewis acidic cation, while
the largest La3+ ion has the strongest Brønsted basicity
among the corresponding rare earth metal hydroxides
(RE(OH)3).6a The use of the LaFAP instead of the LaHAP
gave a moderate yield of the Michael product (entry 4).
The parent HAP16 and FAP17 are reported to act as
heterogeneous catalysts for the Michael reaction of mercap-
tans with chalcone derivatives, but they were found to be
less effective under the present reaction conditions (entries 7
and 8). Among the solvents examined, water was also effective
for the present reaction, affording the Michael adduct in
quantitative yield (entry 9). The use of toluene gave a moder-
ate yield, whereas THF and DMF were poor solvents (entries
10, 14 and 15).
Table 1 Michael reaction of 1a with 2a under several conditionsa
Entry
Catalyst
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
LaHAP
ScHAP
YHAP
LaFAP
La(OTf)3
YbHAP
HAP
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Water
Toluene
Acetonitrile
Dichloromethane
n-hexane
THF
>99
90
67
41
40
39
30
11
>99
58
35
30
21
FAP
9c
10c
11c
12c
13c
14c
15c
a
LaHAP
LaHAP
LaHAP
LaHAP
LaHAP
LaHAP
LaHAP
9
Trace
DMF
Reaction Conditions: catalyst (0.5 mol%), 1a (2.0 mmol), 2a (3.0
b
mmol), 50 1C , 30 min, Ar atmosphere. Yields of products were
determined by GC. Reaction Conditions: catalyst (0.5 mol%), 1a
c
(0.5 mmol), 2a (0.75 mmol), solvent (3 ml), 50 1C, 30 min, Ar
atmosphere.
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Table 2 Michael reaction of 1a with various acceptors
Table 3 Michael reaction of various 1,3-dicarbonyls with 2a
Entry Donor
1c
Methoda La (mol%) Time (h) Yield (%)b
Entry Acceptor
Methoda La(mol%) Time (h) Yield (%)b
A
1.0
1
98
1
A
A
0.5
0.5
0.5
0.5
>99
>99
2c
3
4
B
A
0.5
0.5
0.5
1
>99
97
2c
3c
A
B
1.0
1.0
3
3
97
99
5
6
B
0.5
1.0
4
6
85
86
A
7
8d
B
1.0
1.5
24
89
95
4c
5c
A
B
1.25
1.25
6
24
83
90
A
13
27
24
9d
B
1.5
2.0
64
10d
A
>99
6
7
A
B
0.5
0.5
4
9
99
99
11e
A
2.0
30
40
8
9
A
B
0.5
0.5
2
3
95
99
a
Method A: 1a (2 mmol), acceptor (3 mmol), solvent-free, Ar atmo-
sphere, 50 1C: method B: 1a (0.5 mmol), acceptor (0.75 mmol), H2O
10d
A
2.0
24
65
b
c
(3 ml), Ar atmosphere, 50 1C. Determined by GC analysis. The
third recycling experiment. 80 1C. 100 1C.
d
e
a
Method A: donor (2 mmol), 2a (3 mmol), solvent-free, Ar atmo-
sphere, 50 1C; method B: donor (0.5 mmol), 2a (0.75 mmol), H2O
The LaHAP catalyst was easily separated from the reaction
mixture and retained its inherent catalytic activity; over 99%
yields were attained for at least three recycling experiments for
the reaction of 1a with 2a under solvent-free conditions (entry 2
in Table 2). Moreover, the catalyst was filtered off after ca.
60% conversion at the reaction temperature. Further treatment
of the filtrate under identical reaction conditions did not afford
any products. ICP analysis of the filtrate confirmed that the La
content was determined to be negligible (less than 0.1 ppb). It
can be said that the present reaction undoubtedly proceeds on
the hydroxyapatite surface, which effectively serves as a pro-
mising macroligand for the catalytically active La species.
