A phosphotungstic acid-supported multifunctional organocatalyst containing 9-amino(9-deoxy): Epi -cinchonidine and Br?nsted acid and its application in asymmetric aldol reaction

Article abstract of DOI:10.1039/c6ra08909g

A novel type of supported multifunctional organocatalyst CDNH₂(n)-HPW combined 9-amino(9-deoxy)epi-cinchonidine (CDNH₂) with Br?nsted acid in the backbone of phosphotungstic acid was developed via facile precipitation of sodium tungs

Full text of DOI:10.1039/c6ra08909g

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Phosphotungstic acid-supported multifunctional organocatalyst
containing 9-amino(9-deoxy)epi-cinchonidine and Brønsted acid
and its application in asymmetric aldol reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Ling Lan, Guangxin Xie, Tao Wu, Dandan Feng and Xuebing Ma*
DOI: 10.1039/x0xx00000x
A novel type of supported multifunctional organocatalysts CDNH2(n)–HPW combined 9-amino(9-deoxy)epi-cinchonidine
(CDNH2) with Brønsted acid in the backbone of phosphotungstic acid was developed via facile precipitation of sodium
tungstate with organophosphonic acid. In the aldol addition of cyclohexanone to o, m or p-substituted benzaldehydes
bearing electron-withdrawing substituents (-X and -NO2) afforded the good yields (71–96%) and excellent
stereoselectivities (anti/syn = 94/6–98/2, 87–97 %ee). It was found that the arm length (n) and acid capacity had
significant effects on the cooperative catalysis of CDNH2 and Brøsted acid in aldol reaction. After the completion of aldol
reaction, the catalysts could be readily recovered in quantitative yield by centrifugation and possessed a good reusability
with no significant loss of catalytic performances in the five consecutive asymmetric aldol reactions.
www.rsc.org/
chona alkaloid–derived primary amine has been elusive owing
to the lower catalytic performance compared to homogeneous
counterparts in terms of activity, diastereoselectivity and en-
Introduction
Natural cinchona alkaloid–derived primary amines, employed
as homogeneous organocatalysts in asymmetric aldol,1 Micha-
el,2 α-benzoyloxylation,3 α-alkylation,4 cycloaddition and cas-
antioselectivity. Therefore, from the viewpoint of green chemi-
stry, an efficient and recoverable supported organocatalyst po-
ssessing the multifunctionalities of enamine or iminium active-
tion and acid catalysis is a compulsory task to meet the challe-
nge of green chemistry.
5
cade reaction,6 continued to act as powerful star organocatal-
ysts able to effectively promote the chemical transformations
of carbonyl compounds via enamine or iminium activation. As
far as we know, to improve the economics and sustainability,
the commonly used strategy by means of the heterogenization
of these successful homogeneous organocatalysts by the cova-
lent linkage to organic polymer,7 inorganic material 8 and mag-
netic nanoparticle was well developed in the recent years.10
9
Another effective strategy, known as one-phase catalysis and
two-phase separation, provided an ideal and practical techni-
que to combine the advantages of both homogeneous and he-
terogeneous catalysis, avoiding mass transfer limitation result-
ed from heterogeneous catalytic system.11 However, it is wor-
thwhile to note that most of above-mentioned reactions, no
matter whether in homogeneous or heterogeneous catalytic
system, required cooperative catalysis of primary amine and
various Brønsted acids with different acid strengths such as 2-
nitrobenzoic acid or HFA (10–40 mol%) as a co-catalyst to
achieve a satisfactory catalytic performance.12 Nevertheless,
the simultaneous heterogenization of Brønsted acid and cin-
Scheme 1 Synthesis of phosphotungstic acid-supported multifunctional CDNH2(n)
–HPW possessing enamine activation and acid catalysis
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of
Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715,
P. R. China. E-mail: zcj123@swu.edu.cn; Fax: +86 2368253237; Tel: +86 23
68253237.
