Accepted Manuscript Synthesis of two β- cyclodextrin derivatives containing a vinyl group Yong-Fu Li, Yi-Ming Ha, Qin Guo, Qing-Peng Li PII: DOI: Reference:
S0008-6215(14)00428-5 http://dx.doi.org/10.1016/j.carres.2014.11.012 CAR 6894
To appear in:
Carbohydrate Research
Received Date: Revised Date: Accepted Date:
21 July 2014 28 October 2014 17 November 2014
Please cite this article as: Li, Y-F., Ha, Y-M., Guo, Q., Li, Q-P., Synthesis of two β- cyclodextrin derivatives containing a vinyl group, Carbohydrate Research (2014), doi: http://dx.doi.org/10.1016/j.carres.2014.11.012
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Synthesis of two β- cyclodextrin derivatives containing a vinyl group Yong-Fu Li a,b, Yi-Ming HA* a,b，Qin-Guo a,b，Qing-Peng Li a,b a
Institute of Agro-Products Processing Science and Technology, Chinese Academy of
Agricultural Sciences, 100193 Beijing, China. b
Key Opening Laboratory of Agricultural Products Processing and Quality Control,
Ministry of Agriculture, Beijing 100193, China.
* To whom correspondence should be addressed:
The Institute of Agro-Products
Processing Science and Technology, Chinese Academy of Agricultural Sciences, 100193 Beijing, PR China. Tel.: +86 010 62815972; Fax: +86 010 62815972. Email: [email protected]
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Abstract 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
β-CD maleate (CDM) and β-CD itaconate (CDI) were prepared by esterification of β-cyclodextrin (β-CD) with maleic acid and itaconic acid using phosphate as a catalyst in a semi-dry process. The esterification of β-CD was carried out using [Itaconic acid ] or [Maleic acid ] 4 mol/mol of CD; M/L ratio 1:0.6; temperature 110 ℃ ; [4-methoxyphenol] 2.5% amount of acid; reaction time 3.5h. The esterification rate of CDM and CDI are 70.38% and 21.02%, respectively. We found that CDM and CDI were both monoesters. Here, we also established a new evaluation method for the rate of esterification.
Keywords: cyclodextrin; vinyl group; esterification; double bond content.
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1. Introduction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
β-cyclodextrin (β-CD) is a water-soluble cyclic oligosaccharide composed of seven
D-glucose
units linked by α-1,4-glycosidic bonds (Villalonga et al., 2007;
Buschmann et al., 2001). The geometry of β-CD results in a hydrophobic inner cavity with a depth of 7.8 Å and an internal diameter of 6.5 Å (Prabaharan et al., 2006). Hydrophobic, unstable or volatile substances can fit into this hydrophobic cavity to form supramolecular inclusion complexes that have been served as models systems for studies on the molecular mechanisms of microencapsulation (Indra et al., 2000, Szejtli 1982, Szejtli 1998). β-CD can form inclusion complexes in its inner cavity and has several favorable physicochemical and biological properties. However, the presence of intramolecular hydrogen bonding between its C2 and C3 hydroxyl groups decreases its solubility in water (1.85 g / 100 ml), which limits its applications (Yuan et al., 2006).
Therefore,
investigators have focused on finding ways to increase the solubility of β-CD preparing a variety of β-CD derivatives with different physical and chemical properties. One such derivative links β-CD to a natural biological polysaccharide. The first step for this reaction is the preparation of β-CD vinyl monomer derivatives. Previously, it has been reported that a β-CD itaconate (CDI) vinyl monomer can be prepared using sodium hypophosphite as catalyst (Gaffar et al., 2004). In Gaffer’s study the authors pointed out that CDI is a monoester. Interestingly, we found that CDI is also a monoester. Here, we report the synthesis of another vinyl monomer, β-CD maleate (CDM), and we found that CDM was also a monoester independent of the reaction conditions. In addition, we also established a new evaluation method for 3
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the rate of esterification. 2. Materials and Methods 2.1 Reagents β-cyclodextrin was purchased from China National Pharmaceutical Group Corporation. Before use, add 500g β-CD to 1L hot water (85 °C) and crystallize in 4 °C refrigerator (repeat twice). Then the crystal was dried at 90 °C in an oven for 24 h and stored in a desiccator. Itaconic acid and maleic acid were purchased from Aladdin Industrial Corporation. Sodium phosphite dibasic-5-hydrate (SPD) was purchased from Sigma-Aldrich (USA). KBr, KBrO3, sodium hexametaphosphate (SHMP), sodium dihydrogen phosphate-2-hydrate (MSP), sodium hypophosphite monohydrate (SHP), methylhydroquinone, tert-butylhydroquinone, and 4-methoxyphenol were purhased from China National Pharmaceutical Group Corporation. Monoethyl maleate, diethyl maleate, monoethyl itaconate and diethyl itaconate were purchased from TCI. All reagents were analytically pure unless otherwise noted. 2.2 Synthesis of CDI and CDM CDI and CDM were prepared using the semi-dry reaction method by manually mixing 6.81 g (6 mmol) β-CD with a definite amount of water containing different amounts of itaconic acid (IA, from 6 to 24 mmol) and maleic acid (MA, from 6 to 24 mmol) in the presence or absence of a catalyst (SPD, SHMP, MSP and SHP, from 0.16 to 0.66 mol/mol acid ) and polymerization inhibitors (methylhydroquinone, tert-butylhydroquinone, and 4-methoxyphenol, from 0.5% to 3.5% amount of acid ). The reaction mixture was transferred to a pressure bottle and placed in a circulating 4
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air oven at different reaction temperatures (90-130°C) for 2.5 h. At this point, the reaction mixture were crystallized at 4°C in a refrigerator and the crystals were purified by washing with 95% ethyl alcohol (50ml*4), followed by drying at 60°C in an oven for 24 h. 2.3 NMR spectroscopy Reaction products were characterized using 1H NMR and
13
C spectra using a
Bruker-500 spectrometer at 500MHz. All samples were dissolved in D2O before use. Measurements were done at 25°C. 2.4 Mass spectra Reaction products were characterized by using MALDI-TOF mass spectrometer (Bruker Daltonics Inc. BIFLEX III). 2.5 Sample Characterization FTIR was conducted using a Bruker Tensor37 FT-IR Spectrometer (BRUKER OPTICS, Germany). The diffuse reflectance technique was utilized in the mid-IR (400–4000 cm-1) spectral region. Specifically, the sample was ground with KBr (about 200–400 mg) into a fine powder, placed into the sampling cup, smoothed and compressed into a transparent flake using the tablet machine. At this point, the sample was placed in the light path and the spectrum was obtained. IR spectroscopy measurements were obtained using liquid measurement accessories since monoethyl maleate, diethyl maleate and diethyl itaconate are liquid at room temperature. 2.5 Double bond content The degree of unsaturation of the esterification products was evaluated by 5
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determining the double bond content (DBC), expressed in mequiv./100 g as reported by Wallace & Young (1966).
