Preparation and confinement effect of a heterogeneous 9-amino-9-deoxy-epi- cinchonidine organocatalyst for asymmetric aldol addition in aqueous medium

Article abstract of DOI:10.1039/c2dt12390h

A series of novel porous zirconium phosphonate-supported 9-amino-9-deoxy-epi-cinchonidines of general formulae Zr(OH) _4-2x(O₃PR)_x·nH₂O and Zr(HPO₄)_2-x(O₃PR)_x·nH ₂

Full text of DOI:10.1039/c2dt12390h

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PAPER
Preparation and confinement effect of a heterogeneous 9-amino-9-deoxy-epi-
cinchonidine organocatalyst for asymmetric aldol addition in aqueous
medium†
Wei Wang, Xuebing Ma,* Jingwei Wan, Jun Cao and Qian Tang
Received 12th December 2011, Accepted 29th February 2012
DOI: 10.1039/c2dt12390h
A series of novel porous zirconium phosphonate-supported 9-amino-9-deoxy-epi-cinchonidines of
general formulae Zr(OH)4−2x(O3PR)x·nH2O and Zr(HPO4)2−x(O3PR)x·nH2O with the different arm chain
lengths (n = 2–6) and mean diameters of approximately 20–40 nm have been prepared as heterogeneous
organocatalysts. The different microtextures of zirconium phosphonates were also obtained by using
template guest molecules, such as Et3N, NaH2PO4 and sodium dodecyl benzene sulfonate. In the
heterogeneous asymmetric aldol addition of p-nitrobenzaldehyde to cyclohexanone, excellent catalytic
properties were achieved, especially in an aqueous medium. After completing the reaction, those
zirconium phosphonate-supported 9-amino-9-deoxy-epi-cinchonidine organocatalysts could be readily
recovered in quantitative yield by centrifugation or filtration, and reused for five consecutive runs without
significant loss in catalytic performance. In particular, due to the steric confinement effect of the inorganic
backbone, the single different configuration among possible four stereo-isomers in aldol adducts were
favorably obtained, respectively depending on the interaction between the o-, m- or p-position of
nitrobenzaldehyde and the backbone, which was never observed in homogeneous aldol addition.
pollution that is inherent with organic solvent. In fact, some
proline amide derivatives or small peptides have proved useful
Introduction
The direct asymmetric aldol reaction is one of the most impor-
tant C–C bond-forming reactions in synthetic chemistry and is of
much importance in pharmaceutical, agrochemical, and fine
chemical industries. The design and preparation of highly selec-
tive asymmetric organocatalysts for aldol reaction has attracted
much attention and excellent results have been achieved.1
However, due to economic consideration of different organocata-
lysts, the development, recycling and reuse of these organocata-
lysts is currently a highly sought after goal and urgently desired
for our chemists. Several approaches, including fluorous proline
derivatives,2 solid phase-supported catalysts,3 ionic liquids,4
PEG5 or aqueous media as reaction solvent, have been used to
achieve organocatalyst recovery. Among these strategies, water
as solvent is an environmentally friendly, safe reaction medium
from a practical perspective, which avoids the problem of
for catalyzing aldol reactions with high enantioselectivity in
aqueous media.6
A number of cinchona derivatives have been versatile organo-
catalysts in many asymmetric organic transformations owing to
their excellent performances.7 For example, 9-amino-9-deoxy-
epi-cinchonine, one of the most famous cinchona derivatives,
has been employed as an efficient organocatalyst with excellent
stereoselectivity and activity in asymmetric aldol addition,8
Diels–Alder reaction,9 Friedel–Crafts reaction,10 Henry reac-
tion,11 Mannich reaction,12 Michael addition,13 hydrogenation,14
epoxidation,15 1, 3-dipolar cycloaddition,16 decarboxylation,17
and methanolytic desymmetrization.18 However, the potential
application of those organocatalysts in chemical industry is
rather limited owing to their high cost of chemical transform-
ation. Unfortunately, although the well-known 9-amino-9-deoxy-
epi-cinchonine organocatalyst possessed excellent performance
in many organic asymmetric transformations, its recycling and
reusability in the catalytic process are seldom reported. Just in
2008, it was reported that 9-thiourea cinchona alkaloid supported
on mesoporous silica was used as a highly enantioselective,
recyclable heterogeneous organocatalyst in the asymmetric
Friedel–Crafts reaction of imines with indoles.19
College of Chemistry and Chemical Engineering, Southwest University,
Chongqing, 400715, P.R. China. E-mail: zcj123@swu.edu.cn; Fax:
(+86)23-68253237; Tel: (+86)23-68253237
1
†Electronic supplementary information (ESI) available: H, 13C and 31P
NMR of compounds 1a–e; Elemental analysis of 2a–e; the thermogravi-
metric curves of zirconium phosphonates (Fig. S1); IR spectra (Fig. S2);
XRD of zirconium phosphonates (Fig. S3); the isotherms and distri-
butions of pore diameter of zirconium phosphonates (Fig. S4); AFM
images of 3c, 4c, 5c1 (Fig. S-5–7); HPLC spectra; the influence of other
factors on catalytic properties is shown in Tables S1–3. DOI: 10.1039/
c2dt12390h
In the last thirty years, an emerging class of insoluble phos-
phonates and inorganic–organic phosphonates of tetravalent
metals (mainly ZrIV) with layered or pillared structure have
attracted the attention of researchers because of their interesting
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Scheme 1 The synthetic route to supported 9-amino-9-deoxy-epi-cinchonine organocatalysts.
physical–chemical properties and high versatility,20 especially in
the field of catalysis.21 The layered and porous inorganic back-
bone of zirconium phosphate may be considered as a hook onto
which organic groups with different functionality may be
attached, allowing for the control of both reactivity and selectiv-
ity in organic catalytic processes.22 Such a molecular building
block approach towards heterogeneous asymmetric catalysis will
represent a major advance in chirotechnology owing to both its
tunability as well as reusability.
Recently, we have been involved in the development of novel
chiral organocatalysts to be used in benign reaction media, such
as water, for the definition of chemically and environmentally
efficient organic processes. In this paper, we developed a novel
type of heterogeneous, porous and recycled zirconium phospho-
nate-supported 9-amino-9-deoxy-epi-cinchonine organocatalysts
with the different arm lengths (n = 2–6) (Scheme 1). In the
asymmetric direct aldol addition of p-nitrobenzaldehyde to
cyclohexanone, the high catalytic properties (98% yield, anti/syn
= 83 : 17 and 96%ee anti) and reusability were achieved in water
as sole reaction medium. Especially, due to the steric confine-
ment effect of the inorganic backbone of zirconium phosphonate,
one single configuration among the possible four stereo-isomers
in aldol adducts was favorably obtained, depending on the o-, m-
or p-position of nitrobenzaldehyde, which was never observed in
homogeneous aldol addition.