Electronic Supplementary Information (ESI) available: TGA, TEM and N2 adsorption-
desorption isotherm of catalysts, 1H, 13C NMR and HPLC spectra of intermediates
and products. See DOI: 10.1039/x0xx00000x
In the present study, based on solid acid catalytic property
of phosphotungstic acid displayed especially in esterification,13
15
condensation,14 alkylation and alcoholysis,16 a novel type of
phosphotungstic acid-supported multifunctional 9-amino(9-de-
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oxy)epi-cinchonidine organocatalyst possessing enamine activ- 1031 and 983, 933 and 902, 832, 715 cm-1 (Fig. 1c, d and e). It
ation and acid catalysis was developed by the facile direct pre- was worthwhile to note that the vibrations of P–O in central
cipitation of sodium tungstate with phosphonic acids with diff- tetrahedron and terminal W=O bonds split into two bands res-
erent arm lengths (n = 2, 4 and 6) instead of H3PO4 at various pectively at 1031 and 983, 933 and 902 cm-1, possibly due to
added P/W molar ratios from 0.5 to 4 (Scheme 1). As expected, the formation of central P–O–W and terminal W=O possessing
in the case of the as-synthesized multifunctional organocataly- diverse chemical environments upon the direct precipitation of
sts CDNH2(n)–HPW, Brønsted acid and primary amine Na2WO4 with CDNH2(n4)–PO3H2 at the added P/W molar ratios
CDNH2(n) attached to the same backbone of phosphotungstic equal to or greater than 1. However, when the added molar
acid exhi-bited the concerted catalysis with high catalytic ratio of P/W was 0.5, CDNH2(n4)–HPW/0.5 obtained in the pH
performances and good reusability in aqueous asymmetric = 3–4 range by means of hydrochloric acid showed the similar
aldol addition of different cyclic ketones to various aromatic four characteristic peaks without split phenomenon at 1031,
aldehydes.
933, 832, 715 cm-1 (Fig. 1b) as neat H3PW12O40, which implied
that CDNH2(n4)–HPW/0.5 was more like the similar Keggin str-
ucture of H3PW12O40. Moreover, the C–H stretching vibrations
of –CH2– and –CH– moieties in CDNH2 in the 2800–2980 cm-1
centered at 2930 cm-1 and characteristic phenyl ring in the
1620–1450 cm-1 range clearly corroborated the covalent atta-
Results and discussion
Preparation of phosphotungstic acid-supported CDNH2(n)–HPW
It was well known that 12-tungstophosphoric acid, H3PW12O40
(HPW), was readily prepared through the prolonged reflux of
Na2WO4/H3PO4-mixed solution, acidification by HCl solution
and then extraction with ethyl ether.17 After the replacement
of organic CDNH2(n)–PO3H2 instead of inorganic H3PO4, CDNH2
(n)–HPW/1, CDNH2(n)–HPW/2 and CDNH2(n)–HPW/4 could be
directly precipitated out upon the added molar ratio of CDNH2
(n)–PO3H2/Na2WO4 above 1. However, at the same procedure,
, no CDNH2(n4)–HPW/0.5 was directly precipitated out from
reaction medium upon the added molar ratio of CDNH2(n4)–
PO3H2/Na2WO4 below 1. To our delight, according to the syn-
thetic procedure of 12-tungstophosphoric acid, CDNH2(n4)–
HPW/0.5 could immediately precipitate out from solution after
the medium pH was adjusted to 3–4 using HCl solution. In
order to have a more comprehensive comparison of results,
the effect of ageing the solids with added HCl in the prepara-
tion of CDNH2(n4)–HPW/1 and CDNH2(n4)–HPW/2 as examples
was further investigated. Unfortunately, there was no marked
difference in chemical composition and catalytic performance
in aldol addition. Therefore, we did not set out the further inv-
estigation into the effect of HCl addition.
chment of CDNH2–PO3H2 to the hybrid backbone (see ESI†).
Fig.1 IR spectra of CDNH2(n4)–PO3H2 (a), CDNH2(n4)–HPW/0.5 (b), CDNH2 (n4)–
HPW/1 (c), CDNH2 (n4)–HPW/2 and CDNH2 (n4)–HPW/4.
Structure of phosphotungstic acid-supported CDNH2(n)–HPW
The X-ray powder diffraction patterns of neat H3PW12O40
displayed a set of well-resolved sharp diffraction peaks featur-
ed for the secondary crystal structure.18 However, all these ch-
aracteristic sharp peaks disappeared and several broad diffra-
ction peaks were observed in the case of CDNH2(n4)–HPW/2
and CDNH2(n4)–HPW/0.5 (Fig. 2), which indicated their non-
crystal structure definitely different from the crystal Keggin
structure of neat H3PW12O40. Compared with the character-
Unfortunately, our endeavors to cultivate single crystal to elu-
cidate the real structure of CDNH2(n)–HPW were unsuccessful,
possibly owing to the flexibility of attached bulky CDNH2(n)–
PO3H2. Then, we did our endeavors to clarify the possible stru-
cture and true chemical composition of phosphotungstic acid-
supported multifunctional CDNH2(n)–HPW by means of FT-IR,
XRD, DTA, ICP and elemental analysis.