Dried samples (0.5 g) were added to a stoppered
conical flask and then mixed with 10 ml of frozen KBr/KBrO3 mixture（6.960 g/L KBrO3，30g/L KBr）under the condition of ice fields. At this point 5 ml H2SO4 (2.0 N) was added and the reaction was placed in the dark for 30 minutes. The Br2 released was added to the double bond of the EP samples. Back titration of the excess Br2 was carried out using 10 ml Iodometric titration (20%) for a reaction time of 5 minutes in the dark as (Wallace & Young, 1966). The double bound content (DBC) was calculated by the following equation (1): V V 0.1 100 DBC mequiv. B S 100 g W
(1)
W: weight of the sample (0.5 g); VB: volume of sodium thiosulfate (0.1 N) equivalent to the liberated Br2 in the blank titration (ml); VS: volume of sodium thiosulfate used in the sample titration (ml). 2.6 Esterification rate Mono-ethyl maleate, diethyl maleate and mono-ethyl itaconate were used as standards and their absorbance values at different concentrations was measured using an ultraviolet spectrophotometer at 210nm and 195nm, the wavelengths for maximum absorption for monoethyl malate and diethyl malate respectively. The following standard curve equations were used： Mono-ethyl Maleate (210 nm):
y = 62198x - 0.0009
R² = 0.9999
Mono-ethyl Itaconate (195nm):
y = 90855x + 0.0326
R² = 0.9996
The esterification rate (ER) was calculated as follows (2): 6
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A b V X M W k ER（%） 100% W
(2)
Where α is the coefficient for molecular weight (α= 0.1169); A= samples’ absorbance value; b= intercept of standard curve; K= slope of standard curve; W= sample quality; V= volume of the solution; X= sample dilution multiple; Mw – Sample molecular weight. 2.7 Thermo-gravimetric Analysis (TGA) Thermogravimetric analysis was performed with the Perkin Elmer TG/DTA thermal analyzer and the following experimental conditions:
nitrogen atmosphere
(2.5 ml/min), the heating rate 10 °C / min, scanning temperature range: 45 °C to 450 °C
3. Results and Discussion 3.1 NMR spectra In order to establish a protocol for the synthesis of CDM and determine the influence of temperature on the reaction, we compared the 1H NMR and
13
C NMR
spectra of CDM and β-CD. The synthesis of CDM was monitored by 1H NMR and 13
C spectra. As illustrated in Figure 1, there were H-vinyl chemical shifts at 6.43 ppm
(Fig.1) and
13
C-vinyl chemical shifts at δ 133.63 ppm (Fig.2) respectively as can be
seen in the spectra of CDM. We also found that there is another signal at 170ppm (Fig.2) for the vinyl carbon of carboxylic ester. Interestingly, at temperatures above 110°C there was a tremendous increase in the concentration of the methylene group in the products as seen by the chemical shifts of 1H at 1.25 ppm (Fig.1), 7
13
C at 16.86
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ppm (Fig.2), possibly because that at the higher temperatures the vinyl group of the products reacts with the H2O in the reaction system. This phenomenon could also explain the increase in the concentration of vinyl groups as detected by the consumption of Br2 at temperatures above 110°C. We also found that the signal at 5.5 ppm (Fig.1) is chemical shifts of 1H in the unsaturated ester compounds and increases with the temperature, which means that higher temperature is conducive to the esterification reaction. The structure of β-CD was also changed at the higher temperatures. Specifically, at temperatures above 110°C, the chemical shifts and peak symmetries of H-2, H-4, H-5, H-6 changed due to the ring opening of β-CD.
In
addition, hydrogen bonds were formed between the hydroxyl groups of the different glucose units (Yang, L. J., Chen, W., et.al.). Therefore, the esterification reaction of β-CD with itaconic acid and maleic acid should be take place at temperatures below 110°C. Fig.1 H NMR spectra of β-CD and CDM in D2O at 25 °C
Fig.2 13C NMR spectra of β-CD and CDM in D2O at 25 °C
3.2 FTIR spectra When the reaction temperature was below 110°C there were two absorption peaks: the absorption peaks of the carboxyl (C=O Stretching vibration) group was at 1706 cm-1 and that of the unsaturated ester bond absorption peak(C=O Stretching vibration) was at 1723 cm-1 as shown in Figure 3-A. From this we can deduce that when the reaction temperature is below 110℃, the main reaction product is a CDM monoester. In contrast, at temperatures above 110 ℃, there is only the characteristic 8
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absorption peak of the unsaturated ester bond (C=O stretching vibration) at 1722 cm-1. Therefore, at reaction temperatures above 110 ℃, the main reaction product maybe a monoester or diester. We need to make sure the structure of CDM by the mass information of the products. We also found that there is a stretching vibration absorption peak of the alkene (C=C) bond at 1637 cm-1(Weng, 2009). As shown in Figure 3-B, we found that different dosages of maleic acid at a reaction temperature of 110℃ yielded different types of CDM reaction products. Specifically, when maleic acid: β-CD ratio was below 2:1, the CDM products may be mainly a monoester. When maleic acid: β-CD ratio was higher than 2:1, the CDM products may be mainly a diester. We still need the mass information to make sure of this. As shown by the FTIR spectra of monoethyl itaconate and diethyl itaconate, the absorption peak of the unsaturated ester bond (C=O Stretching vibration) was found at 1731 cm-1 and 1718 cm-1(Lin, 2009; Weng, 2009), respectively (Figure 3-C). For monoethyl itaconate, there was also an absorption peak of the α-carboxyl group (C=O stretching vibration) at 1702 cm-1. However, unlike seen for CDM, neither the reaction temperature or the concentration of itaconic acid, affected the formation of the expected product an unsaturated ester bond and we found the characteristic absorption peak of unsaturated ester bond (C=O Stretching vibration) of CDI occurring at 1718 cm-1. Therefore, we concluded that CDI may be a kind of diester under our experimental conditions, however, we still need mass analysis to make sure. We also found that there is a stretching vibration absorption peak of the alkene (C=C) 9
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bond at 1637 cm-1.