Experimental
Materials and sample characterization
All chemicals were purchased and used without any further
purification. The starting materials 9-amino-9-deoxy-epi-cincho-
nine and HS(CH2)2S(CH2)nP(O)(OC2H5)2 (n = 2–6) were syn-
1
thesized according to the reference and ascertained by H and
13C NMR.22d
TLC, where applicable, was performed on pre-coated alumi-
num-backed plates and spots were made visible by quenching
ultraviolet fluorescence (λ = 254 nm). Fourier transform infrared
spectra were recorded on a Perkin-Elmer Model GX Spec-
trometer using a KBr pellet method with polystyrene as a stan-
dard. Thermogravimetric analysis (TGA) was performed on a
SBTQ 600 Thermal Analyzer (USA) with a heating rate of
20 °C min−1 over a temperature range of 40–800 °C under
1
flowing compressed N2 (100 mL min−1). H, 13C and 31P NMR
were performed on a Bruker AV-300 NMR instrument at ambient
temperature at 300, 75, and 121 MHz, respectively. All chemical
5716 | Dalton Trans., 2012, 41, 5715–5726
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1
shifts were reported downfield in ppm relative to the hydrogen,
carbon, and phosphorus resonance of TMS, chloroform-d1, and
H3PO4 (85%), respectively. The interlayer spacings of samples
were obtained on a DX-1000 automated X-ray power diffracto-
meter (XRD), using Cu Kα radiation and internal silicon powder
as a standard with all samples. The patterns were measured
between 2.00° and 20.00° (2θ) with a step size of 1° min−1 and
X-ray tube settings of 40 kV and 2.5 mA. C, H, and N elemental
analysis was obtained from an EATM 1112 automatic elemental
analyzer instrument (Thermo, USA). The morphologies of the
as-synthesized samples were determined by a Hitachi model
H-800 transmission electron microscope (TEM) and a Multi-
mode SPM atomic force microscopy (AFM). N2 adsorption–des-
orption analysis was carried out at 77 K on an Autosorb-1
apparatus (Quantachrome). The specific surface areas and pore
diameters were calculated by the BET method and BJH model,
respectively. The anti/syn ratio of aldol product was determined
by 1H NMR of crude product and the enantiomeric excess (%ee)
was determined on HPLC with a Chiral OD or AD column (n-
hexane/2-propanol = 95/5) under 20 °C, 254 nm and 0.5 mL
min−1 conditions.
(C-15, JC–P = 42.8 Hz), 31.2 (C-12), 30.0 (C-11), 29.4 (C-5),
2
29.1 (C-7), 27.9 (C-14, d, JC–P = 18.0 Hz), 26.5 (C-4), 25.4
(C-10), 16.2 (CH3, JC–P = 6.8 Hz). δP (121.0 MHz, CDCl3)
29.4. Anal. calcd for C27H42N3O3PS2: C, 58.78; H, 7.67; N,
7.62; Found: C, 58.85; H, 7.74; N, 9.57.
3
Phosphonate 1b. (4.0 g, 68%), brown oily liquid. δH
(300 MHz, CDCl3, Me4Si) 8.84 (1 H, d, 3J = 6.0 Hz, H-2′), 8.27
(1 H, d, 3J = 9.0 Hz, H-5′), 8.07 (1 H, d, 3J = 9.0 Hz, H-8′), 7.65
(1 H, t, 3J = 6.0 Hz, H-7′), 7.54 (1 H, t, 3J = 6.0 Hz, H-6′), 7.50
(1 H, d, 3J = 2.0 Hz, H-3′), 4.64 (1 H, d, 3J = 9.0 Hz, H-9), 4.00
(4 H, m, OCH2), 3.05–3.27 (3 H, m, H-6α, H-2-exo, H-8),
2.38–2.60 (11 H, m, H-12, H-13, H-14, H-11, H-6β, H-2-endo,
H-5α), 1.76–1.79 (4 H, m, H-16, H-15), 1.49–1.64 (6 H, m,
3
H-3, H-4, H-5β, H-7β, H-10), 1.24 (6 H, t, J = 6.0 Hz, CH3),
0.71 (H-7α, dd, 1 H). δC (75.0 MHz, CDCl3) 150.0 (C-6′), 148.1
(C-4′), 148.0 (C-2′), 130.2 (C-10′), 128.9 (C-8′), 127.4 (C-9′),
126.4 (C-7′), 123.1 (C-3′),119.4 (C-5′), 77.0 (C-8), 62.6 (C-2),
61.6 (d, JC–P = 6.8 Hz, OCH2), 55.7 (C-9), 41.3 (C-6), 34.1
(C-14), 32.2 (C-3), 32.0 (C-13), 31.3 (C-12), 31.2 (C-11), 29.9
2
1
(C-5), 29.1 (C-7), 27.2 (C-16, d, JC–P = 15.0 Hz), 25.4 (C-4),
23.2 (C-10), 22.1 (d, 2JC–P = 4.5 Hz, C-15), 16.1 (d, 3JC–P = 6.0
Hz, CH3). δP (121.0 MHz, CDCl3) 32.5. Anal. calcd for
C28H44N3O3PS2: C, 59.44; H, 7.84; N, 7.43; Found: C, 59.55;
H, 7.87; N, 9.38.
General procedure for phosphonates 1a–e
To a flask (100 mL) was charged with 9-amino-9-deoxy-epi-
cinchonine (3.1 g, 10.6 mmol), HS(CH2)2S(CH2)nP(O)-
(O C2H5)2 (n = 2–6) (42.2 mmol) and AIBN (0.43 g,
2.6 mmol), flushed three times with Ar atmosphere and sealed.
Then CHCl3 (60 mL) were added by a syringe and the reaction
mixture was refluxed for 72 h at 80 °C with the tracking of TLC.
During the reaction, AIBN (0.43 g, 2.6 mmol) was added once
per 24 hours. The reaction residue was concentrated under
reduced pressure, adjusted by 10% HCl solution to pH = 1 and
extracted by ethyl acetate (70 mL × 4). In the aqueous phase
concentrated ammonia was added to pH = 10 and extracted by
CH2Cl2 (70 mL × 4). The combined organic phase was washed
with saturated ammonium chloride (50 mL × 3) and brine
(50 mL × 3), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude products were purified by gra-
dient silica gel column chromatography using CHCl3/petroleum
ether (v/v = 2/1) to remove the unreacted HS(CH2)2S(CH2)nP(O)-
(OC2H5)2 (n = 2–6) and then CHCl3/methanol (v/v = 80/1 →
60/1 → 40/1 → 20/1) as the eluents to afford the brown viscous
and oily 1a–e.
Phosphonate 1c. (4.3 g, 70%), brown viscous and oily liquid.
3
δH (300 MHz, CDCl3, Me4Si) 8.90 (1 H, dd, J = 6 Hz, H-2′),
8.37 (1 H, d, 3J = 9.0 Hz, H-5′), 8.14 (1 H, d, 3J = 9.0 Hz, H-8′),
3
3
7.73 (1 H, t, J = 6.0 Hz, H-7′), 7.54 (1 H, t, J = 6.0 Hz, H-6′),
7.50 (1 H, d, 3J = 2.0 Hz, H-3′), 4.77 (1 H, d, 3J = 9.0 Hz, H-9),
4.09 (4 H, m, OCH2), 3.24–3.32 (2 H, m, H-6α, H-2-exo), 3.07
3
(1 H, d, J = 9.0 Hz, H-8), 2.38–2.68 (11 H, m, H-14, H-12,
H-13, H-11, H-6β, H-2-endo, H-5α), 1.67–1.75 (6 H, m, H-15,
H-16, H-17), 1.51–1.59 (6 H, H-3, H-4, H-5β, H-7β, H-10), 1.32
(6 H, t, 3J = 6.0 Hz, CH3), 0.76 (1 H, dd, H-7α). δC (75.0 MHz,
CDCl3) 150.2 (C-6′), 148.6 (C-4′), 148.3 (C-2′), 130.2 (C-10′),
128.9 (C-8′), 127.6 (C-9′), 126.4 (C-7′), 123.1 (C-3′), 119.4
2
(C-5′), 77.1(C-8), 61.7 (C-2), 61.3 (d, JC–P = 6.0 Hz, OCH2),
4
57.4 (C-9), 40.7 (C-6), 34.4 (C-14, d, JC–P = 5.3 Hz), 33.0
2
(C-3), 32.4 (C-13), 32.0 (C-16, d, JC–P = 9.0 Hz), 31.4 (C-12),
30.2 (C-11), 30.1 (C-5), 28.4 (C-7), 26.0 (C-4), 25.4 (C-17, d,
3
1JC–P = 25.5 Hz), 24.1 (C-10), 21.4 (C-15, d, JC–P = 5.3 Hz),
3
16.2 (d, JC–P = 6.0 Hz, CH3). δP (121.0 MHz, CDCl3) 33.0.