It was well known that the IR spectra of neat H3PW12O40
had four characteristic IR bands approximately at 1080 (α–
peak, P–O in the central tetrahedron), 980 (β–peak, terminal
ristics of the Keggin unit with a sharp peak at about 6−10 ° for
pristine H3PW12O40, both CDNH2(n4)–HPW/2 and CDNH2(n4)–
HPW /0.5 presented the most intense and broad peak in the
1
W=O), 896 and 806 cm− (γ– and δ–peaks, asymmetric W–O–
range of 2
anions in the hybrids, in accordance with the above-mentioned
IR spectra. Furthermore, the broad diffraction peaks in the 2
θ = 5–12 °, stating clearly the existence of Keggin
W) associated with pure Keggin structure18 and of M–O–P (M =
metal). Furthermore, the free H–O–P stretching vibration in
metal phosphonate was generally in the range of 1000–1100
cm-1.19 Although the characteristic absorption peaks of CDNH2
(n)–HPW red-shifted about 50–80 cm-1, the hybrid CDNH2(n4)–
HPW/1, CDNH2(n4)–HPW/2 and CDNH2(n4)–HPW/4 series had
the similar four characteristic absorption peaks, respectively at
θ
= 15–40 ° and 45–70 ° ranges were also observed, suggesting
that CDNH2(n4)–HPW/2 and CDNH2(n4)–HPW/0.5 existed in
amorphous states without long-range order.20 This amorphous
structure was in agreement with the HRTEM images for CDNH2
(n4)–HPW /0.5 (Fig. 3). The TEM image showed the irregular
2 | J. Name., 2012, 00, 1-3
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particles of CDNH2(n4)–HPW/0.5 with the diameter of appro- (n)–HPW was constructed by the replacement of the organic
ximate 0.3–0.5 um, whereas some irregular lattice fringes in phosphonic acid in CDNH2(n)–PO3H2 instead of inorganic pho-
-
different directions at the distances of 0.2–0.5 nm in the high sphate H3PO4 as the source of P to coordinate with a WO6
resolution TEM image could be observed.
octahedra unit in parent phosphotungstic acid, and then the
generated phosphotungstic acid was used as an inhert matrix
to support organocatalyst CDNH2.
Chemical composition of phosphotungstic acid-supported
CDNH2(n)–HPW
After 0.1000 g of CDNH2(n4)–HPW/0.5 was calcined for 4 h at
800 °C, the resulting solid was dissolved in 5.0 mL of HNO3 and
15 mL of DI water, pretreated via microwave digestion and
then volumed to 100 mL. The content of wolfram in the mix-
ture was detected by inductively coupled plasma atomic emis-
sion spectrometry (ICP–AES). The wolfram percent in CDNH2
(n4)–HPW/0.5 was calculated to be 61.52%. In addition, the
content of nitrogen (1.24%) in CDNH2(n4)–HPW/0.5, which
was thrice the content of phosphorus in the same molecule,
was detected by elemental analysis. Based on these results,
the molar ratio of wolfram to phosphorus was calculated to be
11.2, which was very close to that of neat H3PW12O40. Mean-
while, based to the nitrogen content, the loading capacity of
CDNH2 in CDNH2(n4)–HPW/0.5 was also calculated to be 0.30
mmol g-1. According to the same method, the molar ratios of
W/P and loading capacities of CDNH2 in CDNH2(n4)–HPW/1,
CDNH2(n4)–HPW/2 and CDNH2(n4)–HPW/4 via direct precipi-
tation were determined to be 10.0 and 0.33 mmol g-1, 9.8 and
0.34 mmol g-1, 10.4 and 0.32 mmol g-1, respectively. Further-
more, with the decrease in the arm length (n) of CDNH2(n)–
PO3H2 from 6 to 2, the W/P molar ratio in CDNH2(n2)–HPW/2
decreased to 8.8, and the loading capacity of CDNH2 increased
to 0.38 mmol g-1. All the data was listed in Table 1. It was noti-
ceable that the slightly lower W/P molar ratios (8.8–11.3) in
CDNH2(n)–HPW than that of neat H3PW12O40 elucidated the
possible coordination of CDNH2(n)–PO3H2 with MO6- octahedra
in the synthetic process of these hybrids.
Fig.2 Powder X-ray diffraction patterns of CDNH2 (n4)–HPW/2 and CDNH2(n4) –
HPW/0.5.
Table 1 The chemical compositions of as-synthesized samples CDNH2(n)–HPW
Cat.
W(wt%)a CDNH2(n)–PO3H2 Hydration water
Molar ratio
(W/P)e
11.2
b
(%/mmol g-1
15.5/0.30
17.4/0.33
17.7/0.34
16.7/0.32
18.6/0.38
18.0/0.33
)
(%c/% d)
CDNH2(n4)–HPW/0.5
CDNH2(n4)–HPW/1
CDNH2(n4)–HPW/2
CDNH2(n4)–HPW/4
CDNH2(n2)–HPW/2
CDNH2(n6)–HPW/2
61.52
60.92
60.98
61.12
61.03
60.95
2.9/3.8
3.2/4.2
3.1/4.4
2.8/4.3
3.0/5.3
3.1/4.7
10.0
9.8
10.4
8.8
10.2
a Determined by ICP. b Determined by elemental analysis. c Determined automatic Karl
Fischer moisture analyzer. d Determined by TGA below 120 °C. e Calculated according to
the data of ICP and elemental analysis.
