Investigation on Main Reaction and Side Reaction Mechanism in the

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Investigation on main reaction and side reaction mechanism in synthetic process of 1-(5-bromothiophen-2-yl)-3-(4nitrophenyl)prop-2-en-1-one using Raman spectroscopy Jiajun Huang, Hongxun Hao, Yongli Wang, Ying Bao, Wei Ye, Chuang Xie, Qiuxiang Yin, and Zhihong Sun Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500234a • Publication Date (Web): 28 Oct 2014 Downloaded from http://pubs.acs.org on November 19, 2014

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Organic Process Research & Development

Investigation on main reaction and side reaction mechanism

in

synthetic

process

of

1-(5-

bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1one using Raman spectroscopy Jiajun Huanga, Hongxun Haoa,b*, Yongli Wanga,b, Ying Baoa,b, Wei Yec , Chuang Xiea,b, Qiuxiang Yina,b , Zhihong Sun a School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China. b The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin 300072, China. c College of Chemical Engineering, Northwest University, Xi’an, Shaanxi 710069, China.

ACS Paragon Plus Environment

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ABSTRACT: 1-(5-bromothiophen-2-yl)-3-(4-nitrophenyl) prop-2-en-1-one (BTNP) has unique and highly attractive properties, which make them a new kind of nonlinear optical (NLO) organic material for wide applications in the fields of optical communication and flat panel display. In this work, BTNP was successfully synthesized by Claisen-Schmidt condensation reaction. To optimize the synthesis process and improve the purity of the product, the synthetic process of BTNP was monitored in situ by Raman spectroscopy to find out the mechanism of main reaction and possible side reactions. The possible side reactions were proposed based on Raman spectroscopy data. The effect of reaction conditions, including dosage of sodium hydroxide and reaction temperature, was investigated and analyzed by using the proposed side reaction scheme. It was found that the sodium hydroxide dosage is the key factor for the main reaction (Claisen-Schmidt condensation reaction) and side reactions. The effect of reaction conditions on the purity of the obtained BTNP products was investigated and analyzed. The results are consistent with those of proposed side reactions. The purity of the obtained product can reach 96.88% under optimized experimental conditions. ■ INTRODUCTION

Nowadays, chalcone and its derivatives have attracted a great deal of interest of scientists and engineers working in biomaterial and optical material, due to their wide applications as antibacterial, anti-inflammatory and cross conjugated nonlinear optical (NLO) chromophores1-4. Chalcone derivatives are also important intermediates in the synthesis of many pharmaceuticals. BTNP, a new member of chalcone derivatives, is one kind of potentially useful NLO organic material because of its good transparency, thermal stability and high second harmonic generation efficiency5.


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It is well-known that the chalcone derivatives are commonly synthesized via the Claisen– Schmidt condensation between substituted acetyl thiophene and substituted benzaldehyde in the presence of an alkali6. In this work, BTNP was synthesized by the condensation between 2acetyl-5-bromothiophene and 4-nitrobenzaldehyde in the presence of sodium hydroxide (The synthetic scheme of BTNP was given in Scheme 1). Thus, the BTNP synthesis process can be regarded as a typical representative of Claisen–Schmidt condensation. In recent years, some researchers have focused on the characterization of optical, thermal and mechanical properties of BTNP5, and others have put their attentions on finding the efficient, simple and inexpensive catalysts for the Claisen–Schmidt condensation reaction7, 8. Nevertheless, there was little attempt to explore the side reaction of Claisen–Schmidt condensation process or BTNP synthesis process, which can greatly affect the purity of the final product. For example, during the BTNP synthesis process, the overproduction of by-products could lead to that the purity of BTNP in the prepared products can not meet the expected requirements. Thus, investigation on the mechanism of side reactions in the BTNP synthesis process is carried out to better understand the reaction process and to optimize the reaction conditions and improve the quality of products. Traditional offline techniques, such as nuclear magnetic resonance (NMR) and fluorescence, usually cannot provide real-time information on the reaction process because they require invasive sample preparation before the measurement, which might change the reaction condition. Recently, efforts have been concentrated on novel monitoring methods in order to confront those drawbacks mentioned above. Several researchers have demonstrated that the in situ techniques, such as Raman spectroscopy and Fourier-transform infrared spectroscopy (FTIR), can be accurate and convenient to study the reaction process9-12. Besides, among these two in situ techniques, the Raman spectroscopy proves to be the promising online spectroscopic method for