Anal. calcd for C29H46N3O3PS2: C, 60.07; H, 8.00; N, 7.25;
Found: C, 60.15; H, 8.08; N, 7.13.
Phosphonate 1a. (3.6 g, 62%), brown oily liquid. δH
(300 MHz, CDCl3, Me4Si) 8.87 (1 H, d, 3J = 6.0 Hz, H-2′), 8.34
(1 H, d, 3J = 9.0 Hz, H-5′), 8.13 (1 H, d, 3J = 9.0 Hz, H-8′), 7.68
(1 H, t, 3J = 6.0 Hz, H-7′), 7.59 (1 H, t, 3J = 6.0 Hz, H-6′), 7.55
(1 H, d, 3J = 2.0 Hz, H-3′), 4.72 (1 H, d, 3J = 9.0 Hz, H-9), 4.08
(4 H, m, –OCH2), 3.22–3.30 (2 H, m, H-6α, H-2-exo), 3.09 (1
Phosphonate 1d. (4.5 g, 72%), brown viscous and oily liquid.
3
δH (300 MHz, CDCl3, Me4Si) 8.80 (1 H, dd, J = 6.0 Hz, H-2′),
8.27 (1 H, d, 3J = 9.0 Hz, H-5′), 8.04 (1 H, d, 3J = 9.0 Hz, H-8′),
3
3
7.63 (1 H, t, J = 6.0 Hz, H-7′), 7.51 (1 H, t, J = 6.0 Hz, H-6′),
7.45 (1 H, d, 3J = 2.0 Hz, H-3′), 4.61 (1 H, d, 3J = 9.0 Hz, H-9),
3.98 (4 H, m, OCH2), 3.14–3.22 (2 H, m, H-6α, H-2-exo), 3.00
3
H, d, J = 9.0 Hz, H-8), 2.70–2.79 (8 H, m, H-14, H-12, H-13,
3
H-6β, H-2-endo), 2.44–2.56 (2 H, m, H-11), 1.95–2.07 (3 H, m,
H-5α, H-15), 1.43–1.67 (6 H, m, H-3, H-4, H-5β, H-7β, H-10),
1.30 (6 H, t, 3J = 6.0 Hz, CH3), 0.76 (1 H, br s, H-7α). δC
(75.0 MHz, CDCl3) 150.1 (C-6′), 148.3 (C-4′), 140.2 (C-2′),
130.2 (C-10′), 128.9 (C-8′), 127.4 (C-9′), 126.4 (C-7′), 123.1
(C-3′), 119.4 (C-5′), 77.1 (C-8), 62.6 (C-2), 61.6 (OCH2, d, 2JC–P
= 6.8 Hz), 55.7 (C-9), 41.3 (C-6), 34.1 (C-13), 33.3 (C-3), 32.5
(1 H, d, J = 9.0 Hz, H-8), 2.37–2.71 (11 H, m, H-14, H-12,
H-13, H-11, H-6β, H-2-endo, H-5α), 1.39–1.68 (14 H, m, H-15,
H-16, H-17, H-18, H-3, H-4, H-5β, H-7β, H-10), 1.22 (6 H, t, 3J
= 9.0 Hz, CH3), 0.65 (1 H, dd, H-7α). δC (75.0 MHz, CDCl3)
150.0 (C-6′), 148.5 (C-4′), 148.2 (C-2′), 130.0 (C-10′), 128.8
(C-8′), 127.5 (C-9′), 126.2 (C-7′), 123.0 (C-3′), 119.3 (C-5′),
2
77.1 (C-8), 61.5 (C-2), 61.2 (d, JC–P = 6.0 Hz, OCH2), 57.3
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5
(C-9), 40.6 (C-6), 34.3 (C-14, d, JC–P = 5.3 Hz), 33.0 (C-3),
(0.72 g, 64%). C, H and N elemental analysis are shown in the
ESI.†
3
32.0 (C-13), 31.7 (d, JC–P = 15.8 Hz, C-16), 30.2 (C-12), 29.9
(C-11), 29.3 (d, JC–P = 17.3 Hz, C-17), 28.8 (C-5), 28.3 (C-7),
26.2 (C-4), 25.4 (d, JC–P = 26.2 Hz, C-18), 24.3 (C-10), 21.7
(d, JC–P = 4.5 Hz, C-15), 16.1 (d, JC–P = 6.0 Hz, CH3). δP
(121.0 MHz, CDCl3) 33.3. Anal. calcd for C30H48N3O3 PS2: C,
60.68; H, 8.15; N, 7.08; Found: C, 60.75; H, 8.21; N, 7.01.
2
1
Zirconium phosphonate 4c. A mixture of phosphonate 1c
(3.2 g, 5.4 mmol), acetic acid (40 mL) and hydrochloric acid
(15 mL, 36%) was stirred at 80 °C for 24 h, concentrated to
10 mL solution and adjusted to pH = 2–3 with aqueous
NaHCO3 solution (0.1 mol L−1). To the reaction mixture was
added sodium dodecyl benzene sulfonate (SDBS, 2.0 g in
70 mL 30% THF aqueous solution) and stirred for another
30 min. Then, 25 mL of ZrOCl2 aqueous solution (6.7 g,
20.6 mmol) was added at room temperature and stirred for 2 h.
The precipitate was filtered, washed with water (20 mL × 3) and
dried at 60 °C under reduced pressure for 12 h to afford off-
white zirconium phosphonate 4c (1.6 g, 76%).
4
3
Phosphonate 1e. (4.9 g, 76%), brown viscous and oily liquid.