The present catalyst showed specific activity only toward
1,3-dicarbonyls as Michael donors. Other active methylene
compounds such as ethylcyanoacetate (pKa = 9) having a
similar pKa value to acetylacetone (1e) did not yield the
Michael product under the same reaction conditions.20 Un-
fortunately, benzalacetone proved to be a poor acceptor,
affording the corresponding Michael adduct in 40% yield,
even when 2.0 mol% La catalyst was employed at 100 1C
(entry 11 in Table 2). The reaction using diethyl malonate (1g)
as a donor, which has a relatively high pKa value of 13.3, was
also retarded using the present catalytic system (entry 10 in
Table 3).
b
(3 ml), Ar atmosphere, 50 1C. Determined by GC analysis.
c
d
80 1C. 130 1C.
the reaction mechanism is considered to involve a ternary
complex with both the 1,3-dicarbonyl compound and the
enone coordinated to a metal center.14,21
In order to elucidate the pathway of the present reaction,
preliminary experiments were carried out. Treatment of 1a
with D2O in the presence of the LaHAP (1.0 mol%) at 40 1C
for 3.5 h led to H–D exchange reaction, giving the a-deuter-
ated compounds in 15% yield as determined by 1H NMR
spectroscopy:22 the exchange reaction did not proceed at all in
the absence of the LaHAP. The LaHAP catalyst also success-
fully promoted typical base-catalyzed carbon–carbon bond-
forming reactions, e.g., (i) aldol and (ii) knoevenagel reactions,
to afford the corresponding condensation products in excellent
yields (Scheme 1).23 Vide supra, the LaHAP catalyst, which
possesses the strongest Brønsted basicity among the corre-
sponding RE(OH)3, showed the highest yield. These results
apparently demonstrate that the LaHAP has a Brønsted base
site, i.e., La–OH species.24 Additionally, the IR spectrum of
the LaHAP upon treatment with 1e showed a shift of the n(C
QO) band toward 1560 cmꢁ1 in comparison to the free
carbonyl group at around 1700 cmꢁ1, suggesting an 1,3-
diketonato La species is formed as a reaction intermediate.25
On the basis of these results, a plausible mechanism is pro-
posed as follows. Initially, a La–OH species abstracts an
a-proton of the donor to form a 1,3-diketonato La species.
Next, an acceptor coordinate to vacant sites of the La species
Mechanistic considerations
Generally, the Michael reaction proceeds in the presence of
Brønsted base catalysts. Transition metal and rare-earth metal
catalysts have also been extensively employed for the Michael
reaction of 1,3-dicarbonyl compounds with enones, in which
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Table 4 Asymmetric Michael reaction of 1h with 2aa
Entry Catalyst Ligand
Yield (%)b Ee(%)c Confgn.d
Scheme 1 Carbon–carbon bond-forming reactions catalyzed by La-
HAP. (i) LaHAP (2.0 mol%), benzaldehyde (0.5 mmol), acetone (2
mL), 60 1C, 37 h. (ii) LaHAP (2.0 mol%), benzaldehyde (1.5 mmol),
ethyl cyanoacetate (1 mmol), toluene (2 mL), 60 1C, 24 h.
1
2
LaFAP
FAP
La(OTf)3
LaFAP
LaFAP
LaHAP
97
18
29
5
>99
>99
60
—
>1
44
50
30
S
—
S
S
S
3e
4f
5g
6
at the carbonyl oxygen to form a ternary La complex, followed
by alkylation and hydrolysis to afford a Michael adduct along
with regeneration of the La–OH species. Kinetic studies
showed pseudo-zero-order dependence on 1a and first-order
relationship with 2a. A kH/kD value of 1.1 was also observed in
the intermolecular competitive reaction between 1e and acetyl-
acetone-3,3-d2 (CH3COCD2COCH3) with 2a as a Michael
acceptor. These results suggest that the alkylation might be a
rate-determining step. The kinetic results are in sharp contrast
with those of homogeneous La(OTf)3 catalysts, which follow
first-order dependence on 1a and a zero-order relationship
with 2a. We believe this phenomenon can be attributed to
Brønsted basicity generated on the surface of the LaHAP
catalyst.