Fig.3 A: FTIR spectra of:
a) maleic acid, b) diethyl maleate, c) monoethyl maleate, d-h) CDM: MA 0.012mol;
β-CD 0.006mol; M/L-ratio 1:1; Time 2.5 h; temperature at 90°C, 100°C , 110°C , 120°C , and 130°C respectively; B: FTIR spectra of CDM using different dosages of maleic acid (β-CD): a)
0.006mol; b)
0.012mol;
c)0.018mol; d) 0.024mol; M/L-ratio 1:1; Time 2.5h; temperature at 110℃); C: FTIR spectra of: a) itaconic acid, b) monoethyl itaconate, c) diethyl itaconate, d-h) CDI: IA 0.012mol; β-CD 0.006mol; M/L-ratio 1:1; Time 2.5h; temperature at 90℃, 100℃, 110℃, 120℃, and 130℃, respectively.
In summary, both maleic acid and itaconic acid are binary unsaturated carboxylic acid. Although both two carboxyl groups of maleic acid are α-COOH, and in the case of itaconic acid one carboxyl group of itaconic acid is α-COOH and the other one is β-COOH. Since there is a methine double bond conjugating with α-COOH, the electron cloud is partial to the carbon-carbon double bond and the polarity of the carbon-oxygen double bond in the carboxyl group becomes smaller. Consequently, the reaction activity of the carboxyl group in maleic acid is weaker than that of itaconic acid (Xu et al., 2008). 3.3 Mass spectra The mass spectra of β-CD, CDM and CDI were shown in Fig.4. According the spectra there were only one molecular ion peak for [β-CD-MA+Na]+ and [β-CD-IA+Na]+, of which m/z were 1255.6 and 1269.4, respectively. Compared with the m/z of [β-CD+Na]+, which was 1157.6, we deduced that the CDM and CDI were both monoester. So according the NMR spectra, FT-IR spectra and mass information of the CDM and CDI, we concluded that CDM and CDI were both monoester. The molecular structure was shown in Fig.5. 10
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Fig.4 The mass spectra of a) β-CD, b) CDM and c) CDI.
Fig.5 The molecular structure of CDM (A) and CDI (B).
3.4 Reaction mechanism Recently, it has been reported that several classes of alkali metal salts of phosphorus-containing acids have a greater accelerating effect on the esterification and crosslinking of cellulose by polycarboxylic acids than strong base catalysts (Andrews et al., 1989). In essence, the alkali metal hypophosphites were found to be effective even with a crosslinking agent such as maleic acid which has only two carboxyl groups per molecule. It is also possible that the two molecules of maleic acid add to one molecule of the alkali metal hypohposphite to yield a tetracarboxylic acid. Together, these results suggest that the esterification of β-CD by maleic acid and itaconic acid in the presence of a catalyst can be explained with a tetracarboxylic acid reactive intermediate mechanism as shown in the following mechanism: (i) Formation of tetracarboxylic acid (Andrews et al., 1989)
where R is the structure of the polycarboxylic acid molecule joined to the 11
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transient anhydride ring. (ii) Esterification of β-CD The mechanism for the formation of CDM is as follows:
In the case of CDI, the esterification of β-CD forms a monoester with the following reaction mechanism:
3.5 Catalyst type and concentration Several alkali metal salts of phosphorus-containing acids have a catalytic effect on the esterification reaction of polycarboxylic acids. We tested different kinds of phosphates as catalysts. As shown in Figure 6-A, the catalytic activity for the different phosphates tested was as follows: SHP>MSP>SPD>SHMP. Although the esterification reaction is more likely to happen in weak alkali conditions (Andrews et al., 1989), SHMP barely had a catalytic effect and MSP (acid ortho-phosphate) had a catalytic ability on the esterification by maleic acid. Therefore, the catalytic ability of phosphates is related to the chemical valence of the phosphorus atom in the phosphate group in addition to the pH value. 3.6 Solid-to-liquid ratio We found that the esterification rate of CDM and CDI increased in a rate proportional to the amount of water in the reaction and was highest when the 12
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solid-to-liquid rario was 1:1 (Fig. 6-B). This could be explained by the fact that intramolecular reactions are favored as the amount of water in the reaction increases. The DBC however decreased as the amount of water in the reaction increased, possibly because higher water concentrations favor polymerization of CDM and CDI. 3.7 Reaction temperature We found that as the reaction temperature increased the DBC of CDM and CDI increased too, but the esterification of CDM was reduced (Figure 6-C). The 1H NMR of CDM shows that high temperatures destroy the vinyl group in CDM and CDI forming a new group- methylene group. The methylene group in turn can react with Br2, but only the ester bond containing the vinyl group has absorption in the ultraviolet light. Therefore the DBC increases and the esterification is reduced with increasing reaction temperatures. Consequently, the reaction temperature for CDM and CDI should be below 110℃ to prevent side reactions.