3
δH (300 MHz, CDCl3, Me4Si) 8.94 (1 H, d, J = 6.0 Hz, H-2′),
8.38 (1 H, d, 3J = 9.0 Hz, H-5′), 8.17 (1 H, d, 3J = 9.0 Hz, H-8′),
3
3
7.75 (1 H, t, J = 6.0 Hz, H-7′), 7.63 (1 H, t, J = 6.0 Hz, H-6′),
7.58 (1 H, d, 3J = 6.0 Hz, H-3′), 4.74 (1 H, d, 3J = 9.0 Hz, H-9),
4.11 (4 H, m, OCH2), 3.28–3.36 (2 H, m, H-6α, H-2-exo), 3.10
3
(1 H, d, J = 9.0 Hz, H-8), 2.29–2.73 (11 H, m, H-14, H-12,
H-13, H-11, H-6β, H-2-endo, H-5α), 1.67–1.79 (16 H, m, H-15,
H-16, H-17, H-18, H-19, H-7α, H-4, H-5β, H-7β, H-10), 1.34 (6
H, t, J = 9.0 Hz, CH3), 0.79 (1 H, dd, H-7α). δC (75.0 M Hz,
Hybrid zirconium phosphate–phosphonates 5c1–3. A mixture
of phosphonate 1c (0.2 g, 0.34 mmol), acetic acid (9 mL) and
hydrochloric acid (3.0 mL, 36%) was stirred at 80 °C for 24 h,
concentrated to 1 mL solution and adjusted to pH = 2–3 by tri-
ethylamine aqueous solution (10 wt%). To the resulting solution
was added saturated NaH2PO4·2H2O (53 mg, 0.34 mmol)
aqueous solution and well mixed. Then, 2 mL of ZrOCl2 (0.2 g,
0.62 mmol) aqueous solution was added. The amorphous pre-
cipitate in the solution was kept at 70 °C for 12 h, cooled to
room temperature, filtered, washed with deionized water and
dried at 60 °C under reduced pressure to afford white solid 5c1
(2.2 g, 78%). According to the same procedure mentioned
above, hybrid zirconium phosphate–phosphonates 5c2 (2.1 g,
82%) and 5c3 (2.1 g, 89%) were also prepared by using the
molar ratio of phosphonate/phosphate = 1/2 and 1/3, respect-
ively. C, H and N elemental analysis are shown in the ESI.†
3
CDCl3) 150.2 (C-6′), 148.5 (C-4′), 148.4 (C-2′), 130.3 (C-10′),
128.9 (C-8′), 127.6 (C-9′), 126.4 (C-7′), 123.1 (C-3′), 119.5
3
(C-5′), 77.1 (C-8), 61.7 (C-2), 61.2 (d, JC–P = 6.8 Hz, OCH2),
57.4 (C-9), 40.8 (C-6), 34.4 (C-14), 34.2 (C-3), 32.2 (C-13),
32.0 (C-15), 30.1 (C-12), 29.9 (C-16), 29.2 (C-17), 28.4 (C-5),
1
28.1 (C-7), 26.4 (C-4), 25.4 (d, JC–P = 22.5 Hz, C-19), 24.5
2
3
(C-10), 22.1 (d, JC–P = 4.5 Hz, C-18), 16.3 (d, JC–P = 6.0 Hz,
CH3). δP (121.0 MHz, CDCl3) 33.0. Anal. calcd for
C31H50N3O3PS2: C, 61.25; H, 8.29; N, 6.91; Found: C, 61.31;
H, 8.34; N, 6.82.
General procedure for various zirconium phosphonates
Zirconium phosphonates 2a–e. A mixture of phosphonates
1a–e (4.1 mmol), acetic acid (30 mL) and hydrochloric acid
(10 mL, 36%) was stirred at 80 °C for 24 h and concentrated
under reduced pressure to 5 mL solution. Then 100 mL of water
was added and pH of solution was adjusted to 1–2. To the
obtained solution was added dropwise 30 mL of zirconium oxy-
chloride (5.7 g, 17.7 mmol) aqueous solution with stirring and
aged at room temperature for another 2 h. The white solids were
filtered, dispersed in 50 mL of water and adjusted to pH = 6–7
using NaHCO3 solution (0.1 mol L−1). The resulting white mud
cake was filtered, washed by deionized water (20 mL × 3) until
the chloride ion was not detected by ion chromatography, and
dried at 60 °C for 12 h under reduced pressure to afford the light
yellow zirconium phosphonates 2a–e (2a: 0.71 g, 47%; 2b:
0.92 g, 56%; 2c: 1.29 g, 63%; 2d: 0.79 g, 54%; 2e: 0.82 g,
42%). C, H and N elemental analysis of 2a–e are shown in the
ESI.†
General asymmetric direct aldol reaction. In a 10 mL vial,
catalyst 2a (10 mg, 0.025 mmol) and TfOH (3.75 μmol), water
(1 mL) and cyclohexanone (0.5 mL, 3.9 mmol) were added con-
secutively. After stirred at room temperature for 15 min in a
closed system, p-nitrobenzaldehyde (37.3 mg, 0.25 mmol) was
added and left under stirring for 96 h at 25 °C (monitored by
TLC). The reaction mixture was quenched with saturated
ammonium chloride solution (5 mL) and extracted with ethyl
acetate (15 mL × 3). Then catalyst 2a was recovered by centrifu-
gation. The combined organic phases were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The crude pro-
ducts were purified by flash column chromatography eluting
with petroleum ether/ethyl acetate (v/v = 10/1) to remove the
unreacted p-nitrobenzaldehyde and then petroleum ether/ethyl
acetate (v/v = 2/1) as an eluent to afford the pure aldol adduct.
The anti/syn ratio was determined by 1H NMR of crude
product in CDCl3; CHOH (d): syn 5.48 ppm, J = 3.0 Hz; anti:
4.90 ppm, J = 9.0 Hz. The enantiomeric excess (%ee) was deter-
mined by chiral HPLC analysis with CHIRALPACK AD-H,
eluting with n-hexane/isopropanol (80/20), flow rate 0.5 mL
min−1 and UV detector (λ = 254 nm).
Zirconium phosphonates 3b and c. A mixture of phosphonate
1b or 1c (3.0 mmol), acetic acid (20 mL) and hydrochloric acid
(6 mL, 36%) was stirred at 80 °C for 24 h and concentrated to
20 mL solution. Under stirring, 20 mL of ZrOCl2 aqueous sol-
ution (3.7 g, 11.5 mmol) was added dropwise and stirred for
another 2 h. The reaction mixture was adjusted to pH = 4–5 with
triethylamine aqueous solution (10 wt%), then white solids pre-
cipitated. The white solids were filtered, washed with methanol
(20 mL × 3) and dried at 50 °C under reduced pressure for 12 h
to afford zirconium phosphonates 3b (0.65 g, 58%) and c
½SRꢀ ꢁ ½RSꢀ
%ee anti ¼
%ee syn ¼
ꢂ 100%;
½RSꢀ þ ½SRꢀ
½SSꢀ ꢁ ½RRꢀ
½RRꢀ þ ½SSꢀ
ꢂ 100%
5718 | Dalton Trans., 2012, 41, 5715–5726
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Table 1 Thermal properties and chemical compositions of various supported organocatalystsa
Cat.
n
Molecular formula
Weight loss (TG)
<150 °C
9.0
8.0
11.8
9.3
3.0
—
6.7
5.8
150–800 °C
40.3
42.0
48.7
39.7
51.0
—
42.4
45.2
24.4
2a
2b
2c
2d
2e
3b
3c
4c
2
3
4
5
6
3
4
4
4
4
4
Zr(OH)3.18(O3PR)0.41·1.98H2O
Zr(OH)3.14(O3PR)0.43·1.76H2O
Zr(OH)2.88(O3PR)0.56·2.89H2O
Zr(OH)3.26(O3PR)0.37·2.02H2O
Zr(OH)3.04(O3PR)0.48·2.28H2O
Zr(OH)3.18(O3PR)0.41·1.12H2O
Zr(OH)3.22(O3PR)0.39·1.47H2O
Zr(OH)3.12(O3PR)0.44·1.41H2O
Zr(O3POH)1.71(O3PR)0.29·2.14H2O
Zr(O3POH)1.78 (O3PR)0.22·1.54H2O
Zr(O3POH)1.81(O3PR)0.19·1.21H2O
5c1
5c2
5c3
11.2
16.9
12.4
18.5
15.6
a Zirconium(IV) and phosphonic acid were determined by quantitative colorimetric assay and solution 31P {1H} NMR respectively; the content of
water was determined by TG.
as space-filling species, (2) as structure-directing agents, and (3)
as true templates.24 Meanwhile, upon introducing a small group,
such as HPO4, hybrid zirconium phosphate–phosphonates 5c1–
c3 of general formula Zr(HPO4)2−x(PO3R)x (x = 0.29, 0.22 and
0.18) were also prepared as amorphous solids by direct precipi-
tation in the absence of hydrofluoric acid (Scheme 1). They were
all characterized by TG, DTA, X-ray, nitrogen adsorption–
desorption isotherm, AFM and TEM.