Fig.3 The TEM and HRTEM images of phosphotungstic acid-supported organo-
catalyst CDNH2(n4)–HPW/0.5.
Furthermore, no precipitate was obtained upon the direct
mixing of sodium tungstate with 9-amino(9-deoxy)epi-cincho-
nidine, which implied that the amino group in CDNH2(n) with-
out phosphonic acid (-PO3H2) could not react sodium tungstate
to afford the analogue of phosphotungstic acid. Combined the
synthetic principle of phosphotungstic acid and the above-me-
ntioned structural information obtained from FT-IR and XRD,
the possible structure of the organic-inorganic hybrids CDNH2
Thermal analysis was performed to monitor the decompo-
sition profiles of CDNH2(n)–HPW. Using CDNH2(n4)–HPW/0.5
as an example, its TG, DTG and DSC curves were depicted in
Fig. 4 and the others were shown in ESI†. The hydration water
in CDNH2(n4)–HPW/0.5, which was verified by IR spectra with
a broad and strong O–H stretching vibration in the 3200–3600
cm-1 range, was detected by automatic Karl Fischer moisture
analyzer to be 2.9% of total weight. Compared with the data of
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weight loss (3.8%) by TG below 120 °C, it was found that the
hydration water in CDNH2(n4)–HPW/0.5 obtained by Karl Fis-
cher method had a relatively lower value with the 0.9% decre-
ment, possibly owing to the effect of porous structure of back-
bone. The protonized water and structural water lost in the
120–800 °C range,21 companied by the weight loss of organic
moiety in CDNH2(n4)–PO3H2 with the exothermic peaks at 305,
432 and 600 °C due to the decomposition of CDNH2(n4)–HPW
Table 2 The surface areas, average pore diameters and pore volumes of as-synthesized
samplesa
Cat.
s
urface areab
Average pore diameterc
Pore volumec
(m2 g-1
)
(nm)
6.9
(×10-3 cm3 g-1
9.7
)
CDNH2(n4)–HPW/0.5
CDNH2(n4)–HPW/1
CDNH2(n4)–HPW/2
CDNH2(n4)–HPW/4
5.6
13.8
18.2
22.1
23.5
16.5
8.4
8.0
23.8
15.2
26.8
68.7
108.2
84.2
/0.5 and Keggin type anion. Based on the content of nitrogen CDNH2(n2)–HPW/2
CDNH2(n6)–HPW/2
157.3
42.8
(1.24%), the weight loss of organic moiety in CDNH2(n4)–HPW
/0.5 was calculated to be 13.1%, and then the total weight loss
a The samples were degassed at 105 °C for 5 h. b Based on the multipoint BET method. c
of protonized water and structural water was summed to be
9.7%. On the whole, the chemical compositions of as-synthe-
sized CDNH2(n)–HPW were approximate to each other (Table
1), although they had a big difference in the added P/W molar
ratios from 0.5 to 4.0.
Based on the desorption data using BJH method.
Fig.4 The TG, DTG and DSC curves of supported multifunctional CDNH2(n4)–
HPW/0.5.
Porous structure of CDNH2(n)–HPW
The N2 adsorption–desorption isotherms of all samples, obtai-
ned at the temperature of 77 K, were shown in ESI†. Phospho-
tungstic acid-supported organocatalysts CDNH2(n4)–HPW/4,
CDNH2(n4)–HPW/2, CDNH2(n2)–HPW/2 and CDNH2 (n6)–HPW
/2, prepared at the added P/W molar ratios equal to or greater
Fig.5 The pore size distributions (PSDs) of CDNH2(n2)–HPW/2 (a), CDNH2(n6)–
HPW/2 (b), CDNH2(n4)–HPW/4 (c), CDNH2(n4)–HPW/2 (d), CDNH2(n4)–HPW/1 (e)
and CDNH2(n4)–HPW/0.5 (f).
than 2, exhibited the classic definition of a Type
Ⅲ isotherm.