3.8 Polymerization inhibitor type and concentration Adding a polymerization inhibitor can raise the DBC of the CDM. In essence, the nhibitor can ablate free radical activity and slow down the speed of polymerization. Adding the inhibitor can also protect the double bond of the CDM, which is important for the subsequent polymerization of CDM in building a polymer system. We found that 4-methoxyphenol is the most efficient inhibitor. Even when its usage is 2.5% of the amount of MA, the DBC value (59.6 mequiv/100g CDM) increased 40.1% compared to the reaction without using inhibitor (Figure 6-D). 13
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Fig.4 A:Effect of catalyst concentration on the DBC of CDM (MA 0.012mol; β-CD 0.006mol; M/L-ratio 1:1; temperature 110℃; time 2.5h;) B: The esterification rate and DBC of CDM and CDI increases as the solid-to-liquid ration increases (β-CD:0.006mol; MA (IA): 0.012mol; SHP: 0.006mol; solid-to-liquid: 1:0.6; temperature: 110; reaction time 2.5 h). C: Effect of the reaction temperature on DBC and the esterification rate of CDM and CDI (β-CD:0.006mol; acid: 0.012mol; SHP: 0.006mol; Solid-to-liquid: 1:0.6; reaction time 2.5 h). D: Effect of polymerization inhibitor concentration on DBC and Esterification rate of CDM. (β-CD:0.006mol; MA: 0.012mol; SHP: 0.636g; Solid-to-liquid: 1:0.6; temperature: 110℃; reaction time 2.5h.) E: Effect of the acid concentration on the DBC and the esterification rate of CDM and CDI
(β-CD:0.006mol;
SHP: 0.5 mol/mol acid; Solid-to-liquid: 1:0.6; temperature: 110℃, reaction time 2.5 h). F: Effect of the reaction time on DBC and the esterification rate of CDM and CDI.
(β-CD:0.006mol; acid: 0.024mol; SHP: 0.012mol;
Solid-to-liquid: 1:0.6; temperature: 110℃).
3.9 Amount of acid As shown in Figure 6-E, we found that with increasing amounts of acid the DBC of CDM and CDI increased.
In contrast, the esterification rate of CDM increased
with the increasing usage of maleic acid and there was no significant influence on the esterification of CDI. This maybe due to differences in molecular size between the acids affecting the rate of esterification. In addition, there could be more than one maleic acid reacting with β-CD for CDM and only one itaconic acid reacting with β-CD for CDI. 3.10 Reaction time As shown in Figure 6-F, we found that at longer reaction times the DBC and the esterification of CDM and CDI were both increased and peaked at 3.5 h.
After 3.5
hrs, the DBC and esterification of CDM and CDI both decreased possibly because reaction times longer than 3.5 hrs at a high temperature have an influence on the vinyl groups of CDM and CDI. 14
3.11 Thermogravimetric Analysis (TGA) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
The DTA curve of CDM, CDI and β-CD showed an endothermic effect below100℃, which shows that there is a loss of water molecules in CDM, CDI and β-CD in the hydrate state (Nazi et al., 2012; Song et al., 2008; Szejtli 1988). The results also indicate that the enthalpy released by the water molecules of CDM and CDI was lower than that of β-CD. In addition, the results also show that the energy of the interactions between the water and the CD molecules of CDM and CDI in the solid state are different from β-CD (as shown in Figure 7 and figure 8). In essence, adding the vinyl group to β-CD changes the affinity of water to the CD.
Fig.7 Thermogravimetric analysis for CDM. Typical TG, DTG and DTA curves of 2mg of the CDM. (β-CD:0.006mol; MA: 0.024mol; SHP: 0.012mol; Solid-to-liquid: 1:0.6; temperature: 110℃, reaction time 3.5 h.
Fig.8 Thermogravimetric analysis for CDI. Typical TG, DTG and DTA curves of 2mg of the CDI. (β-CD:0.006mol; IA: 0.024mol; SHP: 0.012mol; Solid-to-liquid: 1:0.6; temperature: 110℃, reaction time 3.5h).
The TGA and DTG curves show the results of the thermogravimetric analysis of β-CD, CDM and CDI. Compared to β-CD, the stability of CDM and CDI decreased because of the existing vinyl group. We also found out that the synthesis temperature influences the stability of CDM.
In essence, at reaction temperatures below 110℃,
there was only one peak of mass loss similar to β-CD.
In contrast, at reaction
temperatures above 110℃, there were two peaks of mass loss at 222.8℃ and 315.9℃ for CDM prepared at 120℃, and at 92.4℃ and 215.5℃ for CDM prepared at 130℃, respectively (Figure 7). Unlike observed for CDM, there was only one peak of mass 15
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loss for CDI at 316.2℃, independent of the reaction temperature for CDI (Figure 8). This may be due to differences in the stability of itaconic acid and maleic acid. 4. Conclusion Here, two β-cyclodextrin derivatives containing a vinyl group were synthesized by reacting β-cyclodextrin with maleic acid and itaconic acid, respectively, with phosphates as a catalyst. In this research, Mono-ethyl maleate and mono-ethyl itaconate were used as standards to evaluate the content of unsaturated ester bond of the sample we prepared, and their absorbance values at different concentrations was measured using an ultraviolet spectrophotometer at 210nm and 195nm, the wavelengths for maximum absorption for mono-ethyl malate and mono-ethyl itaconate, respectively. The esterification of β-CD was carried out using [Itaconic acid ] or [Maleic acid ] 4 mol/mol of CD; M/L ratio 1:0.6; temperature 110 ℃; [catalyst] 0.25mol/mol of acid; [4-methoxyphenol] 2.5% amount of acid; reaction time 3.5h. The esterification rate of CDM and CDI are 70.38% and 21.02%, respectively. The structure of the products was characterized by using thermal analysis, mass spectra and FT-IR spectroscopy methods. The results showed CDI and CDM were both monoesters independent of the reaction conditions. We found that sodium hypophosphite was the most efficient catalyst for this reaction, similar to the results reported by Gaffar’s group (Gaffar et al., 2004). The vinyl group in β-cyclodextrin was found to be useful to synthesize a polymer in a radical chain reaction, a finding that has applications in the synthesis of carbohydrate polymers. 16
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Acknowledgment This work was financially supported by the “National Science and Technology Supported Program for the Control of Food Biological Toxin Pollution and the Early Warning Technology of the Radioactive Pollution” (Grant No. 2012BAK17B13) and the “Special Fund for Agro-scientific Research in the Public Interest” (Grant No. 201103007)
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Szejtli, J. (1982). Cyclodextrins and their inclusion complexes (pp. 120-122). Budapest: Akademiai Kiado.
Szejtli, J. (1988). Cyclodextrin technology. Dordrecht: Kluwer Academic Publishers.