Results and discussion
Catalyst preparation and characterization
Catalyst preparation. The preparation of zirconium phospho-
nate is closely related to the methods employed for layered α-Zr
(HPO4)2·H2O (α-ZrP), for example, by precipitation of aqueous
solutions of phosphonic acids 1a–e with ZrOCl2 in the absence
of hydrofluoric acid. In general, compared with crystalline zirco-
nium phosphonate, amorphous materials obtained by direct pre-
cipitation in the absence of hydrofluoric acid showed the better
catalytic properties in the field of catalysis, such as hydrogen-
ation reactions, owing to much higher surface area.23 In this
paper, we only paid attention to the preparation of amorphous
zirconium phosphonates by direct precipitation upon adding
ZrOCl2 to the aqueous solution of phosphonic acid (ZrIV/P = 4).
Due to the limited free area (24 Å2) around each phosphorous
atom and steric effect of attached bulky organic moiety on the
surface of Zr layer, typical zirconium phosphonate with molar
ratio of P/Zr = 2, whose theoretical formula is considered to be
Zr(O3PR)2·nH2O (R being an organic group), cannot be obtained
as expected. However, bulky groups can be attached to the Zr
layer to afford functional compounds of the formula Zr(O3PR)-
(O3PR′)·nH2O if their dimensions are compensated by introdu-
cing a small group, such as R′ = H, OH or CH3. Otherwise, in
the presence of a sole bulky phosphonate without a small com-
pensating group, zirconium hydroxide phosphonates of the
formula Zr(OH)4−2x(O3PR)x·nH2O can be prepared by direct pre-
cipitation with ZrOCl2 solution.21d,22a
Ethyl phosphonates 1a–e with different chain lengths (n =
2–6) can be hydrolyzed at 80 °C in HOAc/HCl medium to form
corresponding alkyl phosphoric acids, which were chosen in situ
for the preparation of zirconium hydroxide phosphonate-cova-
lently supported 9-amino-9-deoxy-epi-cinchonine organocata-
lysts 2a–e in 40–50% yields. Considering the effect of internal
and external surface properties of zirconium phosphonate on cat-
alytic properties, Et3N and SDBS were used as template guest
molecules to prepare zirconium phosphonates 3b, c and 4c,
respectively, because amine and surfactant played important
roles in different microtextures and surface morphologies of zir-
conium phosphonate. Apart from acting as charge balancing
cations, amine and surfactant can act in three distinct ways: (1)
Chemical composition. F− is a good ligand for transitional
metals, such as zirconium(IV), with a very high oxidation state.
Upon adding 2 mL of hydrofluoric acid (30%) and 2 mL of de-
ionized water to zirconium phosphonates 2a–e (50 mg) and stir-
ring for 6 h at room temperature in a sealed plastic container,
2a–e were decomposed to the water-soluble mixtures of complex
2−
ZrF6 and organophosphonic acid. The contents of zirconium
(IV) and organophosphonic acid in the resulting solution could
be determined by quantitative colorimetric assay and solution
31P {1H} NMR, respectively. Based on the detected molar ratio
of Zr/P, the x values in empirical formulae of 2a–e [Zr(OH)4−2x
-
(O3PR)x·nH2O, R = organic group] were calculated to be 0.41,
0.43, 0.56, 0.37 and 0.48, respectively (Table 1), which were in
good agreement with the results of elemental analysis. On the
other hand, the molecular formulae of 2a–e, whose x values
were 0.39, 0.40, 0.54, 0.35 and 0.47, were also evaluated by
TGA. However, due to the incomplete combustion, which is
suggested by the typical pale gray color of the residue after
TGA, led to a somewhat reduced weight loss and a minor under-
prediction of the x values. To elucidate the effect of template
molecules Et3N and SDBS on the amount of appended phospho-
nate (x), ethyl phosphonate 1c was used as a representative
example to prepare corresponding zirconium phosphonates 3b, c
and 4c. Compared with zirconium phosphonate 2c, the organic
weight losses of 3c and 4c surprisingly decreased from 48.7% (x
= 0.56) to 42.4 (x = 0.39) and 45.2% (x = 0.44), respectively. By
means of introducing a small compensating group HPO4 in the
presence of NaH2PO4, amorphous organic–inorganic hybrid zir-
conium phosphonates 5c1–c3 of molecular formulae [Zr(HPO4)2−x
-
(PO3R)x] with x = 0.29, 0.22 and 0.18 can be obtained, respectively
by the direct precipitation of the mixture of hydrolytic organopho-
sphonate 1c and NaH2PO4 (molar ratio NaH2PO4/1c = 1, 2 and 3)
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with ZrOCl2 (ZrIV/P = 2) in the absence of hydrofluoric acid
(Table 1).
(O3PR)x·nH2O] consecutively increased from 15.8 to 16.3, 16.7,
20.8 and 25.7 Å (Fig. S3 shown in ESI†). Preliminary attempts
had been made to estimate the effect of template guest mol-
ecules, such as Et3N, on interlayer distances. Interestingly, it was
found that the typical interlayer distances of 3b, c were expanded
to 19.0 and 19.9 Å with 2.7 and 3.2 Å increments, respectively.
In Table 2 were listed, for all as-synthesized zirconium phos-
phonates 2a–e, 3b–c, 4c and 5c, the arm chain length (n), mol-
ecular formula, typical interlayer distance, BET-specific surface
area, average pore diameter and pore volume by BJH analysis.
As a pair of representative and comparative examples, the nitro-
gen adsorption–desorption isotherm plots of 2c and 3c, per-
formed at 77 K, were shown in Fig. 1. Unusually, the isotherm
plots of 2a–e were linear to the P/P0 axis at relative low P/P0
range (0–0.9) and convex to the P/P0 axis at high P/P0 range
(0.9–1.0), which were beyond to classic definitions.26 From the
calculated data in Table 1 and Fig. 1, these pore size distributions
(PSDs) of as-synthesized 2a–e suggested the existence of
10–20 nm micropores together with irregular mesopores, having
From the TG curves, it was observed that thermal decompo-
sition occurred in two steps: the first, between 50 and 150 °C,
corresponded to the initial weight losses of 11.8, 6.7, 5.8 and
11.2% owing to the surface-bound or intercalated water absorbed
in pores; the second, between 150 and 800 °C, corresponded to
the total weight losses of 48.7, 42.4, 45.2 and 24.4% of the
initial and deep decomposition of appended organic fragments,
respectively (Fig. S1 in ESI†).