Upon the decrease in the added P/W molar ratio below 2,
Acid capacity and acid strength
CDNH2(n4)–HPW/1 and CDNH2(n4)–HPW/0.5 showed a step-
Generally, NH3–TPD was employed to reveal acidic site nature
of solid acid.23 Unfortunately, owing to the disturbance of wei-
ght loss resulted from the organic moieties in CDNH2(n)–HPW
in the high 200–600 °C temperature range, the acidic site natu-
re was incapable of being investigated by terms of NH3–TPD
technique. Herein, the acid capacities of CDNH2(n)–HPW were
determined by simple and convenient acid-base titration, and
the acid-base titration curves by NaOH aqueous solution (0.05
mol L-1) were presented in Fig. 6 and Table S1 (ESI†). It was
found that synthetic method had a great influence on the acid
capacities of CDNH2(n)–HPW. Compared with CDNH2(n4)–HPW
/4 (45.0 mmol g-1), CDNH2(n4)–HPW/2 (40.5 mmol g-1) and
CDNH2(n4)–HPW/1 (12.0 mmol g-1) prepared via direct precipi-
tation at the added P/W molar ratio equal to or greater than 1,
the highest acid capacity (61.5 mmol g-1) was observed for
CDNH2(n4)–HPW/0.5 obtained at the lowest added P/W molar
height Type
Ⅵ isotherm, which was possibly related to the un-
iform porous structure.22 The BET-specific surface areas, ave-
rage pore diameters and pore volumes of all samples were list-
ed in Table 2. The overall trend along with the increased molar
ratio of added P/W was towards the enhanced BET-specific
surface areas, average pore diameters and pore volumes.
Especially, when the added P/W molar ratios decreased from
4.0 to 0.5, the pore size distributions, obtained from BJH algo-
rithm on adsorption isotherm, tended from the uneven micro
mesoporous structures to the regular mesopores. From Fig. 5,
it was found that CDNH2 (n4)–HPW/0.5 and CDNH2(n4)–HPW/1
with the relatively low BET-specific surface areas, average pore
diameters and pore volumes possessed the five regular meso-
pores at 1.8, 2.9, 4.5, 6.8 and 15.0 nm, and the other adsorp-
tion Dv values were close to zero.
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ratio in the pH = 3–4 ranges assisted by HCl, although CDNH2 more, owing to the highest acid capacity (61.5 mmol g-1) and
(n4)–HPW/0.5 possessed the lowest surface area, average po- regular mesopore structure (Fig. 5), CDNH2(n4)–HPW/0.5 affo-
re diameter and pore volume. Moreover, the arm lengths (n) rded the excellent stereoselectivity (anti/syn = 93/7, 96 %ee
of attached CDNH2(n)–PO3H2 had no impact on the acid capa- anti, entry 1) in 96 % yield. Unfortunately, along with the decr-
city. It was observed that CDNH2(n2)–HPW/2 (39.5 mmol g-1), ease of acid capacity, the more low yields and stereoselectivi-
CDNH2(n4)–HPW/2 (40.5 mmol g-1) and CDNH2(n6)–HPW/2 ties were observed for CDNH2(n4)–HPW prepared via direct
(39.0 mmol g-1) exhibited the identical level of acid capacity.
precipitation at the added P/W molar ratio equal to or greater
than 1 (entries 2–4).
Table 3 The asymmetric aldol addition of cyclohexanone to p-nitrobenzaldehyde
catalyzed by various multifunctional CDNH2(n)–HPW a
Entry
Cat.
Yield (%)b
Dr (anti/syn)c
93/7
%ee (anti)d
1
2
3
4
5
6
CDNH2(n4)–HPW/0.5
CDNH2(n4)–HPW/1
CDNH2(n4)–HPW/2
CDNH2(n4)–HPW/4
CDNH2(n2)–HPW/2
CDNH2(n6)–HPW/2
96
93
95
93
90
81
96
95
94
94
92
91
89/11
86/14
86/14
85/15
84/16
a
Reaction conditions: cat. (40 mg, 0.012–0.014 mmol ), cyclohexanone (0.5 mL, 4.8 g,
49.0 mmol), p-nitrobenzaldehyde (30.2 mg, 0.2 mmol), water (0.5 mL), 15 °C, 72 h.
bIsolated yield. cDetermined by 1H NMR. d Determined by chiral HPLC.
Fig.6 The acid-base titration curves of CDNH2(n2)–HPW/2 (a), CDNH2(n6)–HPW/2
(b), CDNH2(n4)–HPW/0.5 (c), CDNH2(n4)–HPW/1 (d), CDNH2(n4)–HPW/2 (e) and
CDNH2(n4)–HPW/4 by aqueous NaOH solution (0.05 mol L-1).
