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Chemical Papers DOI: 10.2478/s11696-013-0337-5
ORIGINAL PAPER
Mechanism of α-acetyl-γ-butyrolactone synthesis a,b
a School
Wei Wang, a Sheng-Wan Zhang*, a Mei-Ping Li, a Ying-Yu Ren
of Life Science, b School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China Received 31 May 2012; Revised 20 November 2012; Accepted 21 November 2012
The mechanism of α-acetyl-γ-butyrolactone (ABL) synthesis from γ-butyrolactone (GBL) and ethyl acetate (EtOAc) was explored by detecting the material changes involved and the enthalpies of formation of the synthons, products, and possible intermediates were calculated using the density functional theory. GBL forms a carbanion of γ-butyrolactone by losing an α-H under strongly alkaline conditions. ABL is then obtained via two reaction mechanisms. One of the reaction mechanisms involves direct reaction of the carbanion of GBL with EtOAc to produce ABL. The other involves the formation of a carbanion of α-(2-hydroxy-tetrahydrofuran-2-yl)-γ-butyrolactone through the reaction of two molecules of GBL, and the subsequent combination of this anion with EtOAc to produce ABL. ABL is thus formed through the above two kinds of competitive ester condensation reactions. It is unnecessary to take into account synthons’ local thickness, and their self-condensation under these conditions. Both reactions of the carbanion of GBL with EtOAc and GBL are exothermic, so the control of their reaction rate is the key to their security. Considering the reasons above, this work applied synthon as the solvent, and avoided environmental pollution by alkylbenzene; also, accidents such as red material and fire were avoided by specific surface area of sodium metal control. Effective isolation of the organic and aqueous phases was performed using the salting out method. Thus, an environmentally friendly, safe, simple, and efficient new method for the synthesis of ABL with the yield higher than 90 % has been established. c 2013 Institute of Chemistry, Slovak Academy of Sciences Keywords: mechanism, enthalpy of formation, α-acetyl-γ-butyrolactone, synthesis
Introduction As a five-membered oxygen-containing heterocyclic derivative, α-acetyl-γ-butyrolactone (ABL) is an important synthon in organic chemistry. As an intermediate product, ABL has been used in the synthesis of vitamin B1 and chlorophyll, to delay heartache and as an anti-angina agent. So far, there are only two published methods for ABL synthesis. The first one uses ethylene oxide and ethyl acetoacetate as synthons (Elsasser & Korte, 1993). Ethylene oxide is an inflammable and explosive chemical that has the disadvantages of very dangerous storage and reaction. The reaction proceeds slowly, giving low yields, and the product is difficult to purify. The other method uses γ-butyrolactone (GBL) and acetyl chloride or ethyl acetate (EtOAc) as synthons and alkylbenzene *Corresponding author, e-mail: [email protected]
as the solvent (Jedli´ nski et al., 1987; Koehler & Uhlenbrock, 1998; Lipkin et al., 1988; Qian, 2008). However, this method also has many disadvantages; such as serious safety issues, high costs, and environmental pollution, etc. On the other hand, the use of synthon as the solvent (Zhang et al., 2010a) is safe, proceeds under mild reaction conditions, and causes minimum environmental pollution and low energy consumption. In the present work, the method of ABL synthesis using GBL, AcOEt, and metallic sodium as synthons was systematically studied. First of all, changes in the composition of the material in the reaction process were tracked and detected by GC. The variation correlation diagram of the content of the intermediates, products, and by-products with the reaction time was obtained. The values of the enthalpy of formation of the synthons, products, and possible intermediates, as
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well as the reaction enthalpies of each step according to the proposed mechanism were calculated using the density functional theory. The mechanism of ABL synthesis was experimentally and theoretically investigated. On this basis, a new method for the synthesis of ABL from GBL, EtOAc, and metallic sodium has been established. Synthons were used as solvents and they were added once. The purpose was to avoid environmental pollution and the risks posed by the use of alkylbenzene as the solvent, as well as to reduce the costs.
Experimental
the above basis set to ensure that no imaginary frequency existed in the calculated structure and enthalpy of formation. Reaction enthalpies (Li et al., 2011; Shafagh et al., 2011; Kiselev & Gritsan, 2008; Vessecchi & Galembeck, 2008) of the generated intermediates, by-products, and products were calculated. The reaction enthalpy is an important physical parameter used to assess the stability of molecules and to determine the energy amount released in the reaction (Khrapkovskii et al., 2010; Fu et al., 1990). All calculations were completed using the Gaussian 03 program (Frisch et al., 2003) at the average temperature of 298.15 K and average pressure of 101.325 kPa.