R
7
LaFAP
98
59
R
R
8
LaFAP
>99
50
9
LaFAP
LaFAP
>99
>99
46
32
R
R
10
Asymmetric Michael reaction catalyzed by TA-LaFAP
11
12
LaFAP
55
29
S
The extension to an asymmetric version of Michael reaction is
a challenging task for synthetic organic chemists.26 Various
chiral catalysts have been explored including cinchona alka-
loids,27 alkoxide complexes,28 crown ether-metal alkoxide
complexes,29 transition metal complexes,30 and bimetallic
lanthanide complexes.31 Although remarkable progress has
been achieved using these homogeneous catalysts, only a few
heterogeneous ones are available to date, e.g. polymer-sup-
ported metal complexes,32 polymer-supported cinchona alka-
loids,33 layered double hydroxides containing chiral organic
guests,34 and MCM-41-grafted chiral amines.35
LaFAP
LaFAP
>99
>99
19
7
R
S
13
a
Reaction conditions: catalyst (1.2 mol%), 1h (0.5 mmol), 2a (0.75
b
mmol), toluene (2 mL), room temperature, 6 h, Ar atmosphere. De-
c
termined by GC. Determined by HPLC (Daisel Chiralpak AD-
Building upon the initial success of the present LaHAP
catalyst, further investigations were conducted to develop an
effective heterogeneous catalyst for the asymmetric Michael
reaction. Our strategy focuses on the utilization of organic
modifiers as chiral ligands, since we suppose the immobilized
La species still have vacant coordination sites owing to their
large ionic radius. Our procedure for the preparation of
heterogeneous asymmetric catalysts is quite straightforward.
To a stirred aqueous solution of 1 : 1 of La(OTf)3 and (R,R)-
tartaric acid (TA, 4a) for 30 min was added a fluoroapatite
(FAP), Ca10(PO4)6F2, and then the mixture was further re-
acted for 24 h at 30 1C, affording the TA-LaFAP (La content:
0.36 mmol gꢁ1) as a white powder. From energy-dispersive X-
ray (EDX) analysis of the TA-LaFAP, the atomic ratio of La
to TA was determined to be 1 : 1 (La : C = ca. 1 : 4). The La
K-edge XANES spectrum of the TA-LaFAP (C) was compar-
able with those of the LaHAP (A) and the LaFAP (B), as
shown in Fig. 2. The absence of a peak in the vicinity of 3.7 A
H). Assigned by optical rotation. La(OTf)3 (3.4 ꢃ 10ꢁ3 g, 1.2
d
e
mol%), 4a (8.6 ꢃ 10ꢁ4 g, 1.2 mol%). 10 1C. 40 1C.
f
g
in the FT-EXAFS suggested that no La–O–La contribution
exists (C in Fig. 3). It is clear that the La species exist in a
highly dispersed form having a +3 oxidation state.
At first, several La catalysts and chiral organic ligands were
investigated for the asymmetric Michael reaction of methyl 1-
oxoindan-2-carboxylate (1h) with 2a in toluene at room
temperature, as summarized in Table 4. It was found that
the TA-LaFAP (La: 1.2 mol%) effectively served as a chiral
heterogeneous catalyst to afford (S)-methyl 1-oxo-2-(30-oxo-
butyl)-2-indanecarboxylate ((S)-3a) in 97% yield with a good
enantioselectivity of 60% (entry 1). It is noteworthy that no
enantioselectivity was observed by the combination of either
parent FAP or La(OTf)3 with 4a (entries 2 and 3), showing
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Fig. 5 Solvent effects for asymmetric Michael reaction of 1h with 2a.
Reaction was conducted with TA-LaFAP (1.2 mol% based on 1h), 1h
(0.5 mmol), 2a (0.75 mmol), and toluene (2 mL) at room temperature
for 6 h under Ar atmosphere.
Fig. 6 Effect of metal precursors (RE(OTf)3) for asymmetric Michael
reaction of 1h with 2a. Reaction was conducted with catalyst (1.2
mol% based on 1h), 1h (0.5 mmol), 2a (0.75 mmol), and toluene (2
mL) at room temperature for 6 h under Ar atmosphere. Values in
parentheses are ionic radii of 8-coordination for Sc3+ and 9-coordina-
tion for other metal cations (RE3+).