Using CDNH2(n4)–HPW/0.5 with the best catalytic perform-
ance as a example, the optimized protocol was expanded to
aldol reaction of cyclohexanone and hydroxyacetone to a wide
variety of aldehydes. From Table 4, o, m and p-substituted
benzaldehydes bearing electron-withdrawing substituents (-X
and -NO2) afforded the good yields (71–96%) and excellent ste-
reoselectivities (anti/syn = 98–94:2–6, 97–87 %ee, entries 1–3
and 7–9). For m and p-CN substituted benzaldehydes, the ex-
cellent enantioselectivities and moderate diasteroselectivities
were achieved in good yields (entries 5 and 6). For some un-
fathomable reason, no aldol adduct was obtained in the aldol
addition of cyclohexanone to o-CN substituted benzaldehyde
(entry 4). Unfortunately, the aldol reaction is dramatically de-
pendent on the electronic effect of the substituent at the aro-
matic ring like its homogeneous catalysis. The substrates with
electron-donating o-, m- and p-CH3 and OCH3 groups at the
aromatic ring gave the less unsatisfactory yields (0–59%, en-
tries 10–15), which was attributed to not enough acid strength
and capacity for CDNH2 (n4)–HPW/0.5 to favorably catalyze the
aldol addition. Furaldehyde was also employed in the aldol re-
action which showed the high yield (92%) and enantioselecti-
vity far from satisfactory (69 %ee) (entry 16). Furthermore, we
tested the aldol reaction of hydroxyacetone with benzaldehyd-
es bearing electron-withdrawing o, m or p-nitro substituent
and 2, 4-dinitro multiple substituents. All of them afforded the
The acid strengths of phosphotungstic acid-supported org-
anocatalysts CDNH2(n)–HPW were examined by Hammett indi-
cator method (Table S2, ESI†). Probably owing to the more like
Keggin structure of CDNH2(n4)–HPW/0.5 verified by the IR spe-
ctra (Fig. 1), it was found that CDNH2(n4)–HPW/0.5 possessed
the strongest acid strength (H0 ≤ 0.8). Among the as-synthesiz-
ed multifunctional organocatalysts CDNH2(n)–HPW, CDNH2(n4)
–HPW/1 had the weakest acid strength (H0 ≤ 3.86). Unfortuna-
tely, only based on the structural information obtained from IR
and XRD, the reason can hardly be unconvincingly explained.
Asymmetric aldol addition
To evaluate the multifunctional catalytic performance and reu-
sability of CDNH2(n)–HPW simultaneously containing attached
organocatalyst CDNH2(n) and Brøsted acid, the asymmetric
aldol addition of cyclohexanone to benzaldehydes was select-
ed as a model reaction at 15 °C. Generally, aldol reaction, cata-
lyzed by 9-amino(9-deoxy)epi-cinchona alkaloid, needs an add-
itional acid co-catalyst such as F3CSO3H to achieve a desired
excellent catalytic performance. Excitedly, owing to the strong
acidity of CDNH2(n)–HPW resulted from the backbone of phos-
photungstic acid verified by Hammett indicator, it was highli-
ghted that the aldol reaction smoothly carried out without the
addition of an external acidic additive.
high yields (89
–
syn/anti = 72 81/19
95%), but unfortunately, only the moderate
28 and moderate to good 77 91 %ee ob-
From Table 3, it was found that the arm length (n) and acid
capacity of CDNH2(n)–HPW had a significant effect on the co-
operative catalysis of 9-amino(9-deoxy)epi-cinchonidine and
Brøsted acid. The optimal arm length (n) was n = 4 in terms of
the excellent yield (95%) and good stereoselectivity (anti/syn =
86/14, 94 %ee anti, entries 3, 5 and 6). Notably, when the arm
length increased to n = 6, the cooperative catalysis between 9-
amino(9-de-oxy)epi-cinchonidine and Brøsted acid was getting
weaker and resulted in the unsatisfactory catalytic performan-
ces (81% yield, anti/syn = 86/14, 91 %ee anti, entry 6). Further-
–
–
–
tained for benzaldehydes bearing o, m or p-nitro substituent.
To our delight, the excellent stereoselectivities (syn/anti = 94/
6 and 95 %ee) were achieved for benzaldehyde bearing 2, 4-
dinitro substituents.
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Journal Name
16
17
92
95
86/14
69
88
Table 4 The asymmetric aldol addition of cyclohexanone and hydroxyacetone to various
aldehydes a
Entry Main product
1
Yield (%)b
83
Dr (anti/syn)c
% eed
95
98/2
19/81
2
3
90
96
93/7
93/7
96
96
18
19
90
89
30/70
28/72
77
91
4
5
-
-
-
20
94
6/94
95
80
84/16
95
6
7
76
74
85/15
98/2
98
97
a Reaction conditions: CDNH2(n4)–HPW/0.5 (40 mg, 0.012 mmol, 6.0 mol%),
cyclohexanone (0.5 mL, 4.8 g, 49.0 mmol), various benzaldehyde derivatives (0.2
mmol), water (0.5 mL), 15 °C, 72 h. bIsolated yield. cDetermined by 1H NMR. d
Determined by chiral HPLC.
On the whole, compared to the ever-reported heterogene-
ous catalytic aldol additions, CDNH2(n4)–HPW/0.5 without the
assistance of additional Brøsted acid afforded the higher stere-
oselectivity than the other 9-amino(9-deoxy)epi-cinchona alka-
loid supported on inorganic backbones suah as zirconium pho-
8
9
71
75
95/5
94/6
94
87
8a
sphonate and Fe3O4 MNPs,9 especially in the aldol addition
of cyclohexanone to o, m and p-substituted benzaldehydes
bearing electron-withdrawing (-X, -NO2 and -CN) substituents
and hydroxyacetone to 2, 4-dinitrobenzaldehyde.