Materials and methods
Synthesis of ABL
γ-Butyrolactone (GBL) and α-acetyl-γ-butyrolactone (ABL) were purchased from J & K Scientific. Ethyl acetate (EtOAc), ethanol (EtOH), petroleum ether (60–90 ◦C), and phosphoric acid (85 %) were purchased from Beijing Chemical Plant. Distilled water was prepared by a Milli-Q water system. Sodium and silica gel (100–200 mesh) were purchased from Chengdu XiYa Chemical Technology Co. 1 H NMR spectra were performed using a Bruker Avance 600 spectrometer with tetramethylsilane (TMS) as an internal standard and dimethyl sulfoxide (DMSO-d6 ) as the solvent. Infrared spectra (in KBr pellets) were recorded on a FTIR Nicolet 380 instrument in the range of 4000–400 cm−1 , with 4 cm−1 spectral resolution and 32 scan accumulation. A Shimadzu GC-2010 equipped with a split injector and a flame ionisation detector was used. GC separation was performed in a RTX-1 capillary column (30 m × 0.25 mm × 0.25 µm). Injector and detector temperatures were 300 ◦C and 250 ◦C, respectively. Temperature of the oven was maintained at 85 ◦C for 5 min. Then, it was programmed to increase from 85 ◦C to 250 ◦C at 5.5 ◦C min−1 , and maintained at 250 ◦C for 30 min. Nitrogen was used as the carrier gas at 0.5 mL min−1 . The injection of 0.2 µL was made in the split mode (60 : 1). Mass spectrometry was performed using an Agilent GC7890-MS5975C under the same GC conditions described above, except for helium being used as the carrier gas. Mass spectrometer was operated in the scan monitoring mode using electron impact ionisation (70 eV); MS transfer line and the ion sources temperature were set to 280 ◦C and 230 ◦C, respectively. The density functional theory (Ochterski et al., 1995; Borges dos Santos et al., 2002; Fascella et al., 2004; Francisco-Márquez et al., 2008; Waterlot et al., 2011; Ghule et al., 2011) was used to verify the proposed mechanism. The RB3LYP/UB3LYP/631+G(d,p) basis set was used to optimise the structure of the synthons, intermediates, by-products, and products for the ABL synthesis. Frequency of the obtained molecular structure was then calculated using
GBL (58.4 g, 0.68 mol), EtOAc (89.5 g, 1.02 mol), and metallic sodium (17.2 g, 0.75 mol) with the specific surface area of 6.18 cm2 g−1 were placed in a 250 mL three-necked flask with an electric stirrer, a condenser, and a thermometer. After the stirrer was started, the temperature was increased to 80 ◦C for 8 h (for acylation), and then decreased to 55–60 ◦C for 30 min. Phosphoric acid (51 mass %) (134.8 g) was added at 55–60 ◦C to adjust the pH to 3–4; stirring was stopped and the system was left to stand at 60 ◦C for 1 h. The water phase was separated and the organic phase was distilled at diminished pressure to obtain the product. To study the quantity changes of each reaction component and to explore the reaction mechanism, the reaction process was monitored via aliquots collected at predetermined time intervals. Phosphoric acid (51 mass %) was added to adjust the pH to 3–4 and the reaction mixture was allowed to stand for 1 h. The organic phase was separated and analysed by GC and GC–MS. The content was calculated by the area normalisation method.
Results and discussion First, the reaction mechanism of ABL synthesis was explored by monitoring the changes of each compound during the reaction process to obtain ABL under mild reaction conditions with high yield, good stability, and minimal environmental hazard. Then, the enthalpies of formation of the reactants, products, and intermediates were calculated using the density functional theory. Characterisation of reaction components and their changes during the reaction Gas chromatogram of the reaction mixture (organic phase) after 340 min during the synthesis of ABL is shown in Fig. 1. Structures of ABL, EtOH, EtOAc, GBL, and α-(2-hydroxy-tetrahydrofuran-2yl)-α-acetyl-γ-butyrolactone (2-HTABL) were deter-
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Fig. 1. Gas chromatogram of the reaction mixture after 340 min reaction time. Reaction components: EtOH (1), EtOAc (2), GBL (3), ABL (4), Va (5), 2-HTABL (6).
mined by GC–MS using the NIST 05 mass spectral library and the MS data analysis depending on standard samples. Moreover, retention time of the standard compounds was used to validate their structures. α-(2-Tetrahydrofuranylidene-γ-butyrolactone (Va) was purified by column chromatography and its structure was confirmed by 1 H NMR, GC–MS, and IR spectral data. More details are given in Table 1. Changes of the components with the reaction time during the ABL synthesis are shown in Fig. 2. Contents of GBL and EtOAc decreased, whereas those of ABL and EtOH increased. Contents of both Va and 2-HTABL initially increased and then decreased. After 140 min of the reaction, contents of GBL and EtOAc decreased from 35.50 % to 3.08 % and from 64.50 % to 33.87 %, respectively. Contents of Va and 2-HTABL reached a maximum of 13.02 % and 5.16 %, respectively. During the process, the formation rate of ABL and EtOH is relatively high. Contents of ABL and EtOH increased from 0 to 22.16 % and 17.64 %, respectively. For the reaction time of 140–560 min, the formation rates of ABL and EtOH are relatively low,
Fig. 2. Content of the reaction components versus the reaction time: EtOH ( ), EtOAc ( ), GBL (), ABL ( ), Va (), 2-HTABL ( ).
•
and the contents of ABL and EtOH increased from 22.16 % to 46.57 % and from 17.64 % to 29.06 %, respectively. The content of GBL remained at 1.46– 1.63 %. Thus, the increasing content of ABL is not derived from GBL but from another pathway occurring during this process. Contents of Va and 2-HTABL decreased from 13.02 % and 5.16 % to 2.11 % and 0.77 %, respectively. This phenomenon shows that there is a direct relationship between the increasing contents of ABL, Va, and 2-HTABL. The formation of ABL essentially reached the equilibrium in 460–580 min, the content of ABL changed from 46.57 % to 47.12 %. Mechanism of ABL synthesis The density functional theory was used to calculate the enthalpies of formation (∆f H 0 ) of synthons, products, and potential intermediates (Table 2). The reaction enthalpies were calculated for each step of the reaction and the energy changes were used to explain the mechanisms (Przybylek & Gaca, 2012) shown in Fig. 3.