that the immobilization of La species on the FAP surface is
essential for attaining asymmetric catalysis. To the best of our
knowledge, this is the first demonstration of an asymmetric
reaction utilizing an apatite catalyst.36 The enantioselectivity
achieved by the TA-LaFAP for the asymmetric Michael
reaction of 1h with 2a was higher than those reported for
other catalyst systems,37 such as the N,N0-dioxide-Sc(OTf)3
complex (39% ee),30f diaminodiol-CoII complex (38% ee),30c
chiral amidine (8% ee),38 poly(cinchona alkaloid-co-acryloni-
trile) (42% ee).33a This value is also comparable with those
with polymer-supported quinine (65% ee),33b 1,10-bi-2-
naphthol-Na complex (57% ee),28 and quinine (56% ee).27a
Enantioselectivity was dependent on the reaction temperature;
when the reaction temperature was lowered to 10 1C, the yield
significantly decreased with 40% ee (entry 4), whereas the
reaction at a higher temperature of 40 1C resulted in decrease
of enantioselectivity to 50% in spite of high chemical yield
(entry 5). This nonlinear relationship between enantioselec-
tivity and temperature has been reported previously for the
Michael reaction catalyzed by MCM-41-grafted chiral
amines.35 Interestingly, the use of the HAP instead of the
FAP as a support gave a 30% ee with an opposite configura-
tion (entry 6). In the case of (S,S)-tartaric acid (4b), (R)-3a was
obtained with the same level of chemical yield and enantios-
electivity as compared to those of 4a, revealing that the
absolute configuration of the Michael adducts is determined
by the employed ligand. Other dicarboxylic acid ligands such
as (S)-malic acid (4c) and (R,R)-O,O0-dibenzoyltartaric acid
(4d) favored excess formation of the (R)-isomer with moderate
enantioselectivity (entries 8 and 9). The reaction that employed
(S)-serine (4g) and (S)-threonine (4h) containing amino and
monocarboxyl groups was less efficient (entries 12 and 13). As
a consequence, it was found that the presence of dicarboxylic
acids group showed beneficial effects on the enentioselectivity.
Next, the catalytic activities for the TA-LaFAP in the
reaction of 1h with 2a were compared with various solvents
using the TA-LaHAP. Fig. 5 shows the effect of solvents
together with dielectric constant values (e) as one of the criteria
of polarity. Non-polar solvents with low dielectric constants
such as toluene, n-hexane, and diethyl ether were good sol-
vents among those examined, whereas polar solvents with
higher dielectric constant values, such as methanol and
DMF, gave poor results with respect to enantiomeric excess.
The use of water afforded a completely racemic product
despite offering high chemical yield. These results clearly
suggest that specific interactions (e.g. hydrogen-bonding) be-
tween solvent and catalyst surface significantly influence the
conformation of the transition state in the enantioselectivity-
determining step. Vide supra, the decrease in enantioselectivity
using TA-LaHAP could be ascribed to the negative effect of
hydrogen-bonding between a surface hydroxyl group on the
HAP and 4a.39 The critical role of hydrogen-bonding in the
transition state was also observed in the amino acid-catalyzed
asymmetric aldol reaction, in which addition of water to the
reaction mixture severely decreased enantioselectivity.40
Another important parameter that affects the activity and
enantioselectivity of the reaction is the choice of metal pre-
cursor. As shown in Fig. 6, we have evaluated the effect of
RE(OTf)3 precursors having various ionic radii.41 It should be
noted that catalytic performance varied significantly with ionic
radius:42 the largest La3+ cation afforded the Michael adduct
with the highest yields as well as enantioselectivity, while the
use of smaller cations such as Y, Yb, and Sc gave unsatisfac-
tory results in terms of both chemical and optical yields. The
higher activities and enantioselectivities attained with larger
cations might be attributed to increased coordination num-
bers, where the further binding of chiral organic modifiers and
substrates to metals would be allowed to access a reasonable
transition state even on the solid surface. In contrast, the
decrease in ionic radii severely limits the interaction of chiral
organic modifiers and substrates with metals because of the
decrease in number of available vacant coordination sites.
The lifetime and leaching of active metal species into the
reaction solution are crucial points to consider when chiral
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species via coordination of two carboxylate groups in a
bidentate manner. Although the precise transition state is
unclear, the attainment of the desirable geometry might be
directed by the hydrogen-bonding between OH groups of 4a
and the substrate, in which the use of polar solvents with high
dielectric constants values might prohibit this effective inter-
action, giving poor results with respect to enantiomeric excess.