The covalent attachment of 9-amino-9-deoxy-epi-cinchonine
on the frame of zirconium phosphonate was also successfully
verified by infrared spectra in the range of 4000–400 cm−1
(Fig. S2 shown in ESI†). The broad, strong and wide absorption
band extending from 3700–2500 cm−1 and centered at
3450 cm−1 was assigned to the O–H stretching vibration, which
was indicative of the presence of hydrogen bonds between
hydroxyl groups or adsorbed waters on the internal and external
surfaces. The moderate absorption bands at 1641, 1610, and
623 cm−1 were attributed to the stretching vibration mode and
flexural vibration of the aryl group, respectively. The flexural
vibration of C–H in CH2 groups, which emerged at 1398 cm−1
,
Table 2 The layered and mesoporous properties of as-synthesized
was strengthened with the increase in arm chain length (n) from
2 to 6. The strong and wide absorption band at about 1091 cm−1
was caused by the characteristic Zr–O–P stretching vibration.25
zirconium phosphonatesa
Surface areab Average pore Pore volumed
Interlayer
distance (Å)
Cat.
n
(m2 g−1
)
diameterc (Å) (×10−3 cc g−1
)
Layered and porous structure. The layered structure and d-
spacing of zirconium planes for crystalline and semi-crystalline
zirconium phosphonate can be determined from the 00n peak in
powder XRD pattern (via the Bragg equation, nλ = 2dsin θ). The
X-rays of zirconium phosphonates 2a–e and 3b–c showed the
amorphous nature with the broad peak, which illustrated that
they possessed layered structures with different interlayer dis-
2a
2b
2c
2d
2e
3b
3c
4c
2
3
4
5
6
3
4
4
4
4
4
12.6
16.3
28.1
29.9
33.2
16.5
12.8
16.2
32.1
30.1
30.4
50.4
50.0
52.0
55.8
57.8
58.0
59.8
53.0
94.2
91.8
94.3
32.1
38.4
43.0
38.8
38.2
19.7
18.6
43.2
71.8
78.3
143.2
4.5, 15.8
4.7, 16.3
4.8, 16.7
4.9, 20.8
5.0, 25.7
4.7, 19.1
5.0, 19.9
5.1, 19.8
7.8, 19.2
—
5c1
5c2
5c3
tances: 4.5–5.0
Å
typical of Zr(OH)4
phase and
2x
−
15.8–25.7 Å typical of Zr(O3PR)x phase arose from the packing
of alternate layers with different interlayer distances, one richer
in hydroxide (OH) and the other in phosphonate (O3PR),
respectively. With the increase of arm chain length (n) from 2 to
—
a The sample was degassed at 100 °C for 5 h. b Based on multipoint
BET method. c Based on the desorption data using BJH method. d Based
on the desorption data of BJH method.
6, the typical interlayer distances of 2a–e [Zr(OH)4−2x
-
Fig. 1 Nitrogen adsorption–desorption isotherm plots obtained with catalysts 2c and 3c.
5720 | Dalton Trans., 2012, 41, 5715–5726 This journal is © The Royal Society of Chemistry 2012

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Fig. 2 (a) TEM image of 2b; (b) TEM image of 2c; (c) AFM image of 3c; (d) AFM image of 4c; (e) TEM image of 5c1; (f) TEM image of 3c; (g)
AFM image of 5c1; (h) SEM image of 3c.
broad peaks in the range of about 2–50 nm. As expected, the
average pore diameters and surface areas of 2a–e increased from
50.4 to 57.8 Å and 12.6 to 33.2 m2 g−1, respectively, with the
increase of arm chain length (n) from 2 to 6. Unfortunately, the
as-synthesized zirconium phosphonates 2a–e presented the low
pore volumes (18.6–43.0 × 10−3 cc g−1). Upon adding template
with about 200 nm length and 20 nm width was directly evi-
denced by TEM image, which was similar to that of typical crys-
talline particles. Interestingly, compared with zirconium
phosphonate 2c, it is worth noting that zirconium phosphonate
3c apparently became smaller in size and more regular in shape
owing to the action of template guest molecule (Et3N). From the
TEM images (Fig. 2a, b, e and f), it was concluded that the
different surface morphologies could be obtained by using differ-
ent template guest molecules.
AFM was also used to observe the morphologies and particle
sizes in water. The samples were prepared as follows: 1.0 mg of
particles was dispersed in 3 mL of water, followed by ultrasonic
stirring for 10 min. A thin film of the suspension on mica was
prepared by spin coating, and the particles were left on the mica
surface after volatilization of water for three days. The two-
dimensional AFM images of zirconium phosphonates 3c, 4c and
5c1 were shown in Fig. 2c, d and g, and the three-dimensional
AFM images were shown in the ESI.† Among the statistically
analyzed 29 particles for zirconium phosphonate 3c, the dia-
meter and height ranged from 4.4–95.5 nm and 4.0–22.1 nm
with 33.8 nm mean diameter and 8.1 nm mean height, respect-
ively. Similar results with 39.9 nm mean diameter and 10.2 nm
mean height were also observed for zirconium phosphonate 4c.
For hybrid material 5c1, 142 particles were statistically analyzed
and the smaller mean diameter (23.1 nm) and height (4.0 nm)
were obtained in aqueous medium.
guest molecule (Et3N), the surface areas (16.5 and 12.8 m2 g−1
)
and pore volumes (19.7 and 18.6 × 10−3 cc g−1) of zirconium
phosphonates 3b, c decreased by 20 and 57%, respectively,
except for a little increase of average pore diameters (50.0 →
58.0 Å and 52.0 → 59.8 Å, respectively). Surface-active agent
(SDBS) showed no pronounced change in average pore diameter
and pore volume of zirconium phosphonate 4c. After introducing
a small HPO4 group, the hybrid zirconium phosphate–phospho-
nates 5c1–c3 possessed higher surface areas, average pore dia-
meters and pore volumes owing to their rigid and classic
skeleton construction.
Surface morphology. Taking into account the compact
relationship between the physical surface properties of a sup-
ported catalyst and its catalytic performance, it was necessary
that zirconium phosphonates 2a–e, 3b, c, 4c, 5c be well eluci-
dated by SEM, TEM and AFM to understand surface mor-
phologies and particle sizes in different states. After being well-
dispersed in water (10 mg sample in 10 mL of H2O) for 10 min
under ultrasonic radiation, sputtered over copper wire, and evap-
orated under infrared radiation for 10 min, the TEM images were
observed under an accelerating rate voltage of 200 keV. From
Fig. 2 as representative and comparative examples, the spherical
particles 2b and 2c in water, with a uniform diameter of approxi-
mately 20–30 nm, were observed, and the spherical particles
closely connected to each other to form the filiform structure. As
expected, upon adding NaH2PO4, the surface morphology of 5c1
Seen from the outside, it seemed to be a contradiction among
SEM, TEM and AFM images. In fact, they clearly reflected the
different surface morphologies of zirconium phosphonate in
different states. The SEM image with about 500 nm, which was
observed in the solid state, could be considered to mirror the
surface morphology of catalyst in solid state. Due to being well-
dispersed in water, the TEM and AFM images could be
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Table 3 The direct asymmetric aldol reaction of p-nitrobenzaldehyde
identified as efficiently elaborating the surface morphologies of
zirconium phosphonate in aqueous solution, which seemed to
simulate the existing state of zirconium phosphonate in water in
aldol addition. It was worthy noting that the smaller particle
sizes and being more homogeneously dispersed were observed
by using AFM images owing to the more diluted solution
(0.3 mg mL−1).
and cyclohexanone over various zirconium phosphonates in watera
Yieldb Anti-productc Syn-productc
Dr
Entry Cat.
n
(%)
(%ee)
(%ee)
(anti/syn)d
Catalytic activity
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
3b
3c
4c
2
3
4
5
6
3
4
4
4
4
4
75
94
98
90
82
98
99
91
92
75
70
97
82
83
88
85
80
92
95
70
91
85
82
99
22
20
21
30
42
23
26
30
25
25
9
70/30
68/32
70/30
67/33
71/29
77/23
81/19
85/15
73/27
63/37
64/36
84/16
In particular, the asymmetric aldol reaction is a key C–C bond-
forming reaction that has tremendous synthetic utility and is
often the platform of choice to examine new organocatalysts.