Table 1. Spectral data and retention time (tr ) of reaction components Compound
tr /min
Spectral data
EtOH EtOAc GBL ABL
7.55 7.15 10.93 17.67
Va
31.76
2-HTABL
34.92
MS, m/z (Ir /%): 46 (M+ , 34), 31 (CH3 , 100) MS, m/z (Ir /%): 88 (M+ , 8), 73 (C3 H5 O2 , 8), 70 (C4 H6 O, 19), 61 (C2 H5 O, 20), 43 (C2 H3 O, 100) MS, m/z (Ir /%): 86 (M, 50), 56 (C3 H4 O, 33), 42 (C2 H2 O, 100) MS, m/z (Ir /%): 128 (M+ , 7), 113 (C5 H5 O3 , 6), 86 (C4 H5 O2 , 100), 85 (C4 H4 O2 , 22), 43 (C2 H3 O, 85) IR, ν ˜ /cm−1 : 1728 (C— —O), 1680 (C— —C), 1375 (C—H), 1258 (C—O—C) 1 H NMR (DMSO-d ), δ: 2.05 (m, 2H), 2.79 (t, 2H), 2.97 (t, 2H), 4.23 (t, 2H), 4.28 (t, 2H) 6 MS, m/z (Ir /%): 154 (M+ , 100), 125 (C7 H8 O2 , 8), 113 (C5 H4 O3 , 40), 96 (C5 H4 O2 , 85), 83 (C4 H4 O2 , 13), 69 (C4 H6 O, 10), 68 (C4 H5 O, 10), 55 (C2 O2 , 26) MS, m/z (Ir /%): 214 (M+ , 0), 171 (C8 H11 O4 , 1), 154 (C8 H10 O3 , 26), 153 (C8 H9 O3 , 10), 129 (C6 H9 O3 , 13), 128 (C6 H8 O3 , 32), 113 (C5 H5 O3 , 22), 87 (C4 H7 O2 , 100), 86 (C4 H6 O2 , 96), 85 (C4 H5 O2 , 15), 69 (C4 H6 O, 31), 43 (C2 H3 O, 94)
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Table 2. Values of the theoretical absolute enthalpies of formation (∆f H0 ) at 25 ◦C of the reaction components Substance Na2 Na+ GBL ABL H2 O C2 H 5 O − C2 H5 OH H2 CH3 COOC2 H5 H3 O+ I II III IV V VI VII Va VIa
∆f H0 /(kJ mol−1 ) –852191.853 –426059.708 –804456.771 –1205125.477 –200582.161 –405189.739 –406848.425 –3050.910 –807590.252 –201633.858 –801894.309 –1610519.323 –1203440.563 –1607132.665 –1607373.449 –2414903.919 –2007728.829 –1408232.582 –2009672.671
The reaction of GBL and EtOAc is a typical α-H Claisen ester condensation reaction of two ester group containing compounds under strongly alkaline conditions. In theory, at least four products can be generated (Fig. 4). However, the changes in the material showed that the main reaction product is GBL, which loses an α-H to form a carbanion of GBL, and then attacks another carbonyl carbon of GBL and/or EtOAc in the reaction process. The loss of an α-H of EtOAc to form a carbanion which can attack another carbonyl compound is a minor side reaction. This is in agreement with the fact that the secondary carbanion is theoretically more stable than the primary one. The p electrons of the carbanion form a p–π conjugate with the adjacent carbonyl groups. The temperature of the reaction solution is high (80–88 ◦C) in the inducing phase, which increases also the temperature of the metallic sodium. When the surface of the metallic sodium gets into contact with the mixture of GBL and EtOAc,
Fig. 3. Mechanism of the transformation of GBL into ABL under alkaline conditions. Molar enthalpies (in kJ mol−1 ) for individual reaction steps: i) 1073.238, ii) –1034.745, iii) 204.137, iv) 26.234, v) –633.207, vi) –781.571, vii) –240.789, viii) 59.789, ix) 187.987, x) –59.078, xi) –168.490, xii) –633.207, xiii) –389.614.
W. Wang et al./Chemical Papers
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Fig. 4. Claisen ester condensation of EtOAc and GBL.
the low boiling point EtOAc (77 ◦C) is vapourised, while the high boiling point GBL (204 ◦C) is adsorbed on the surface of the metallic sodium, which leads to the formation of a GBL carbanion. A reaction mechanism for ABL synthesis under strongly alkaline conditions is proposed (Fig. 4), where sodium initially attacks the α-H (H atom adjacent to the carbonyl group) of GBL to form carbanion I (Fig. 3, reaction scheme Eq. (1)). The molar enthalpy of formation is 1073.238 kJ mol−1 . The reaction is endothermic and it is required to provide sufficient energy for its completion, which was also confirmed by theoretical calculations. The absolute enthalpy of formation of carbanion I is –801988.367 kJ mol−1 . Carbanion I is highly reactive and it easily reacts with the carbonyl carbon of GBL and EtOAc. Another possible mechanism of the ABL synthesis is the direct reaction of carbanion I with EtOAc (Fig. 3, reaction scheme Eq. (2)). Carbanion I attacks the carbonyl carbon atoms of EtOAc to form a C—C bond. The C—O double bond is transformed into a single bond to form oxygen anion II, and the enthalpy of formation is –1034.745 kJ mol−1 . Oxygen anion II attacks the connected carbons to form a C—O double bond. The ethoxy group is then eliminated to form ABL and the enthalpy of formation is 204.137 kJ mol−1 . The highly reactive ethoxy anion attacks the activated hydrogen of the β-dicarbonyl group in ABL and its removal results in the formation of the π–p–π conjugate III. The energy needed for this reaction is only 26.234 kJ mol−1 . The ratecontrolling step of this reaction mechanism (Fig. 3, reaction schemes Eq. (1) and Eq. (2)) is the formation of intermediate I. Carbanion III and a sodium ion form
a salt which is precipitated. Thus, the reaction process favours the formation of ABL. In the synthesis of ABL, the second mechanism involves GBL transformation to intermediate V, and its conversion into ABL (Fig. 3, reaction scheme Eq. (3)). Carbanion I attacks another carbonyl carbon of GBL and consequently the π bond of the C—O double bond opens to produce oxygen anion IV. The oxygen anion and α-H of GBL rearrange to form carbanion V. As spontaneous exothermic reactions, their molar enthalpies of formation are –781.571 kJ mol−1 and –240.789 kJ mol−1 , respectively. The p electrons of carbanion V and the carbonyl π bond form a p–π conjugate which is more stable than the intermediate oxygen anion IV. The centre of the activated carbanion in carbanion V is connected to three neighbouring carbon atoms attached to different groups, which increased the steric hindrance of the carbanion. Collision frequency between the carbanion centre and the carbon atom in the carbonyl group of EtOAc was decreased. The intermediate carbanion V attacks the carbonyl carbon in EtOAc and opens the π bond to form oxygen anion VI. The formation energy of the oxygen anion is 59.789 kJ mol−1 . The oxygen anion attacks the adjacent carbon to form a C—O double bond and to remove the ethoxy group to produce intermediate VIa with 187.987 kJ mol−1 . Under strongly alkaline conditions, hydrogen is removed from the hydroxyl group to form oxygen anion VII with –59.078 kJ mol−1 . The oxygen anion attacks the connected carbon to produce a C—O double bond and to form carbanion III as well as GBL. This reaction occurs spontaneously and is exothermic with the enthalpy of formation of –168.490 kJ mol−1 . The rate-