Conclusions
We have developed a method for the design of nanostructured
catalysts using apatites. Characterizations by physicochemical
methods revealed the formation of a stable monomeric La
phosphate complex on the surface of hydroxyapatite, which
proved to be an efficient heterogeneous catalyst with superior
activity for the Michael reaction. Further extension to an
asymmetric version by the TA-LaFAP was also demonstrated.
To the best of our knowledge, this is the first example of an
asymmetric reaction achieved by an apatite catalyst. The
features of the present apatite catalysts, such as facile pre-
paration, robust structure, and easy recovery as well as simple
recycling, are particularly important in the industrial synthesis
of optically active compounds. Studies are ongoing to design
novel asymmetric heterogeneous catalysts with enhanced en-
antioselectivity.
Fig. 7 Time profile for the asymmetric Michael reaction of 1g with 2a
catalyzed by TA-LaFAP. Reaction conditions: TA-LaFAP (0.016 g,
1.2 mol% based on 1g), 1g (0.5 mmol), 2a (0.75 mmol), toluene (2
mL), room temperature, 6 h, Ar atmosphere.
heterogeneous catalysts are employed for industrial and phar-
maceutical applications.43 As shown in Fig. 7, the time course
for the Michael reaction of 1h with 2a was monitored periodi-
cally. No induction period and degradation was observed in
the reaction catalyzed by the TA-LaFAP. The enantioselec-
tivity appeared to be independent of the conversion level and
remained unchanged at around 60% during the reaction,
suggesting that racemization of the Michael adduct did not
take place. Upon completion of the Michael reaction, the TA-
LaFAP catalyst was easily separated from the reaction mix-
ture and could be reused with retention of its activity and
enantioselectivity in the absence of an externally added chiral
organic ligand; over 97% yields and 59% ee could be kept for
at least three recycling experiments of the reaction between 1h
and 2a. Again, ICP analysis of the filtrate could not detect the
metal species. XAFS analysis revealed that no structural
changes around the La3+ center were observed. It can be said
that the catalyst deactivation, leaching, and product inhibition
do not occur, and that the present asymmetric Michael reac-
tion undoubtedly proceeds on the chiral heterogeneous apatite
surface.
Experimental
Materials
La(OTf)3 and (R,R)-tartaric acid were obtained from Tokyo
Kasei Kogyo Co., Ltd. and used without further purification.
Fluoroapatite (FAP), (NH4)2HPO4, and Ca(NO3)2 ꢂ 4H2O
were purchased from Wako Pure Chemical Ind., Ltd. Solvents
and all commercially available compounds were purified by
standard procedures before use. Methyl 1-oxoindan-2-carbox-
ylate (1h) was synthesized according to the literature proce-
dure.44 All of the products are well known compounds and
their identities were confirmed by comparison with IR, MS,
and NMR spectra.
Characterization
Powder X-ray diffraction patterns were recorded using Philips
X’Pert-MPD with Cu Ka radiation. X-ray photoelectron
spectroscopy was measured on a Shimadzu ESCA-KM using
MgKa radiation. Energy-dispersive X-ray measurement was
performed using a Philips EDAX DX-4 attached to a SEM.
Infrared spectra were obtained with a JASCO FTIR-410.
Elemental analysis was carried out using a Perkin Elmer
2400CHN. Inductively coupled plasma measurements were
performed on a Nippon Jarrell-Ash ICAP-575 Mark II. X-
ray absorption spectra were recorded in transmission mode at
room temperature using a Si (311) monochromator on the
BL01B1 station at SPring-8, JASRI, Harima, Japan (prop.