Reusability of phosphotungstic acid-supported CDNH2(n4)–
HPW/0.5
10
35
85/15
97
After the completion of aldol addition of cyclohexanone to o-
nitrobenzaldehyde, the reaction mixture was centrifuged, de-
canted, and the recovered catalyst CDNH2(n4)–HPW/0.5 was
reused directly for the next run after being washed with ethyl
acetate (2.0 mL × 3). To our delight, it was found that the con-
stant excellent stereoselectivity (96 %ee and anti/syn = 93/7)
and yield (96%) were maintained in five consecutive cycles.
Even at the eighth run, there was only a slight drop in the yield
(96% → 94%), diastereoselectivity (anti/syn = 93/7 → 89/11)
and enantioselectivity (96 %ee → 94%). After the completion
of aldol reaction, the aqueous phase was evaporated, pretreat-
ed via microwave digestion in HNO3 (1.0 mL) and DI water (3.0
mL) and volumed to 10 mL. The content of wolfram in the
resulting solution was checked by ICP-AES. It was found that
there was no leaching of wolfram during aldol reaction. How-
ever, after being reused seven times, the sulphur content in
CDNH2(n4)–HPW/0.5 was found to decrease from 1.91% to
1.85% detected by elemental analysis, which elucidated that
3.1% weight loss of CDNH2(n4) resulted in the decrease of
CDNH2(n4)–HPW/0.5 in catalytic performances.
11
12
59
20
82/18
91/9
95
88
13
19
78/22
90
14
15
36
-
86/14
76
-
-
6 | J. Name., 2012, 00, 1-3
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Chiralpak chiral OD-H column (4.6 mm × 25 cm), eluting with n-
hexane/isopropanol (95/5) at a flow rate of 0.5 mL min-1 under
20 °C.
Conclusions
In summary, we had developed a novel type of supported mul-
tifunctional organocatalysts containing 9-amino(9-deoxy)epi-
cinchonidine and Brønsted acid on the backbone of phospho-
tungstic acid via facile precipitation of sodium tungstate with
organophosphonic acid for the first time, and successfully app-
lied these supported organocatalysts in the asymmetric aldol
addition of cyclohexanone and hydroxyacetone to various aro-
matic aldehydes bearing electron-withdrawing substituents
with good to excellent catalytic performances. From the view-
point of green chemistry, these phosphotungstic acid-support-
ed organocatalysts achieved the simultaneous green circula-
tion of organocatalyst and Brønsted acid and possessed a good
reusability with no significant loss of catalytic performances in
the five consecutive asymmetric aldol addition. Furthermore,
the authentic structure of CDNH2(n)–HPW and their applica-
tions for other challenging enantioselective cooperative catal-
ysis is under the further investigation.
Preparation of various supported organocatalysts CDNH2(n)–HPW
CDNH2(n4)–PO3H2 (n = 4) (30.5 mg, 0.05 mmol) in DI water (0.5
mL) was added 0.5 mL of aqueous sodium tungstate solution
(29.4 mg, 0.1 mmol), and mixed under stirring at room temper-
ature to afford a transparent solution. The medium pH was ad-
justed to 3–4 using hydrochloric acid (36.5–38.0%), and light
yellow solid precipitated immediately. After being aged for an-
other 6 h, the resulting precipitate was filtered, washed with
DI water (2 mL × 3) and dried under vacuum at 50 °C to afford
phosphotungstic acid-supported multifunctional organocataly-
st, donated as CDNH2 (n4)–HPW/0.5 (48 mg, 81%). Found C
8.86, H 1.23, N 1.24, S 1.91 by elemental analysis and W 61.52
by ICP-AES for CDNH2(n4)–HPW/0.5.
According to the same above-mentioned procedure, when
the added molar ratios of CDNH2(n4)–PO3H2 to sodium tungst-
ate equalled to 1, 2 and 4, corresponding supported multifunc-
tional organocatalysts CDNH2(n4)–HPW/1 (27 mg, 45%),
CDNH2(n4)–HPW/2 (30 mg, 50%) and CDNH2(n4)–HPW/4 (34
mg, 57%) could precipitated out directly in the absence of hy-
drochloric acid (36.5–38.0%). Found C 10.01, H 1.26, N 1.40, S
2.14 by elemental analysis and W 60.92 by ICP-AES for
CDNH2(n4)–HPW/1; found C 10.14, H 1.30, N 1.42, S 2.18 by
elemental analysis and W 60.98 by ICP-AES for CDNH2(n4)–
HPW/2, and found C 9.58, H 1.27, N 1.34, S 2.06 by elemental
analysis and W 61.12 by ICP-AES for CDNH2(n4)–HPW/4.