Szejtli, J. (1998). Introduction and general overview of cyclodextrin chemistry. Chemical reviews, 98(5), 1743-1754. 18
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Villalonga, R., Cao, R., & Fragoso, A. (2007). Supramolecular chemistry of cyclodextrins in enzyme technology. Chemical reviews, 107(7), 3088-3116.
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19
1. β-cyclodextrin derivatives containing a vinyl group. 2. A new evaluation method for the esterification rate of monounsaturated ester. 3. β-CD maleate andβ-CD itaconate were both monoesters.
S0008-6215(14)00428-5 http://dx.doi.org/10.1016/j.carres.2014.11.012 CAR 6894
To appear in:
Carbohydrate Research
Received Date: Revised Date: Accepted Date:
21 July 2014 28 October 2014 17 November 2014
Please cite this article as: Li, Y-F., Ha, Y-M., Guo, Q., Li, Q-P., Synthesis of two β- cyclodextrin derivatives containing a vinyl group, Carbohydrate Research (2014), doi: http://dx.doi.org/10.1016/j.carres.2014.11.012
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Synthesis of two β- cyclodextrin derivatives containing a vinyl group Yong-Fu Li a,b, Yi-Ming HA* a,b，Qin-Guo a,b，Qing-Peng Li a,b a
Institute of Agro-Products Processing Science and Technology, Chinese Academy of
Agricultural Sciences, 100193 Beijing, China. b
Key Opening Laboratory of Agricultural Products Processing and Quality Control,
Ministry of Agriculture, Beijing 100193, China.
* To whom correspondence should be addressed:
The Institute of Agro-Products
Processing Science and Technology, Chinese Academy of Agricultural Sciences, 100193 Beijing, PR China. Tel.: +86 010 62815972; Fax: +86 010 62815972. Email: [email protected]
1
Abstract 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
β-CD maleate (CDM) and β-CD itaconate (CDI) were prepared by esterification of β-cyclodextrin (β-CD) with maleic acid and itaconic acid using phosphate as a catalyst in a semi-dry process. The esterification of β-CD was carried out using [Itaconic acid ] or [Maleic acid ] 4 mol/mol of CD; M/L ratio 1:0.6; temperature 110 ℃ ; [4-methoxyphenol] 2.5% amount of acid; reaction time 3.5h. The esterification rate of CDM and CDI are 70.38% and 21.02%, respectively. We found that CDM and CDI were both monoesters. Here, we also established a new evaluation method for the rate of esterification.
Keywords: cyclodextrin; vinyl group; esterification; double bond content.
2
1. Introduction 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
β-cyclodextrin (β-CD) is a water-soluble cyclic oligosaccharide composed of seven
D-glucose
units linked by α-1,4-glycosidic bonds (Villalonga et al., 2007;
Buschmann et al., 2001). The geometry of β-CD results in a hydrophobic inner cavity with a depth of 7.8 Å and an internal diameter of 6.5 Å (Prabaharan et al., 2006). Hydrophobic, unstable or volatile substances can fit into this hydrophobic cavity to form supramolecular inclusion complexes that have been served as models systems for studies on the molecular mechanisms of microencapsulation (Indra et al., 2000, Szejtli 1982, Szejtli 1998). β-CD can form inclusion complexes in its inner cavity and has several favorable physicochemical and biological properties. However, the presence of intramolecular hydrogen bonding between its C2 and C3 hydroxyl groups decreases its solubility in water (1.85 g / 100 ml), which limits its applications (Yuan et al., 2006).
Therefore,
investigators have focused on finding ways to increase the solubility of β-CD preparing a variety of β-CD derivatives with different physical and chemical properties. One such derivative links β-CD to a natural biological polysaccharide. The first step for this reaction is the preparation of β-CD vinyl monomer derivatives. Previously, it has been reported that a β-CD itaconate (CDI) vinyl monomer can be prepared using sodium hypophosphite as catalyst (Gaffar et al., 2004). In Gaffer’s study the authors pointed out that CDI is a monoester. Interestingly, we found that CDI is also a monoester. Here, we report the synthesis of another vinyl monomer, β-CD maleate (CDM), and we found that CDM was also a monoester independent of the reaction conditions. In addition, we also established a new evaluation method for 3
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the rate of esterification. 2. Materials and Methods 2.1 Reagents β-cyclodextrin was purchased from China National Pharmaceutical Group Corporation. Before use, add 500g β-CD to 1L hot water (85 °C) and crystallize in 4 °C refrigerator (repeat twice). Then the crystal was dried at 90 °C in an oven for 24 h and stored in a desiccator. Itaconic acid and maleic acid were purchased from Aladdin Industrial Corporation. Sodium phosphite dibasic-5-hydrate (SPD) was purchased from Sigma-Aldrich (USA). KBr, KBrO3, sodium hexametaphosphate (SHMP), sodium dihydrogen phosphate-2-hydrate (MSP), sodium hypophosphite monohydrate (SHP), methylhydroquinone, tert-butylhydroquinone, and 4-methoxyphenol were purhased from China National Pharmaceutical Group Corporation. Monoethyl maleate, diethyl maleate, monoethyl itaconate and diethyl itaconate were purchased from TCI. All reagents were analytically pure unless otherwise noted. 2.2 Synthesis of CDI and CDM CDI and CDM were prepared using the semi-dry reaction method by manually mixing 6.81 g (6 mmol) β-CD with a definite amount of water containing different amounts of itaconic acid (IA, from 6 to 24 mmol) and maleic acid (MA, from 6 to 24 mmol) in the presence or absence of a catalyst (SPD, SHMP, MSP and SHP, from 0.16 to 0.66 mol/mol acid ) and polymerization inhibitors (methylhydroquinone, tert-butylhydroquinone, and 4-methoxyphenol, from 0.5% to 3.5% amount of acid ). The reaction mixture was transferred to a pressure bottle and placed in a circulating 4
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air oven at different reaction temperatures (90-130°C) for 2.5 h. At this point, the reaction mixture were crystallized at 4°C in a refrigerator and the crystals were purified by washing with 95% ethyl alcohol (50ml*4), followed by drying at 60°C in an oven for 24 h. 2.3 NMR spectroscopy Reaction products were characterized using 1H NMR and
13
C spectra using a
Bruker-500 spectrometer at 500MHz. All samples were dissolved in D2O before use. Measurements were done at 25°C. 2.4 Mass spectra Reaction products were characterized by using MALDI-TOF mass spectrometer (Bruker Daltonics Inc. BIFLEX III). 2.5 Sample Characterization FTIR was conducted using a Bruker Tensor37 FT-IR Spectrometer (BRUKER OPTICS, Germany). The diffuse reflectance technique was utilized in the mid-IR (400–4000 cm-1) spectral region. Specifically, the sample was ground with KBr (about 200–400 mg) into a fine powder, placed into the sampling cup, smoothed and compressed into a transparent flake using the tablet machine. At this point, the sample was placed in the light path and the spectrum was obtained. IR spectroscopy measurements were obtained using liquid measurement accessories since monoethyl maleate, diethyl maleate and diethyl itaconate are liquid at room temperature. 2.5 Double bond content The degree of unsaturation of the esterification products was evaluated by 5
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determining the double bond content (DBC), expressed in mequiv./100 g as reported by Wallace & Young (1966).