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controlling step of this reaction mechanism (Fig. 3, reaction scheme Eq. (3)) is the formation of intermediate VI. In this mechanism, the content of GBL is substantially constant while the content of ABL increases drastically. The results revealed the presence of intermediates Va and VIa, which further confirms the feasibility of the proposed mechanism. Intermediate V is protonated to obtain intermediate Va by the removal of a water molecule during the acid-catalysed reaction (Fig. 3, reaction scheme Eq. (4)). The enthalpy of formation of Va is –389.614 kJ mol−1 . Thus, the content of intermediate Va is representative of the content of intermediate V in the reaction system. In summary, GBL forms carbanion I by losing an α-H under strongly alkaline conditions. ABL is then obtained via two reaction mechanisms. One involves direct reaction of carbanion I with EtOAc to produce ABL. The other involves the formation of carbanions IV and V, by the reaction of carbanion I with GBL, followed by a proton shift (Fig. 3, I, IV, and V). The subsequent combination of carbanion V with EtOAc produces ABL. The formation of intermediates II, IV, and V is spontaneous, releases a lot of energy, and leads to by-products EtOH and EtOAc vapourisation giving rise to the occurrence of red material, fire, and explosion. It is very important to study the reaction mechanism not only to provide effective theoretical guidance, but also to design a reasonable production process. Selection of reaction conditions Research on the above mechanism shows that the rate of formation and the amount of generated carbanion I represent the key information for the security of the entire reaction in such an ABL synthesis process. This study examines the temperature increase rate and the specific surface area of metallic sodium. When the EtOAc/GBL and the sodium/GBL mole ratios are 1.5 and 1.1, respectively, the specific surface area of metallic sodium is 6.18 cm2 g−1 . The synthons are added at once and heated up slowly until the system starts to reflux; the reaction becomes steady ensuring thus the safety of the whole reaction, and the accidents, such as the production of red materials and/or fire, are eliminated completely (Zhang et al., 2010b). The mechanism of ABL synthesis indicates that the two reaction mechanisms ultimately form the target product. Therefore, it is unnecessary to consider problems of the synthon, either its local thickness or self-condensation. In this study, synthon was used as the solvent instead of alkylbenzene. The sodium/GBL mole ratio was 1.1, and the effect of the EtOAc/GBL mole ratio of 1.1 to 1.9 on the reaction was examined. The correction diagram of the yield as a function of the EtOAc/GBL mole ratio is shown in Fig. 5. Fig. 5 shows that the EtOAc/GBL mole ratio of
Fig. 5. Correlation diagram of the yield as a function of the EtOAc/GBL mole ratio.
1.5 is preferable and completely avoids the environmental pollution caused by using alkylbenzene. Thus, the yield of GBL conversion into ABL reaches a maximum. Under these conditions, ABL was isolated with a 90 % yield, which is by 10 % higher than the yield of the process which uses toluene as the solvent. It is shown that the π–p–π conjugate structure with sodium cation formed by both mechanisms of ABL synthesis is stable. In this study, the principle of salting out was applied, a phosphate acid was selected as the neutralising acid, and the effects of different concentrations of the phosphate acid and different separation temperatures of the organic and aqueous phase on the separation result were investigated. The results indicate that optimum separation is achieved when the phosphate acid concentration reaches 51 mass % and the separation temperature of the organic and aqueous phases reaches 60 ◦C. Under these reaction conditions, the aqueous phase does not need to be extracted by organic solvents, which greatly simplifies the purification process.
Conclusions The mechanism of ABL synthesis was experimentally and theoretically investigated. Theoretical simulations adopted the density functional theory. The ABL synthesis was explored via two proposed mechanisms. A rate-controlling step was determined for each possible reaction mechanisms. The rate-controlling step for the first reaction mechanism (Fig. 3, reaction schemes Eq. (1) and Eq. (2)) was the formation of intermediate I, and that for the second reaction mechanism (Fig. 3, reaction scheme Eq. (3)) was the formation of intermediate VI. The overall ratecontrolling step was the formation of intermediate VI. A new method for the ABL synthesis using synthon as the solvent, where the synthons are added at once while controlling the specific surface area of metallic
W. Wang et al./Chemical Papers
sodium, is presented. The proposed method can be easily applied under mild reaction conditions avoiding thus pollution of the environment by the use of alkylbenzene as the solvent. More importantly, the method has been applied in a local industrial production and a higher yield of ABL, 90 %, was obtained.