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monitoring this kind of reaction processes because of its low sensitivity to water and widespread applicability to both homogeneous and heterogeneous reaction media. Hence, in this work, the BTNP was synthesized by the condensation between 2-acetyl-5bromothiophene and 4-nitrobenzaldehyde in the presence of sodium hydroxide. The mechanism of side reactions in the synthetic process of BTNP was investigated by in situ Raman spectroscopy. . After the Raman spectroscopic analysis, the main side reactions in the process of BTNP synthesis was demonstrated. Moreover, the effect of temperature and amount of sodium hydroxide on the side reactions was also examined. ■ RESULTS AND DISCUSSION

Scheme 1. Synthetic scheme of BTNP In Situ Monitoring of the Claisen–Schmidt Condensation. From Scheme 1, it can be seen that the C=C bond of BTNP is formed by Claisen–Schmidt condensation reaction, which is resulted from the condensation between an methyl groups of 2-acetyl-5-bromothiophene and an aldehyde group of 4-nitrobenzaldehyde. Thus, investigation on the changing process of methyl,


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aldehyde and C=C bond groups by Raman spectroscopy is carried out to analyze the mechanism of main reaction and possible side reactions in the BTNP synthesis process. First of all, the consumption or/and accumulation of methyl, aldehyde and C=C bond groups was monitored by in situ Raman spectroscopy at 40 oC ( The amount of sodium hydroxide aqueous solution was fixed at 5 ml). The designation and corresponding Raman responses (wavenumber) of all functional groups used in this work are given in Table 1 (data is from the book named Spectrum analytical method13 and the raman spectrum database of Kaiser Optical Systems). In Raman spectral region of reaction medium, the stretching mode at 1731 and 1401 cm-1 are characteristic peaks of aldehyde (C=O) and methyl (C-H) respectively while the characteristic peak at 1655 cm-1 attributes to the vibration modes of the band 7 (C=C bonds). During the reaction processes, the profiles of these three Raman peaks are shown in Figure 1. From Figure 1, it can be found that the intensity of peaks at 1401 and 1731 cm-1 began to decrease correspondingly while the peaks at 1655 cm-1 began to increase correspondingly. These results are reasonable since C=C bonds will be formed while C=O and C-H will be destroyed in the Claisen–Schmidt condensation reaction. However, it should be noted that the intensity of peak 1655 cm-1 starts to gradually decrease after reaching maximum at some point. This result indicates that side reactions, which may be caused by other functional groups of the reaction medium, should exist in the synthesis process of BTNP.


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Table 1. The designation and corresponding Raman responses of all functional groups used in this work: all the functional groups are numbered sequentially for the discussion. No.

Wavenumber (cm-1)

Assignments

1

1401

CH3 wagging

2

655

C-Br stretch

3

1442

N=N symmetric stretch

4

1594

N-H symmetric stretch

5

1351

NO2 asymmetric stretch

6

1731

C=O symmetric stretch

7

1655

C=C symmetric stretch

8

870

C-C-O stretch


Functional groups

6

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9

640

C-Br stretch

10

844

C-O-N stretch

11

1803

O-H stretch

12

933

ring breathing vibration

13

1001

ring puckering vibration

14

540

C-Br stretch

Figure 1. Real-time Raman analysis of the Claisen–Schmidt condensation at 40oC


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Mechanism of Side Reactions . In order to further investigate the mechanism of side reaction s, it is necessary to focus on limited number of Raman peaks of reaction medium to monitor the change of main covalent bonds of reagent and solvent (ethanol) during the condensation reaction. First of all, the changing process of group 2(-Br) with characteristic Raman peak at 655 cm-1 and group 5(-NO2) with characteristic Raman peak at 1351 cm-1,which correspond to CBr stretching vibration and NO2 asymmetric stretching vibration respectively, was monitored to figure out whether they were involved in the side reaction or not. The intensity of these two Raman peaks should remain constant during the reaction if groups 2 and 5 do not get involved into the side reaction during the condensation reaction. Nevertheless, it was found in Figure 2 and Figure 3 that the characteristic Raman peaks of these two groups decreased with the addition of sodium hydroxide aqueous solution. It is reasonable to assume that the consumption of groups 5(-NO2) is due to the side reactions, which are described in step 1 and step 2 of Scheme 2 which shows the mechanism of side reactions during the synthesis process. The intensity of Raman spectra of groups 3(N=N), 4(-NH2) and 5(-NO2) presented in Figure 2 clearly shows that the part of groups 5 transformed into groups 3(N=N) and 4(-NH2) under alkali condition. Similar findings were published by other researches14,15. They found that Nitro groups attached to an aromatic ring can be reduced into amino and groups 3(N=N) under alkaline media. Besides, it is interesting to note that the concentration of groups 4(-NH2) initially increased at the early stage of reaction and then remarkably decreased when the reaction time exceeds 50min. This big undulation of –NH2 concentration indicates that groups 4(-NH2) should be involved into further side reaction.