No. 2005A0694-NXa-np). Data reductions were performed
with a FACOM M-780 computer system of the Data Proces-
sing Center of Kyoto University. The Fourier transform was
performed on EXAFS in the k range of 3.0–14 A. The detailed
procedure for data analysis is described elsewhere.45
Asymmetric induction
As mentioned above, preliminary screening of the chiral
organic modifiers revealed that (R,R)-tartaric acid (4a) is the
most suitable ligand to achieve high enantioselectivity, sug-
gesting that dicarboxylic acids play an important role in the
conformation of the enantio-differentiating complex on the
solid surface. In the IR spectrum of the TA-LaFAP, the CQO
stretching vibration appeared at around 1630 cmꢁ1, which is
lower than that of the free 4a (1720 cmꢁ1). Furthermore, it was
found that (S)-malic acid (4c) and (R,R)-O,O0-dibenzoyl-
tartaric acid (4d), which contain dicarboxylic acids, also act
as good organic modifiers, as shown in Table 5. Upon con-
sideration of the above observations as well as the results that
the atomic ratio of La to TA was 1 : 1 determined by EDX
analysis, organic modifiers are thought to bond with the La
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Syntheses and reactions
subjected to HPLC analysis. The enantiomeric excess was
determined by chiral HPLC (Daisel Chiralpak AD-H, eluent:
iPrOH/hexane = 1 : 9, flow rate: 1.0 mL minꢁ1, 254 nm, tR of
(S)-3a =12.0 min, tR of (R)-3a =13.5 min) The absolute
configuration was determined by the optical rotation of 3a
Synthesis of hydroxyapatite-bound lanthanum catalyst.
(NH4)2HPO4 (40.0 mmol) was dissolved in deionized water
(150 mL) and the pH was adjusted to 11 with an aqueous NH3
solution. To a solution of Ca(NO3)2 ꢂ 4H2O (66.7 mmol) in
deionized water (120 mL) adjusted to pH 11 with an aqueous
NH3 solution was added drop-wise over 30 min the above
solution with vigorous stirring at room temperature, and then
the resultant milky solution was heated at 90 1C for 10 min.
The precipitate was filtered, washed with deionized water, and
dried at 110 1C, giving stoichiometric hydroxyapatite, Ca10(-
PO4)6(OH)2 (HAP). Treatment of the HAP (2.0 g) with an
aqueous solution of La(OTf)3 (2.6 ꢃ 10ꢁ3 M) at room
temperature for 9 h followed by filtration and drying under
vacuum, yielded LaHAP (La content: 0.16 mmol gꢁ1) as a
white powder.
25
rt
[a]D = ꢁ41 (c 0.24, benzene) for 60% ee. Lit. [a]578
=
ꢁ77.0 (c 2.0, benzene) for (S)-isomer. IR 1734, 1710 cmꢁ1; 1H
NMR (CDCl3) d 2.13 (s, 3H), 2.15–2.30 (m, 2H), 2.40–2.70 (m,
2H), 3.04 (d, J = 16.0 Hz, 1H), 3.66 (d, J = 16.0 Hz, 1H), 3.70
(s, 3H), 7.41–7.8 (m, 4H); 13C NMR d 28.6, 29.8, 37.8, 38.7,
52.7, 59.1, 124.8, 126.4, 127.9, 135.0, 135.5, 152.5, 171.5, 202.2,
207.3.
Acknowledgements
This work is supported by the Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan. We thank Dr Tomoya
Uruga (JASRI) for XAFS measurement. T. H. thanks the
JSPS Research Fellowships for Young Scientists.
Typical example for Michael reaction under solvent-free
conditions (method A). Into a reaction vessel with a reflux
condenser were placed LaHAP (0.0625 g, La: 0.5 mol%), 1a (2
mmol), and 2a (3 mmol). The reaction mixture was stirred at
50 1C under an Ar atmosphere. Progress of the reaction was
monitored by GC analysis. After 30 min, 99% yield of Michael
adduct was obtained.
References
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Synthesis of hydroxyapatite-bound lanthanum catalyst mod-
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solution of La(OTf)3 and (R,R)-tartaric acid (5.3 ꢃ 10ꢁ3 M)
for 30 min was added 1.0 g of the fluoroapatite (FAP),
Ca10(PO4)6F2, and then the mixture was further reacted at
30 1C for 24 h. After filtration and drying under vacuum, the
TA-LaFAP (La content: 0.36 mmol gꢁ1) was obtained as a
white powder.
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ꢀc
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ꢀc
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52 | New J. Chem., 2006, 30, 44–52