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ORIGINAL PAPER
Mechanism of α-acetyl-γ-butyrolactone synthesis a,b
a School
Wei Wang, a Sheng-Wan Zhang*, a Mei-Ping Li, a Ying-Yu Ren
of Life Science, b School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China Received 31 May 2012; Revised 20 November 2012; Accepted 21 November 2012
The mechanism of α-acetyl-γ-butyrolactone (ABL) synthesis from γ-butyrolactone (GBL) and ethyl acetate (EtOAc) was explored by detecting the material changes involved and the enthalpies of formation of the synthons, products, and possible intermediates were calculated using the density functional theory. GBL forms a carbanion of γ-butyrolactone by losing an α-H under strongly alkaline conditions. ABL is then obtained via two reaction mechanisms. One of the reaction mechanisms involves direct reaction of the carbanion of GBL with EtOAc to produce ABL. The other involves the formation of a carbanion of α-(2-hydroxy-tetrahydrofuran-2-yl)-γ-butyrolactone through the reaction of two molecules of GBL, and the subsequent combination of this anion with EtOAc to produce ABL. ABL is thus formed through the above two kinds of competitive ester condensation reactions. It is unnecessary to take into account synthons’ local thickness, and their self-condensation under these conditions. Both reactions of the carbanion of GBL with EtOAc and GBL are exothermic, so the control of their reaction rate is the key to their security. Considering the reasons above, this work applied synthon as the solvent, and avoided environmental pollution by alkylbenzene; also, accidents such as red material and fire were avoided by specific surface area of sodium metal control. Effective isolation of the organic and aqueous phases was performed using the salting out method. Thus, an environmentally friendly, safe, simple, and efficient new method for the synthesis of ABL with the yield higher than 90 % has been established. c 2013 Institute of Chemistry, Slovak Academy of Sciences Keywords: mechanism, enthalpy of formation, α-acetyl-γ-butyrolactone, synthesis
Introduction As a five-membered oxygen-containing heterocyclic derivative, α-acetyl-γ-butyrolactone (ABL) is an important synthon in organic chemistry. As an intermediate product, ABL has been used in the synthesis of vitamin B1 and chlorophyll, to delay heartache and as an anti-angina agent. So far, there are only two published methods for ABL synthesis. The first one uses ethylene oxide and ethyl acetoacetate as synthons (Elsasser & Korte, 1993). Ethylene oxide is an inflammable and explosive chemical that has the disadvantages of very dangerous storage and reaction. The reaction proceeds slowly, giving low yields, and the product is difficult to purify. The other method uses γ-butyrolactone (GBL) and acetyl chloride or ethyl acetate (EtOAc) as synthons and alkylbenzene *Corresponding author, e-mail: [email protected]
as the solvent (Jedli´ nski et al., 1987; Koehler & Uhlenbrock, 1998; Lipkin et al., 1988; Qian, 2008). However, this method also has many disadvantages; such as serious safety issues, high costs, and environmental pollution, etc. On the other hand, the use of synthon as the solvent (Zhang et al., 2010a) is safe, proceeds under mild reaction conditions, and causes minimum environmental pollution and low energy consumption. In the present work, the method of ABL synthesis using GBL, AcOEt, and metallic sodium as synthons was systematically studied. First of all, changes in the composition of the material in the reaction process were tracked and detected by GC. The variation correlation diagram of the content of the intermediates, products, and by-products with the reaction time was obtained. The values of the enthalpy of formation of the synthons, products, and possible intermediates, as
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well as the reaction enthalpies of each step according to the proposed mechanism were calculated using the density functional theory. The mechanism of ABL synthesis was experimentally and theoretically investigated. On this basis, a new method for the synthesis of ABL from GBL, EtOAc, and metallic sodium has been established. Synthons were used as solvents and they were added once. The purpose was to avoid environmental pollution and the risks posed by the use of alkylbenzene as the solvent, as well as to reduce the costs.
Experimental
the above basis set to ensure that no imaginary frequency existed in the calculated structure and enthalpy of formation. Reaction enthalpies (Li et al., 2011; Shafagh et al., 2011; Kiselev & Gritsan, 2008; Vessecchi & Galembeck, 2008) of the generated intermediates, by-products, and products were calculated. The reaction enthalpy is an important physical parameter used to assess the stability of molecules and to determine the energy amount released in the reaction (Khrapkovskii et al., 2010; Fu et al., 1990). All calculations were completed using the Gaussian 03 program (Frisch et al., 2003) at the average temperature of 298.15 K and average pressure of 101.325 kPa.