Dried samples (0.5 g) were added to a stoppered
conical flask and then mixed with 10 ml of frozen KBr/KBrO3 mixture（6.960 g/L KBrO3，30g/L KBr）under the condition of ice fields. At this point 5 ml H2SO4 (2.0 N) was added and the reaction was placed in the dark for 30 minutes. The Br2 released was added to the double bond of the EP samples. Back titration of the excess Br2 was carried out using 10 ml Iodometric titration (20%) for a reaction time of 5 minutes in the dark as (Wallace & Young, 1966). The double bound content (DBC) was calculated by the following equation (1): V V 0.1 100 DBC mequiv. B S 100 g W
(1)
W: weight of the sample (0.5 g); VB: volume of sodium thiosulfate (0.1 N) equivalent to the liberated Br2 in the blank titration (ml); VS: volume of sodium thiosulfate used in the sample titration (ml). 2.6 Esterification rate Mono-ethyl maleate, diethyl maleate and mono-ethyl itaconate were used as standards and their absorbance values at different concentrations was measured using an ultraviolet spectrophotometer at 210nm and 195nm, the wavelengths for maximum absorption for monoethyl malate and diethyl malate respectively. The following standard curve equations were used： Mono-ethyl Maleate (210 nm):
y = 62198x - 0.0009
R² = 0.9999
Mono-ethyl Itaconate (195nm):
y = 90855x + 0.0326
R² = 0.9996
The esterification rate (ER) was calculated as follows (2): 6
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A b V X M W k ER（%） 100% W
(2)
Where α is the coefficient for molecular weight (α= 0.1169); A= samples’ absorbance value; b= intercept of standard curve; K= slope of standard curve; W= sample quality; V= volume of the solution; X= sample dilution multiple; Mw – Sample molecular weight. 2.7 Thermo-gravimetric Analysis (TGA) Thermogravimetric analysis was performed with the Perkin Elmer TG/DTA thermal analyzer and the following experimental conditions:
nitrogen atmosphere
(2.5 ml/min), the heating rate 10 °C / min, scanning temperature range: 45 °C to 450 °C
3. Results and Discussion 3.1 NMR spectra In order to establish a protocol for the synthesis of CDM and determine the influence of temperature on the reaction, we compared the 1H NMR and
13
C NMR
spectra of CDM and β-CD. The synthesis of CDM was monitored by 1H NMR and 13
C spectra. As illustrated in Figure 1, there were H-vinyl chemical shifts at 6.43 ppm
(Fig.1) and
13
C-vinyl chemical shifts at δ 133.63 ppm (Fig.2) respectively as can be
seen in the spectra of CDM. We also found that there is another signal at 170ppm (Fig.2) for the vinyl carbon of carboxylic ester. Interestingly, at temperatures above 110°C there was a tremendous increase in the concentration of the methylene group in the products as seen by the chemical shifts of 1H at 1.25 ppm (Fig.1), 7
13
C at 16.86
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ppm (Fig.2), possibly because that at the higher temperatures the vinyl group of the products reacts with the H2O in the reaction system. This phenomenon could also explain the increase in the concentration of vinyl groups as detected by the consumption of Br2 at temperatures above 110°C. We also found that the signal at 5.5 ppm (Fig.1) is chemical shifts of 1H in the unsaturated ester compounds and increases with the temperature, which means that higher temperature is conducive to the esterification reaction. The structure of β-CD was also changed at the higher temperatures. Specifically, at temperatures above 110°C, the chemical shifts and peak symmetries of H-2, H-4, H-5, H-6 changed due to the ring opening of β-CD.
In
addition, hydrogen bonds were formed between the hydroxyl groups of the different glucose units (Yang, L. J., Chen, W., et.al.). Therefore, the esterification reaction of β-CD with itaconic acid and maleic acid should be take place at temperatures below 110°C. Fig.1 H NMR spectra of β-CD and CDM in D2O at 25 °C
Fig.2 13C NMR spectra of β-CD and CDM in D2O at 25 °C
3.2 FTIR spectra When the reaction temperature was below 110°C there were two absorption peaks: the absorption peaks of the carboxyl (C=O Stretching vibration) group was at 1706 cm-1 and that of the unsaturated ester bond absorption peak(C=O Stretching vibration) was at 1723 cm-1 as shown in Figure 3-A. From this we can deduce that when the reaction temperature is below 110℃, the main reaction product is a CDM monoester. In contrast, at temperatures above 110 ℃, there is only the characteristic 8
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absorption peak of the unsaturated ester bond (C=O stretching vibration) at 1722 cm-1. Therefore, at reaction temperatures above 110 ℃, the main reaction product maybe a monoester or diester. We need to make sure the structure of CDM by the mass information of the products. We also found that there is a stretching vibration absorption peak of the alkene (C=C) bond at 1637 cm-1(Weng, 2009). As shown in Figure 3-B, we found that different dosages of maleic acid at a reaction temperature of 110℃ yielded different types of CDM reaction products. Specifically, when maleic acid: β-CD ratio was below 2:1, the CDM products may be mainly a monoester. When maleic acid: β-CD ratio was higher than 2:1, the CDM products may be mainly a diester. We still need the mass information to make sure of this. As shown by the FTIR spectra of monoethyl itaconate and diethyl itaconate, the absorption peak of the unsaturated ester bond (C=O Stretching vibration) was found at 1731 cm-1 and 1718 cm-1(Lin, 2009; Weng, 2009), respectively (Figure 3-C). For monoethyl itaconate, there was also an absorption peak of the α-carboxyl group (C=O stretching vibration) at 1702 cm-1. However, unlike seen for CDM, neither the reaction temperature or the concentration of itaconic acid, affected the formation of the expected product an unsaturated ester bond and we found the characteristic absorption peak of unsaturated ester bond (C=O Stretching vibration) of CDI occurring at 1718 cm-1. Therefore, we concluded that CDI may be a kind of diester under our experimental conditions, however, we still need mass analysis to make sure. We also found that there is a stretching vibration absorption peak of the alkene (C=C) 9
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bond at 1637 cm-1.