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Scheme 2. The side reaction scheme of primary groups in the synthesis process of BTNP. Furthermore, previous studies have pointed out that the group 2(-Br) can be substituted by aliphatic hydroxyl groups (-OH) under alkali condition due to its high polarizability16,17. It might be possible that some side reactions may be resulted from the combination between group 2(-Br) and solvent (ethanol). In order to investigate whether this side reaction occurred, the changing process of bands 2, 8, 9 and 11 was detected by in situ Raman (as shown in Figure 3). It can be observed that the intensity of Raman shift at 1803 cm-1 which is assigned to OH stretching vibration from thienol increased with the consumption of -Br and aliphatic hydroxyl groups(-OH). This indicates


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that the substitution reaction (step 4 of Scheme.2) did happen. Moreover, the consumption of band 8 indicates that the alcoholic hydroxyl group is involved into the nucleophilic substitution to yield band 11 ( phenolic group (-OH)). Nevertheless, it worth noting again that the Raman intensity of phenolic group (-OH) of thienol start to decease after reaching maximum at some point with further progressing of the reaction. This phenomenon is similar to the changing trend of the group 4(NH2). This also indicates that something else will happen to the phenolic group (-OH).

Figure 2. Real-time in situ Raman analysis of the side reactions involving group 5 (-NO2) at 40oC when the sodium hydroxide aqueous solution was fixed at 5 ml. The similar changing trend of phenolic group 11 (-OH) and group 4 (-NH2) implies that there might be strong correlation between these two groups. It is known that the band 10 (Table 1) at 844 cm-1 is attributed to C-O-N stretching vibration. It can be seen from Figure 3 that the intensity of C-O-N signal increases with the decreasing of the intensities of -OH signal and -NH2 signal. This result indicates that the neutralization reaction between the phenolic group 11 (-OH)


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of thienol and group 4 (-NH2) has happened, which is described as the step 3 of Scheme 2. This is reasonable when considering that the phenolic group (-OH) is weak acid and groups 4 (-NH2) is alkali18.

Figure 3. Real-time in situ Raman analysis of the side reaction involving step 3 and 4 at 40oC From the Raman intensity profile of group 7 (C=C) in Figure 4, it can be seen that the concentration of BTNP starts to decrease after some time. It indicates that target product BTNP is also involved into some further side reaction. It has been reported that the consumption of group 7 (C=C) may be resulted from the side reaction between C=C and -Br. However, from the above discussion about the variation of -Br and -NO2, and considering the flat changing trend of Raman intensity of group 14, it can be concluded that no side reaction between C=C and -Br has happened. Besides, the dehydrogenation also should be excluded due to the absence of dehydrogenation catalyst. Hence, further investigation is carried out to determine whether the


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side reaction is the reason of the C=C consumption. From literatures, it can be assumed that the consumption of C=C group may be a result of series of reactions including addition or/and cyclization between C=C group catalyzed by N=N group produced from -NO2 group, which was described as the step 5 of Scheme 2. To test this hypothesis, two Raman signals at 933 cm-1 and 1001 cm-1, which are attributed to the breathing vibration (group 12) and puckering vibration (group 13) of cyclobutane ring, respectively, and other signal which is attributed to C=C (group 7), were monitored and the evolution of these signals are given in Figure 4. It can be clearly seen from Figure 4 that the intensity of breathing vibration and puckering vibration signals of cyclobutane ring increase while the C=C signal decreases with time. This result indicates that the consumption of C=C group is due to side reaction, which is resulted from the cyclization reaction of C=C group. As the earlier research suggested, this cyclization reaction can be regarded as two steps. The first step is the formation of radical under the condition of initiating agent of radical which contains group 3 (N=N)19,20. And the second step is the radical addition of two group 7 (C=C) to finish cyclizations in organic media21-23. Through the above investigation of the side reactions during the synthesis of title compound (BTNP) by Raman spectroscopy, the mechanism of all possible side reactions are clearly found . The high sensitivity of in situ Raman technique is also confirmed.