Furthermore, CDNH2(n)–PO3H2 with the different arm leng-
ths (n = 2 and 6) were used instead of CDNH2(n4)–PO3H2 (n = 4)
to afford CDNH2(n2)–HPW/2 (28 mg, 47%) and CDNH2(n6)–
HPW/2 (39 mg, 65%) according to the same procedure as
CDNH2(n4)–HPW/2. Found C 12.20, H 1.52, N 1.58, S 2.43 by
elemental analysis and W 61.03 by ICP-AES for CDNH2(n2)–
HPW/2, and found C 10.57, H 1.39, N 1.37, S 2.11 by elemental
analysis and W 60.95 by ICP-AES for CDNH2(n6)–HPW/2.
Determination of acid capacity
Experimental
Chemicals
All the chemicals including hydrochloric acid (36.5–38.0%) and
sodium tungstate dehydrate (Na2WO4·2H2O, ≥ 99.0%) were
purchased and used without any further purification. Phospho-
nic acids CDNH2(n)–PO3H2 (n = 2, 4 and 6) were synthesized by
24
the click reaction of 9-amino(9-deoxy)epi-cinchonidine with
HS(CH2)2S(CH2)nPO(OC2H5)2 and subsequent hydrolysis of ethyl
phoshonate according to the references.8a, 9
Characterization
1H and 13C NMR spectra were conducted using a Bruker av-600
NMR instrument, in which all chemical shifts were reported
down-field in ppm relative to the hydrogen and carbon resona-
nces of TMS. FT-IR spectroscopy was performed on a Perkin-
Elmer model GX spectrometer using KBr pellet. Thermogravi-
metry-differential thermal analysis was recorded on SBTQ600
thermal analyzer at a heating rate of 10 °C min−1 from 40 °C to
800 °C using N2 as a protective gas (100 mL min−1). Elemental
analysis was obtained using a vario Micro cube elemental ana-
lyzer. The morphology was observed by Tecnai G2 F20 transmi-
ssion electron microscope, operated at 200 kV. X–ray powder
diffraction patterns were detected on an XRD–7000 S/L instru-
ment: Cu-Kα radiation, X–ray tube settings of 40 kV/30 mA and
In 100 mL round-bottom flask, the sample (100 mg) was imme-
rsed in 10 wt% aqueous sodium chloride (50 mL), well-dispers-
ed under sonic radiation for 30 min, and the medium pH was
monitored by a pH meter till pH was constant (about 24 h).
The acid content in the resulting solution was determined by
acid-base titration method using NaOH solution (0.05 mol L-1).
General procedure for asymmetric aldol reaction
a step size of 2° min−1 in the 2
θ range of 5–70 °. N2 adsorption–
In a 25 mL microreactor, CDNH2(n4)–HPW/0.5 (40 mg, 0.012
mmol of CDNH2(n4) ), DI water (0.5 mL) and cyclohexanone
(0.5 mL) were well mixed at 15 °C for about 15 min. Subsequ-
ently, p-nitrobenzaldehyde (30.2 mg, 0.2 mmol) was added,
and the resulting mixture was allowed to react at 15 °C for 48–
72 h. The reaction process was monitored by TLC. After the co-
mpletion of the reaction, CDNH2 (n4)–HPW/0.5 was recovered
by centrifugal separation, and the centrifugate was extracted
with ethyl acetate (4 mL × 3). The combined organic phases
were dried over anhydrous Na2SO4 and evaporated under re-
duced pressure to afford a crude product, which was purified
by flash column chromatography and eluted with petroleum
desorption isotherm was carried out at 77.4 K using an Auto-
sorb–1 apparatus (Quantachrome), in which the sample was
degassed at 120 °C for 12 h before measurement and specific
surface area and pore diameter were calculated by a BET me-
thod and BJH model, respectively. The water content in sample
was detected by means of MA-1 automatic Karl Fischer moi-
sture analyzer. The anti/syn ratios were determined by peak
area ratios of syn- and anti-CHOH protons, respectively at δ
1
5.3–5.9 ppm and δ 4.7–5.4 ppm in H NMR (see ESI†), and the
enantiomeric excess (%ee) was determined by Agilent LC-1200
HPLC with a 220 nm or 254 nm UV-vis detector using Daicel
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Zhang, Org. Biomol. Chem., 2014,12, 9101; d) H. Zhao, Y.
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Table of contents entry
Novel phosphotungstic acid-supported multifunctional organocatalyst containing 9-amino(9-
deoxy)epi-cinchonidine and Brønsted acid was developed through facile precipitation for the first
time and afforded aldol adducts in excellent catalytic performance with good reusability.