Fig.3 A: FTIR spectra of:
a) maleic acid, b) diethyl maleate, c) monoethyl maleate, d-h) CDM: MA 0.012mol;
β-CD 0.006mol; M/L-ratio 1:1; Time 2.5 h; temperature at 90°C, 100°C , 110°C , 120°C , and 130°C respectively; B: FTIR spectra of CDM using different dosages of maleic acid (β-CD): a)
0.006mol; b)
0.012mol;
c)0.018mol; d) 0.024mol; M/L-ratio 1:1; Time 2.5h; temperature at 110℃); C: FTIR spectra of: a) itaconic acid, b) monoethyl itaconate, c) diethyl itaconate, d-h) CDI: IA 0.012mol; β-CD 0.006mol; M/L-ratio 1:1; Time 2.5h; temperature at 90℃, 100℃, 110℃, 120℃, and 130℃, respectively.
In summary, both maleic acid and itaconic acid are binary unsaturated carboxylic acid. Although both two carboxyl groups of maleic acid are α-COOH, and in the case of itaconic acid one carboxyl group of itaconic acid is α-COOH and the other one is β-COOH. Since there is a methine double bond conjugating with α-COOH, the electron cloud is partial to the carbon-carbon double bond and the polarity of the carbon-oxygen double bond in the carboxyl group becomes smaller. Consequently, the reaction activity of the carboxyl group in maleic acid is weaker than that of itaconic acid (Xu et al., 2008). 3.3 Mass spectra The mass spectra of β-CD, CDM and CDI were shown in Fig.4. According the spectra there were only one molecular ion peak for [β-CD-MA+Na]+ and [β-CD-IA+Na]+, of which m/z were 1255.6 and 1269.4, respectively. Compared with the m/z of [β-CD+Na]+, which was 1157.6, we deduced that the CDM and CDI were both monoester. So according the NMR spectra, FT-IR spectra and mass information of the CDM and CDI, we concluded that CDM and CDI were both monoester. The molecular structure was shown in Fig.5. 10
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Fig.4 The mass spectra of a) β-CD, b) CDM and c) CDI.
Fig.5 The molecular structure of CDM (A) and CDI (B).
3.4 Reaction mechanism Recently, it has been reported that several classes of alkali metal salts of phosphorus-containing acids have a greater accelerating effect on the esterification and crosslinking of cellulose by polycarboxylic acids than strong base catalysts (Andrews et al., 1989). In essence, the alkali metal hypophosphites were found to be effective even with a crosslinking agent such as maleic acid which has only two carboxyl groups per molecule. It is also possible that the two molecules of maleic acid add to one molecule of the alkali metal hypohposphite to yield a tetracarboxylic acid. Together, these results suggest that the esterification of β-CD by maleic acid and itaconic acid in the presence of a catalyst can be explained with a tetracarboxylic acid reactive intermediate mechanism as shown in the following mechanism: (i) Formation of tetracarboxylic acid (Andrews et al., 1989)
where R is the structure of the polycarboxylic acid molecule joined to the 11
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transient anhydride ring. (ii) Esterification of β-CD The mechanism for the formation of CDM is as follows:
In the case of CDI, the esterification of β-CD forms a monoester with the following reaction mechanism:
3.5 Catalyst type and concentration Several alkali metal salts of phosphorus-containing acids have a catalytic effect on the esterification reaction of polycarboxylic acids. We tested different kinds of phosphates as catalysts. As shown in Figure 6-A, the catalytic activity for the different phosphates tested was as follows: SHP>MSP>SPD>SHMP. Although the esterification reaction is more likely to happen in weak alkali conditions (Andrews et al., 1989), SHMP barely had a catalytic effect and MSP (acid ortho-phosphate) had a catalytic ability on the esterification by maleic acid. Therefore, the catalytic ability of phosphates is related to the chemical valence of the phosphorus atom in the phosphate group in addition to the pH value. 3.6 Solid-to-liquid ratio We found that the esterification rate of CDM and CDI increased in a rate proportional to the amount of water in the reaction and was highest when the 12
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solid-to-liquid rario was 1:1 (Fig. 6-B). This could be explained by the fact that intramolecular reactions are favored as the amount of water in the reaction increases. The DBC however decreased as the amount of water in the reaction increased, possibly because higher water concentrations favor polymerization of CDM and CDI. 3.7 Reaction temperature We found that as the reaction temperature increased the DBC of CDM and CDI increased too, but the esterification of CDM was reduced (Figure 6-C). The 1H NMR of CDM shows that high temperatures destroy the vinyl group in CDM and CDI forming a new group- methylene group. The methylene group in turn can react with Br2, but only the ester bond containing the vinyl group has absorption in the ultraviolet light. Therefore the DBC increases and the esterification is reduced with increasing reaction temperatures. Consequently, the reaction temperature for CDM and CDI should be below 110℃ to prevent side reactions.