Materials and methods
Synthesis of ABL
γ-Butyrolactone (GBL) and α-acetyl-γ-butyrolactone (ABL) were purchased from J & K Scientific. Ethyl acetate (EtOAc), ethanol (EtOH), petroleum ether (60–90 ◦C), and phosphoric acid (85 %) were purchased from Beijing Chemical Plant. Distilled water was prepared by a Milli-Q water system. Sodium and silica gel (100–200 mesh) were purchased from Chengdu XiYa Chemical Technology Co. 1 H NMR spectra were performed using a Bruker Avance 600 spectrometer with tetramethylsilane (TMS) as an internal standard and dimethyl sulfoxide (DMSO-d6 ) as the solvent. Infrared spectra (in KBr pellets) were recorded on a FTIR Nicolet 380 instrument in the range of 4000–400 cm−1 , with 4 cm−1 spectral resolution and 32 scan accumulation. A Shimadzu GC-2010 equipped with a split injector and a flame ionisation detector was used. GC separation was performed in a RTX-1 capillary column (30 m × 0.25 mm × 0.25 µm). Injector and detector temperatures were 300 ◦C and 250 ◦C, respectively. Temperature of the oven was maintained at 85 ◦C for 5 min. Then, it was programmed to increase from 85 ◦C to 250 ◦C at 5.5 ◦C min−1 , and maintained at 250 ◦C for 30 min. Nitrogen was used as the carrier gas at 0.5 mL min−1 . The injection of 0.2 µL was made in the split mode (60 : 1). Mass spectrometry was performed using an Agilent GC7890-MS5975C under the same GC conditions described above, except for helium being used as the carrier gas. Mass spectrometer was operated in the scan monitoring mode using electron impact ionisation (70 eV); MS transfer line and the ion sources temperature were set to 280 ◦C and 230 ◦C, respectively. The density functional theory (Ochterski et al., 1995; Borges dos Santos et al., 2002; Fascella et al., 2004; Francisco-Márquez et al., 2008; Waterlot et al., 2011; Ghule et al., 2011) was used to verify the proposed mechanism. The RB3LYP/UB3LYP/631+G(d,p) basis set was used to optimise the structure of the synthons, intermediates, by-products, and products for the ABL synthesis. Frequency of the obtained molecular structure was then calculated using
GBL (58.4 g, 0.68 mol), EtOAc (89.5 g, 1.02 mol), and metallic sodium (17.2 g, 0.75 mol) with the specific surface area of 6.18 cm2 g−1 were placed in a 250 mL three-necked flask with an electric stirrer, a condenser, and a thermometer. After the stirrer was started, the temperature was increased to 80 ◦C for 8 h (for acylation), and then decreased to 55–60 ◦C for 30 min. Phosphoric acid (51 mass %) (134.8 g) was added at 55–60 ◦C to adjust the pH to 3–4; stirring was stopped and the system was left to stand at 60 ◦C for 1 h. The water phase was separated and the organic phase was distilled at diminished pressure to obtain the product. To study the quantity changes of each reaction component and to explore the reaction mechanism, the reaction process was monitored via aliquots collected at predetermined time intervals. Phosphoric acid (51 mass %) was added to adjust the pH to 3–4 and the reaction mixture was allowed to stand for 1 h. The organic phase was separated and analysed by GC and GC–MS. The content was calculated by the area normalisation method.
Results and discussion First, the reaction mechanism of ABL synthesis was explored by monitoring the changes of each compound during the reaction process to obtain ABL under mild reaction conditions with high yield, good stability, and minimal environmental hazard. Then, the enthalpies of formation of the reactants, products, and intermediates were calculated using the density functional theory. Characterisation of reaction components and their changes during the reaction Gas chromatogram of the reaction mixture (organic phase) after 340 min during the synthesis of ABL is shown in Fig. 1. Structures of ABL, EtOH, EtOAc, GBL, and α-(2-hydroxy-tetrahydrofuran-2yl)-α-acetyl-γ-butyrolactone (2-HTABL) were deter-
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Fig. 1. Gas chromatogram of the reaction mixture after 340 min reaction time. Reaction components: EtOH (1), EtOAc (2), GBL (3), ABL (4), Va (5), 2-HTABL (6).
mined by GC–MS using the NIST 05 mass spectral library and the MS data analysis depending on standard samples. Moreover, retention time of the standard compounds was used to validate their structures. α-(2-Tetrahydrofuranylidene-γ-butyrolactone (Va) was purified by column chromatography and its structure was confirmed by 1 H NMR, GC–MS, and IR spectral data. More details are given in Table 1. Changes of the components with the reaction time during the ABL synthesis are shown in Fig. 2. Contents of GBL and EtOAc decreased, whereas those of ABL and EtOH increased. Contents of both Va and 2-HTABL initially increased and then decreased. After 140 min of the reaction, contents of GBL and EtOAc decreased from 35.50 % to 3.08 % and from 64.50 % to 33.87 %, respectively. Contents of Va and 2-HTABL reached a maximum of 13.02 % and 5.16 %, respectively. During the process, the formation rate of ABL and EtOH is relatively high. Contents of ABL and EtOH increased from 0 to 22.16 % and 17.64 %, respectively. For the reaction time of 140–560 min, the formation rates of ABL and EtOH are relatively low,
Fig. 2. Content of the reaction components versus the reaction time: EtOH ( ), EtOAc ( ), GBL (), ABL ( ), Va (), 2-HTABL ( ).
•
and the contents of ABL and EtOH increased from 22.16 % to 46.57 % and from 17.64 % to 29.06 %, respectively. The content of GBL remained at 1.46– 1.63 %. Thus, the increasing content of ABL is not derived from GBL but from another pathway occurring during this process. Contents of Va and 2-HTABL decreased from 13.02 % and 5.16 % to 2.11 % and 0.77 %, respectively. This phenomenon shows that there is a direct relationship between the increasing contents of ABL, Va, and 2-HTABL. The formation of ABL essentially reached the equilibrium in 460–580 min, the content of ABL changed from 46.57 % to 47.12 %. Mechanism of ABL synthesis The density functional theory was used to calculate the enthalpies of formation (∆f H 0 ) of synthons, products, and potential intermediates (Table 2). The reaction enthalpies were calculated for each step of the reaction and the energy changes were used to explain the mechanisms (Przybylek & Gaca, 2012) shown in Fig. 3.