There are a number of small molecule-organocatalyzed aldol
reactions that are capable of asymmetric induction in organic sol-
vents. However, from a green chemistry perspective, the use of
water instead of organic solvent and the reuse of organocatalyst
are preferred to decrease environmental contamination and lower
the cost of the organocatalyst.27 For the above-mentioned
reasons, we draw attention to particular aspects of developing
asymmetric aldol reactions in water and the recycling of small-
molecule organocatalyst owing to striving for environmentally
benign chemical processes and economic benefits. Zirconium
phosphonate, a kind of widely recognized porous and layered
materials with accessible channels as well as good thermal and
hydrothermal stability, was applied as a support for 9-amino-9-
deoxy-epi-cinchonine in this work. The aldol addition of p-nitro-
benzaldehyde to cyclohexanone to give anti and syn diastereo-
mers of 2-[hydroxy(4-nitrophenyl)methyl]cyclohexanone was
chosen as a model reaction for evaluating the asymmetric cataly-
tic performances of various zirconium phosphonates-supported
organocatalysts.
9
5c1
5c2
5c3
10
11
12
e
—
22
a Reaction conditions: p-nitrobenzaldehyde (0.25 mmol), cyclohexanone
(0.39 mmol), catalyst (0.025 mmol, 10 mol%), 25 °C, 96 h, 1 mL of
water, TfOH (3.75 × 10−3 mmol). b Isolated yield. c Determined by
chiral HPLC, Daicel Chiralpak AD-H column. d Determined by 1H
NMR. e 9-Amino-9-deoxy-epi-cinchonine as “blank” reaction.
The influence of arm chain lengths (n) and different prep-
aration conditions. Our initial experiments were performed
using p-nitrobenzaldehyde as a model substrate with cyclohexa-
none over 10 mol% 2a–e with different organic arm chain
lengths (n = 2–6) at 25 °C for 96 h in water. It was exciting to
observe that the corresponding aldol adducts in 75–98% isolated
yields with 80–88%ee anti, 19–42%ee syn and about anti/syn =
70/30 were favorably obtained in the presence of 1.5 mol%
triflic acid (Table 3, entries 1–5). With the increase of arm chain
length (n) from 2 to 6, the yields and enantioselectivities of anti-
aldol adducts were gradually enhanced first (75 → 98% and 82
→ 88%ee anti), then decreased at n = 5 (98 → 82% and 88 →
80%ee anti). This phenomenon was possibly related to the
different confinement effects of the backbones in 2a–e owing to
the arm chain lengths (n), in which 9-amino-9-deoxy-epi-cincho-
nine moiety possessed the different distances from Zr layers
(Fig. 3). The optimum arm chain length was found to be n = 4 in
terms of enantioselectivity, diastereoselectivity and reactivity
(98% yield, 88%ee anti) (Table 3, entry 3). Too far or too near
from the Zr layer was not beneficial to the confinement effect of
zirconium phosphonate. Moreover, it was worth noting that the
successively enhanced enantioselectivities (20 → 42%ee) and
similar dr values (anti/syn = 70/30) of syn-adducts were
observed with the increase of arm chain lengths (n) from 2 to 6.
The sole difference in synthetic procedure between 2a–e and
3b, c was using inorganic base NaHCO3 or organic base Et3N to
Fig. 3 The possible mechanism of the asymmetric aldol reaction in the
confined backbone of zirconium phosphonate.
neutralize the surface acidity of zirconium phosphonates. To our
surprise, although the decrease in the x value, surface area and
pore volume for 3c, based on TGA and nitrogen adsorption–
adsorption isotherms, was observed, the enantioselectivities (88
→ 95%ee) and diastereoselectivities (70/30 → 81/19) of aldol
adducts were remarkably improved (Table 3, entries 6 and 7).
Perhaps, the improvement of catalytic performance could be
attributed to the acid–base reaction between the organic base
Et3N and the surface acid of the hydroxyl over the zirconium
layer to form triethylamine hydrochloride and result in the
change in surface morphology evidenced by TEM (Fig. 2).
Unfortunately, upon adding template guest molecule SDBS in
the synthetic procedure of zirconium phosphonate 4c, the %ee of
anti-products dropped significantly but the dr value unexpect-
edly increased for reasons unknown (Table 3, entry 8). It was
noteworthy that hybrid zirconium phosphonate 5c1 (x = 0.29)
5722 | Dalton Trans., 2012, 41, 5715–5726
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Table 4 The direct asymmetric aldol addition of benzaldehyde
derivatives to cyclohexanone in watera
Yieldb Anti-productc Syn-productc Dr
Entry
R
(%)
(%ee)
(%ee)
(anti/syn)d
1
2-NO2
2-NO2
3-NO2
3-NO2
4-NO2
4-NO2
4-CN
4-F
81
83
90
98
98
97
86
11
47
14
15
20
95
94
98
96
99
94
94
91
93
86
94
5
−90
−44
7
36
32
22
32
47
−53
66
34
28
1/99
98/2
2e
3
90/10
86/16
83/17
84/16
74/26
77/23
95/5
82/18
78/22
68/32
90/10
4e
5
6e
7
8
9
10
11
12
13
4-Cl
4-Br
4-CH3
4-OCH3 12
30
H
−63
a Reaction conditions: Benzaldehydes (0.25 mmol), cyclohexanone
(0.39 mmol), catalyst 3c (0.025 mmol, 10 mol%), 25 °C, 96 h, 1 mL of
water, TfOH (3.75 × 10−3 mmol). b Isolated yield. c Determined by
chiral HPLC (Daicel Chiralpak AD-H column). d Determined by 1H
NMR. e 9-Amino-9-deoxy-epi-cinchonine as “blank” reaction (25 °C,
6 h).
ee syn-adduct were obtained. In the relatively high temperature
range from 25–40 °C, the %ee anti dropped successively and
slightly from 96 to 90%ee, and the %ee syn fell badly from 87 to
19%ee without significant change in the reactivities (93–98%)
and diastereoselectivities (anti/syn = 80/20) (Fig. 4-1). The best
result was obtained at 25 °C in 1 mL of water per 0.25 mmol of
p-nitrobenzaldehyde with excellent conversion (98% yield) and
high stereoselectivity (anti/syn = 81/19, 96%ee anti). Fig. 4-2
showed the catalytic properties of supported organocatalyst 3c as
a function of the used H2O volume. At the lower used amount of
water, a strong inhibiting influence on the yields of aldol adducts
(0.2 mL, 81%; 0.5 mL, 86%) was clearly observed owing to the
poorer mass diffusion in the mesopores of supported organocata-
lyst 3c. Of particular note was that at the higher used amounts of
H2O volume (2 and 3 mL), the %ee of aldol syn-adducts
changed from a positive value (major S,S-configuration) to a
negative value (major R,R-configuration). The same phenom-
enon was also observed in the catalytic process using the higher
amounts of catalyst (>15 mol%) (see Fig. S8 in ESI†). There-
fore, we conjectured that, at low substrate concentration
(<0.03 mol L−1) or high used amount of catalyst (>15 mol%),
the reactants in the mesopores of catalyst 3c were considered to
be in the diluted state, and in such a state the re-facial attack on
arylaldehyde to form the R,R-configuration was favored owing to
steric confinement. In conclusion, the optimum and excellent
catalytic properties (98% yield, 96%ee anti and 83/17 dr) were
obtained by using 10 mol% 3c at 25 °C in 1 mL water for 96 h
(Fig. 4-3).