3.8 Polymerization inhibitor type and concentration Adding a polymerization inhibitor can raise the DBC of the CDM. In essence, the nhibitor can ablate free radical activity and slow down the speed of polymerization. Adding the inhibitor can also protect the double bond of the CDM, which is important for the subsequent polymerization of CDM in building a polymer system. We found that 4-methoxyphenol is the most efficient inhibitor. Even when its usage is 2.5% of the amount of MA, the DBC value (59.6 mequiv/100g CDM) increased 40.1% compared to the reaction without using inhibitor (Figure 6-D). 13
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Fig.4 A:Effect of catalyst concentration on the DBC of CDM (MA 0.012mol; β-CD 0.006mol; M/L-ratio 1:1; temperature 110℃; time 2.5h;) B: The esterification rate and DBC of CDM and CDI increases as the solid-to-liquid ration increases (β-CD:0.006mol; MA (IA): 0.012mol; SHP: 0.006mol; solid-to-liquid: 1:0.6; temperature: 110; reaction time 2.5 h). C: Effect of the reaction temperature on DBC and the esterification rate of CDM and CDI (β-CD:0.006mol; acid: 0.012mol; SHP: 0.006mol; Solid-to-liquid: 1:0.6; reaction time 2.5 h). D: Effect of polymerization inhibitor concentration on DBC and Esterification rate of CDM. (β-CD:0.006mol; MA: 0.012mol; SHP: 0.636g; Solid-to-liquid: 1:0.6; temperature: 110℃; reaction time 2.5h.) E: Effect of the acid concentration on the DBC and the esterification rate of CDM and CDI
(β-CD:0.006mol;
SHP: 0.5 mol/mol acid; Solid-to-liquid: 1:0.6; temperature: 110℃, reaction time 2.5 h). F: Effect of the reaction time on DBC and the esterification rate of CDM and CDI.
(β-CD:0.006mol; acid: 0.024mol; SHP: 0.012mol;
Solid-to-liquid: 1:0.6; temperature: 110℃).
3.9 Amount of acid As shown in Figure 6-E, we found that with increasing amounts of acid the DBC of CDM and CDI increased.
In contrast, the esterification rate of CDM increased
with the increasing usage of maleic acid and there was no significant influence on the esterification of CDI. This maybe due to differences in molecular size between the acids affecting the rate of esterification. In addition, there could be more than one maleic acid reacting with β-CD for CDM and only one itaconic acid reacting with β-CD for CDI. 3.10 Reaction time As shown in Figure 6-F, we found that at longer reaction times the DBC and the esterification of CDM and CDI were both increased and peaked at 3.5 h.
After 3.5
hrs, the DBC and esterification of CDM and CDI both decreased possibly because reaction times longer than 3.5 hrs at a high temperature have an influence on the vinyl groups of CDM and CDI. 14
3.11 Thermogravimetric Analysis (TGA) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
The DTA curve of CDM, CDI and β-CD showed an endothermic effect below100℃, which shows that there is a loss of water molecules in CDM, CDI and β-CD in the hydrate state (Nazi et al., 2012; Song et al., 2008; Szejtli 1988). The results also indicate that the enthalpy released by the water molecules of CDM and CDI was lower than that of β-CD. In addition, the results also show that the energy of the interactions between the water and the CD molecules of CDM and CDI in the solid state are different from β-CD (as shown in Figure 7 and figure 8). In essence, adding the vinyl group to β-CD changes the affinity of water to the CD.
Fig.7 Thermogravimetric analysis for CDM. Typical TG, DTG and DTA curves of 2mg of the CDM. (β-CD:0.006mol; MA: 0.024mol; SHP: 0.012mol; Solid-to-liquid: 1:0.6; temperature: 110℃, reaction time 3.5 h.
Fig.8 Thermogravimetric analysis for CDI. Typical TG, DTG and DTA curves of 2mg of the CDI. (β-CD:0.006mol; IA: 0.024mol; SHP: 0.012mol; Solid-to-liquid: 1:0.6; temperature: 110℃, reaction time 3.5h).
The TGA and DTG curves show the results of the thermogravimetric analysis of β-CD, CDM and CDI. Compared to β-CD, the stability of CDM and CDI decreased because of the existing vinyl group. We also found out that the synthesis temperature influences the stability of CDM.
In essence, at reaction temperatures below 110℃,
there was only one peak of mass loss similar to β-CD.
In contrast, at reaction
temperatures above 110℃, there were two peaks of mass loss at 222.8℃ and 315.9℃ for CDM prepared at 120℃, and at 92.4℃ and 215.5℃ for CDM prepared at 130℃, respectively (Figure 7). Unlike observed for CDM, there was only one peak of mass 15
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loss for CDI at 316.2℃, independent of the reaction temperature for CDI (Figure 8). This may be due to differences in the stability of itaconic acid and maleic acid. 4. Conclusion Here, two β-cyclodextrin derivatives containing a vinyl group were synthesized by reacting β-cyclodextrin with maleic acid and itaconic acid, respectively, with phosphates as a catalyst. In this research, Mono-ethyl maleate and mono-ethyl itaconate were used as standards to evaluate the content of unsaturated ester bond of the sample we prepared, and their absorbance values at different concentrations was measured using an ultraviolet spectrophotometer at 210nm and 195nm, the wavelengths for maximum absorption for mono-ethyl malate and mono-ethyl itaconate, respectively. The esterification of β-CD was carried out using [Itaconic acid ] or [Maleic acid ] 4 mol/mol of CD; M/L ratio 1:0.6; temperature 110 ℃; [catalyst] 0.25mol/mol of acid; [4-methoxyphenol] 2.5% amount of acid; reaction time 3.5h. The esterification rate of CDM and CDI are 70.38% and 21.02%, respectively. The structure of the products was characterized by using thermal analysis, mass spectra and FT-IR spectroscopy methods. The results showed CDI and CDM were both monoesters independent of the reaction conditions. We found that sodium hypophosphite was the most efficient catalyst for this reaction, similar to the results reported by Gaffar’s group (Gaffar et al., 2004). The vinyl group in β-cyclodextrin was found to be useful to synthesize a polymer in a radical chain reaction, a finding that has applications in the synthesis of carbohydrate polymers. 16
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Acknowledgment This work was financially supported by the “National Science and Technology Supported Program for the Control of Food Biological Toxin Pollution and the Early Warning Technology of the Radioactive Pollution” (Grant No. 2012BAK17B13) and the “Special Fund for Agro-scientific Research in the Public Interest” (Grant No. 201103007)
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1. β-cyclodextrin derivatives containing a vinyl group. 2. A new evaluation method for the esterification rate of monounsaturated ester. 3. β-CD maleate andβ-CD itaconate were both monoesters.