Table 1. Spectral data and retention time (tr ) of reaction components Compound
tr /min
Spectral data
EtOH EtOAc GBL ABL
7.55 7.15 10.93 17.67
Va
31.76
2-HTABL
34.92
MS, m/z (Ir /%): 46 (M+ , 34), 31 (CH3 , 100) MS, m/z (Ir /%): 88 (M+ , 8), 73 (C3 H5 O2 , 8), 70 (C4 H6 O, 19), 61 (C2 H5 O, 20), 43 (C2 H3 O, 100) MS, m/z (Ir /%): 86 (M, 50), 56 (C3 H4 O, 33), 42 (C2 H2 O, 100) MS, m/z (Ir /%): 128 (M+ , 7), 113 (C5 H5 O3 , 6), 86 (C4 H5 O2 , 100), 85 (C4 H4 O2 , 22), 43 (C2 H3 O, 85) IR, ν ˜ /cm−1 : 1728 (C— —O), 1680 (C— —C), 1375 (C—H), 1258 (C—O—C) 1 H NMR (DMSO-d ), δ: 2.05 (m, 2H), 2.79 (t, 2H), 2.97 (t, 2H), 4.23 (t, 2H), 4.28 (t, 2H) 6 MS, m/z (Ir /%): 154 (M+ , 100), 125 (C7 H8 O2 , 8), 113 (C5 H4 O3 , 40), 96 (C5 H4 O2 , 85), 83 (C4 H4 O2 , 13), 69 (C4 H6 O, 10), 68 (C4 H5 O, 10), 55 (C2 O2 , 26) MS, m/z (Ir /%): 214 (M+ , 0), 171 (C8 H11 O4 , 1), 154 (C8 H10 O3 , 26), 153 (C8 H9 O3 , 10), 129 (C6 H9 O3 , 13), 128 (C6 H8 O3 , 32), 113 (C5 H5 O3 , 22), 87 (C4 H7 O2 , 100), 86 (C4 H6 O2 , 96), 85 (C4 H5 O2 , 15), 69 (C4 H6 O, 31), 43 (C2 H3 O, 94)
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Table 2. Values of the theoretical absolute enthalpies of formation (∆f H0 ) at 25 ◦C of the reaction components Substance Na2 Na+ GBL ABL H2 O C2 H 5 O − C2 H5 OH H2 CH3 COOC2 H5 H3 O+ I II III IV V VI VII Va VIa
∆f H0 /(kJ mol−1 ) –852191.853 –426059.708 –804456.771 –1205125.477 –200582.161 –405189.739 –406848.425 –3050.910 –807590.252 –201633.858 –801894.309 –1610519.323 –1203440.563 –1607132.665 –1607373.449 –2414903.919 –2007728.829 –1408232.582 –2009672.671
The reaction of GBL and EtOAc is a typical α-H Claisen ester condensation reaction of two ester group containing compounds under strongly alkaline conditions. In theory, at least four products can be generated (Fig. 4). However, the changes in the material showed that the main reaction product is GBL, which loses an α-H to form a carbanion of GBL, and then attacks another carbonyl carbon of GBL and/or EtOAc in the reaction process. The loss of an α-H of EtOAc to form a carbanion which can attack another carbonyl compound is a minor side reaction. This is in agreement with the fact that the secondary carbanion is theoretically more stable than the primary one. The p electrons of the carbanion form a p–π conjugate with the adjacent carbonyl groups. The temperature of the reaction solution is high (80–88 ◦C) in the inducing phase, which increases also the temperature of the metallic sodium. When the surface of the metallic sodium gets into contact with the mixture of GBL and EtOAc,
Fig. 3. Mechanism of the transformation of GBL into ABL under alkaline conditions. Molar enthalpies (in kJ mol−1 ) for individual reaction steps: i) 1073.238, ii) –1034.745, iii) 204.137, iv) 26.234, v) –633.207, vi) –781.571, vii) –240.789, viii) 59.789, ix) 187.987, x) –59.078, xi) –168.490, xii) –633.207, xiii) –389.614.
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Fig. 4. Claisen ester condensation of EtOAc and GBL.
the low boiling point EtOAc (77 ◦C) is vapourised, while the high boiling point GBL (204 ◦C) is adsorbed on the surface of the metallic sodium, which leads to the formation of a GBL carbanion. A reaction mechanism for ABL synthesis under strongly alkaline conditions is proposed (Fig. 4), where sodium initially attacks the α-H (H atom adjacent to the carbonyl group) of GBL to form carbanion I (Fig. 3, reaction scheme Eq. (1)). The molar enthalpy of formation is 1073.238 kJ mol−1 . The reaction is endothermic and it is required to provide sufficient energy for its completion, which was also confirmed by theoretical calculations. The absolute enthalpy of formation of carbanion I is –801988.367 kJ mol−1 . Carbanion I is highly reactive and it easily reacts with the carbonyl carbon of GBL and EtOAc. Another possible mechanism of the ABL synthesis is the direct reaction of carbanion I with EtOAc (Fig. 3, reaction scheme Eq. (2)). Carbanion I attacks the carbonyl carbon atoms of EtOAc to form a C—C bond. The C—O double bond is transformed into a single bond to form oxygen anion II, and the enthalpy of formation is –1034.745 kJ mol−1 . Oxygen anion II attacks the connected carbons to form a C—O double bond. The ethoxy group is then eliminated to form ABL and the enthalpy of formation is 204.137 kJ mol−1 . The highly reactive ethoxy anion attacks the activated hydrogen of the β-dicarbonyl group in ABL and its removal results in the formation of the π–p–π conjugate III. The energy needed for this reaction is only 26.234 kJ mol−1 . The ratecontrolling step of this reaction mechanism (Fig. 3, reaction schemes Eq. (1) and Eq. (2)) is the formation of intermediate I. Carbanion III and a sodium ion form
a salt which is precipitated. Thus, the reaction process favours the formation of ABL. In the synthesis of ABL, the second mechanism involves GBL transformation to intermediate V, and its conversion into ABL (Fig. 3, reaction scheme Eq. (3)). Carbanion I attacks another carbonyl carbon of GBL and consequently the π bond of the C—O double bond opens to produce oxygen anion IV. The oxygen anion and α-H of GBL rearrange to form carbanion V. As spontaneous exothermic reactions, their molar enthalpies of formation are –781.571 kJ mol−1 and –240.789 kJ mol−1 , respectively. The p electrons of carbanion V and the carbonyl π bond form a p–π conjugate which is more stable than the intermediate oxygen anion IV. The centre of the activated carbanion in carbanion V is connected to three neighbouring carbon atoms attached to different groups, which increased the steric hindrance of the carbanion. Collision frequency between the carbanion centre and the carbon atom in the carbonyl group of EtOAc was decreased. The intermediate carbanion V attacks the carbonyl carbon in EtOAc and opens the π bond to form oxygen anion VI. The formation energy of the oxygen anion is 59.789 kJ mol−1 . The oxygen anion attacks the adjacent carbon to form a C—O double bond and to remove the ethoxy group to produce intermediate VIa with 187.987 kJ mol−1 . Under strongly alkaline conditions, hydrogen is removed from the hydroxyl group to form oxygen anion VII with –59.078 kJ mol−1 . The oxygen anion attacks the connected carbon to produce a C—O double bond and to form carbanion III as well as GBL. This reaction occurs spontaneously and is exothermic with the enthalpy of formation of –168.490 kJ mol−1 . The rate-