Fig. 4 The effects of temperature and amounts of water and catalyst
used on the catalytic properties.
with the cylindrical morphology showed that the good catalytic
activity (92% yield) and enantioselectivity (91%ee anti, anti/syn
= 73/27) (Table 3, entry 9) were also achieved. However, 5c2
and 5c3 gave more and more disappointing results in the catalytic
properties along with the decrease in the x values (0.29 → 0.19)
of appended 9-amino-9-deoxy-epi-cinchonine determined by
TGA (Table 3, entries 10 and 11), although they possessed
higher surface areas, average pore diameters and pore volumes
(Table 2). In conclusion, the preliminary investigation showed
that the synthetic conditions played an important role in the
microtexture and surface morphology of zirconium phosphonate,
which resulted in different catalytic results in the asymmetric
aldol addition in water.
The influence of temperature and used amount of water and
catalyst. In order to further improve the catalytic activity of zir-
conium phosphonate 3c, we investigated the effect of tempera-
ture and used amount of water and catalyst on reactivity and
selectivity in the presence of 1.5 mol% triflic acid (Fig. 4). Low-
ering the reaction temperature to 10 °C, the reactivity decreased
to 76% yield. However, the higher 97%ee anti-adduct and 87%
Confinement effect of zirconium phosphonate. The optimized
protocol was expanded to a wide variety of benzaldehydes
(Table 4). The results of these trials indicated that the aldol
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Dalton Trans., 2012, 41, 5715–5726 | 5723

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reaction was dramatically dependent on the electronic effect of
the substituents similar to proline and its derivatives. 4-, 3-, 2-
Nitrobenzaldehydes and 4-cyanobenzaldehyde with electron-
drawing groups at the aromatic ring underwent asymmetric aldol
addition smoothly with cyclohexanone in good to excellent
yields (81–98%), excellent enantioselectivities (90–96%ee) and
diastereoselectivities (anti/syn = 1–90/99–26) (Table 4, entries 1,
3, 5, 7). However, unsubstituted benzaldehyde was less reactive
and afforded the aldol adducts in 30% yield with −63%ee syn
and good anti/syn = 90/10 (Table 4, entry 13). Meanwhile, the
substituted benzaldehydes with halogen groups (X = 4-F, Cl and
Br) and electron donating groups, such as CH3 and OCH3, at the
aromatic ring were not suitable for aldol addition in 11–47%
yield and 86–94%ee anti (Table 4, entries 8–13).
In the reported asymmetric homogeneous aldol addition of
substituent nitrobenzaldehydes to cyclohexanone, whether the
nitro substituent was in the o-, m- or p- position of the aromatic
ring, the major product of aldol addition had (2S,1′R) absolute
stereochemistry.8c,28 However, it was worth noting that the
stereoselectivities of aldol adducts catalyzed by heterogeneously
supported organocatalyst 3c were extremely related to the o-, m-
or p-position of the substituent (NO2) at aromatic ring (Fig. 5).
Especially, when the nitro substituent group was at the ortho-
position of benzaldehyde, the major syn-aldol adduct with good
−90%ee and excellent anti/syn = 1/99 were obtained. This
phenomenon was never observed in the homogeneous catalysis
of 9-amino-9-deoxy-epi-cinchonine (Table 4, entry 1). Under the
same catalytic conditions, m-nitrobenzaldehyde afforded (2S,1′
R)-configuration with 94%ee anti and anti/syn = 90/10 (Table 4,
entry 3), and the same (2S,1′R)-configuration was also achieved
by p-nitrobenzaldehyde in 98% yield, 96%ee anti and anti/syn =
83/17 (Table 4, entry 5). For m- and p-nitrobenzaldehydes, their
stereoselectivities were in accordance with the results catalyzed
by homogeneous 9-amino-9-deoxy-epi-cinchonine (Table 4,
entries 4, 6). Based on the different stereochemical results in
homogeneous and heterogeneous catalysis, we speculated that,
in the confined pores of zirconium phosphonate, the different
steric strains caused by the steric interactions between the o-pos-
ition of nitro substituent and the backbone of 3c made planar
nitrobenzaldehyde in different steric direction, and resulted in
the apofacial or facial attack to form the different configurations
(Fig. 3). The further mechanistic understanding involving both
experimental and complementary computational exploration is
under detailed investigation.
Fig. 5 Stereoisomers determined by HPLC in the aldol reaction of
o-, m-, or p-nitrobenzaldehydes with cyclohexanone.
(Table 5, entry 9), although there was appreciable drop in the
yield (8%) and enantioselectivity (4%ee anti). In order to seek
the reason why the catalytic activity decreased slightly, TEM,
TGA and nitrogen adsorption–desorption isotherm were used to
monitor the surface morphology, weight percent of organic
moiety and pore structure of the recycled catalyst 3c in the fifth
run (Fig. 6). Compared with fresh catalyst 3c, the similar spheri-
The recovery and reuse of catalyst
At the end of the catalytic aldol reaction, zirconium phosphonate
3c was readily recovered from the reaction mixture by simple
centrifugal separation, washed with ethyl acetate and reused
without any other further treatment. To our disappointment, the
catalytic activity was observed to have a sharp decline, even at
the first run (Table 5, entries 1–4). To make clear what is respon-
sible for the sharp decease in the catalytic activity, the supported
organocatalyst 3c was stirred in 10 mL of 30 wt% Et3N aqueous
solution for 15 min in every recycle run, centrifuged and dried
in a vacuum. It is exciting that the 88% yield, 91%ee anti and
anti/syn = 78/22 were still observed, even in the fifth run
cal particles with
a uniform diameter of approximately
20–30 nm were also observed. However, it was found that the
organic weight loss of organic moiety in the temperature range
of 150–800 °C increased from 42.4 to 65.9% and the average
pore diameter sharply decreased from 59.8 to 5.9 Å, which
implied that the adsorbed reactants, products, or impurity occu-
pied some pores, covered the catalytic active sites and resulted in
the decrease in catalytic activity.
5724 | Dalton Trans., 2012, 41, 5715–5726
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Table 5 The direct asymmetric aldol addition of p-nitrobenzaldehyde
to cyclohexanone over the recycled zirconium phosphonate 3c in watera
accessibility of reactants in the mesopores played an important
role in determining the configuration and enantiomeric excess
among the four stereo-isomers in the asymmetric aldol addition
of nitrobenzaldehyde to cyclohexanone. Based on this phenom-
enon, the relationship between the structure and its catalytic
property of catalyst is under the further investigation in detail in
our lab by tuning the pore structure and tailoring the confor-
mation of 9-amino-9-deoxy-epi-cinchonine in various metal
phosphonates (M = Zr, Ti, Ni, Zn and Ga).
Recycle
Entry run
Yieldb
(%)
Anti-productc Syn-productc Dr
(%ee)
(%ee)
(anti/syn)
1
2
3
4
5
6
7
8
9
1d
2d
3d
4d
1e
2e
3e
4e
5e
95
91
83
80
95
96
91
90
88
95
82
78
72
96
94
95
92
91
36
34
38
30
38
40
32
37
12
80/20
56/44
55/45
55/45
88/12
78/22
77/23
77/23
78/22
Acknowledgements
The work was supported by the National Science Foundation of
China (grants 21071116) and Chongqing Scientific Foundation,
P.R. China (CSTC, 2010BB4126).
a Reaction conditions: p-nitrobenzaldehyde (0.25 mmol), cyclohexanone
(0.39 mmol), catalyst 3c (0.025 mmol, 10 mol%), 25 °C, 96 h, 1 mL of
water, TfOH (3.75 × 10−3 mmol). b Isolated yield. c Determined by
chiral HPLC, Daicel Chiralpak AD-H column. d Washed with ethyl
acetate. e Washed with Et3N.
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