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controlling step of this reaction mechanism (Fig. 3, reaction scheme Eq. (3)) is the formation of intermediate VI. In this mechanism, the content of GBL is substantially constant while the content of ABL increases drastically. The results revealed the presence of intermediates Va and VIa, which further confirms the feasibility of the proposed mechanism. Intermediate V is protonated to obtain intermediate Va by the removal of a water molecule during the acid-catalysed reaction (Fig. 3, reaction scheme Eq. (4)). The enthalpy of formation of Va is –389.614 kJ mol−1 . Thus, the content of intermediate Va is representative of the content of intermediate V in the reaction system. In summary, GBL forms carbanion I by losing an α-H under strongly alkaline conditions. ABL is then obtained via two reaction mechanisms. One involves direct reaction of carbanion I with EtOAc to produce ABL. The other involves the formation of carbanions IV and V, by the reaction of carbanion I with GBL, followed by a proton shift (Fig. 3, I, IV, and V). The subsequent combination of carbanion V with EtOAc produces ABL. The formation of intermediates II, IV, and V is spontaneous, releases a lot of energy, and leads to by-products EtOH and EtOAc vapourisation giving rise to the occurrence of red material, fire, and explosion. It is very important to study the reaction mechanism not only to provide effective theoretical guidance, but also to design a reasonable production process. Selection of reaction conditions Research on the above mechanism shows that the rate of formation and the amount of generated carbanion I represent the key information for the security of the entire reaction in such an ABL synthesis process. This study examines the temperature increase rate and the specific surface area of metallic sodium. When the EtOAc/GBL and the sodium/GBL mole ratios are 1.5 and 1.1, respectively, the specific surface area of metallic sodium is 6.18 cm2 g−1 . The synthons are added at once and heated up slowly until the system starts to reflux; the reaction becomes steady ensuring thus the safety of the whole reaction, and the accidents, such as the production of red materials and/or fire, are eliminated completely (Zhang et al., 2010b). The mechanism of ABL synthesis indicates that the two reaction mechanisms ultimately form the target product. Therefore, it is unnecessary to consider problems of the synthon, either its local thickness or self-condensation. In this study, synthon was used as the solvent instead of alkylbenzene. The sodium/GBL mole ratio was 1.1, and the effect of the EtOAc/GBL mole ratio of 1.1 to 1.9 on the reaction was examined. The correction diagram of the yield as a function of the EtOAc/GBL mole ratio is shown in Fig. 5. Fig. 5 shows that the EtOAc/GBL mole ratio of
Fig. 5. Correlation diagram of the yield as a function of the EtOAc/GBL mole ratio.
1.5 is preferable and completely avoids the environmental pollution caused by using alkylbenzene. Thus, the yield of GBL conversion into ABL reaches a maximum. Under these conditions, ABL was isolated with a 90 % yield, which is by 10 % higher than the yield of the process which uses toluene as the solvent. It is shown that the π–p–π conjugate structure with sodium cation formed by both mechanisms of ABL synthesis is stable. In this study, the principle of salting out was applied, a phosphate acid was selected as the neutralising acid, and the effects of different concentrations of the phosphate acid and different separation temperatures of the organic and aqueous phase on the separation result were investigated. The results indicate that optimum separation is achieved when the phosphate acid concentration reaches 51 mass % and the separation temperature of the organic and aqueous phases reaches 60 ◦C. Under these reaction conditions, the aqueous phase does not need to be extracted by organic solvents, which greatly simplifies the purification process.
Conclusions The mechanism of ABL synthesis was experimentally and theoretically investigated. Theoretical simulations adopted the density functional theory. The ABL synthesis was explored via two proposed mechanisms. A rate-controlling step was determined for each possible reaction mechanisms. The rate-controlling step for the first reaction mechanism (Fig. 3, reaction schemes Eq. (1) and Eq. (2)) was the formation of intermediate I, and that for the second reaction mechanism (Fig. 3, reaction scheme Eq. (3)) was the formation of intermediate VI. The overall ratecontrolling step was the formation of intermediate VI. A new method for the ABL synthesis using synthon as the solvent, where the synthons are added at once while controlling the specific surface area of metallic
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sodium, is presented. The proposed method can be easily applied under mild reaction conditions avoiding thus pollution of the environment by the use of alkylbenzene as the solvent. More importantly, the method has been applied in a local industrial production and a higher yield of ABL, 90 %, was obtained.
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