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Figure 4. Real-time in situ Raman analysis of the addition cyclization involving group 7(C=C) The Influence of Reaction Conditions on Synthesis Process. After discovering the mechanism of side reactions, to optimize the synthesis process of BTNP, the effect of different reaction conditions on the main reaction and side reactions were investigated in detail. All the experiments were in situ monitored by the Raman spectroscopy. The Effect of Reaction Conditions on the Claisen-Schmidt Condensation. First of all, the effect of sodium hydroxide dosages was investigated. The data of Raman spectroscopy obtained for the Claisen-Schmidt condensation reaction (primary reaction process) at three different sodium hydroxide dosages (0.5 ml, 1 ml, 12 ml) are shown in Figure 5. It can be observed from Figure 5 (c) that the content of C=C group is stable at around zero, which indicates that the Claisen-Schmidt condensation reaction is negligible due to the little amount of sodium hydroxide (0.5ml). When the dosage of sodium hydroxide dosage was increased to 1ml, it can be seen from Figure 5 (b) that the content of C=C group increased apparently due to the Claisen-Schmidt condensation reaction and its content remains constant after reaching maximum. This means that


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the obtained BTNP product is stable under this condition and will not get involved into further side reaction. However, when the sodium hydroxide dosage was increased further to 5ml (Figure 5 (a)), the content of C=C group apparently increases first and then starts to decrease with time. This indicates that the Claisen-Schmidt condensation reaction could happen under this condition but the obtained BTNP will be involved into further reaction in which BTNP will be a reactant. This can be explained by the result of side reaction (step 5 of Scheme 2). This phenomenon reveals that the appropriate sodium hydroxide dosage (1 ml) should be used to promote the Claisen-Schmidt condensation reaction, without causing the side reaction of C=C group. Furthermore, the effect of temperatures on the Claisen–Schmidt condensation process was also investigated at fixed sodium hydroxide dosage (2 ml). The results are shown in Figure 6. It can be observed from Figure 6 that the Claisen–Schmidt condensation could happen at either 10 oC or 50 oC. But when the temperature is increased from 10 oC to 50 oC, the content of C=C group starts to decrease after reaching maximum. This means that when temperature is too high it could also result in further side reactions of BTNP synthesis. By comparing the effect of temperature and the dosage of sodium hydroxide, it can be concluded that sodium hydroxide dosage is the key factor which will greatly affect the Claisen–Schmidt condensation reaction and its side reactions.


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Figure 5. Effect of sodium hydroxide dosage on the Claisen–Schmidt condensation at 30oC ( 5ml (a) , 1ml (b) , 0.5ml (c) )


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Figure 6. Effect of temperature on the Claisen–Schmidt condensation at the sodium hydroxide dosage of 2 ml ( 50oC (a) , 10oC (b) ) The Effect of Reaction Conditions on The Addition Cyclization of C=C (group 7). As discussed above, it has been known that the decrease of C=C group during synthesis is due to the generation of cyclo-butane ring by cyclization reaction. In order to investigation the effect of reaction conditions (temperature and sodium hydroxide dosage) on the cyclization reaction of C=C group, the characteristic Raman signal of cyclo-butane ring (band 12 and 13) and band 3 (N=N) (generated from -NO2 as mentioned above, acting as catalyst for cyclization reaction) at 1442 cm-1 are monitored. The effect of temperature on the addition cyclization is shown in Figure 7 (with sodium hydroxide dosage of 2 ml). It can be observed that the significant increase of the content of cyclo-butane ring ( band 12 and band 13) is accompanied by the decrease of the content of group 7(C=C) at higher temperature (50oC). While at lower temperature (25 oC ), the increasing trend of the content of cyclo-butane ring ( band 12 and band 13) is much slower . It indicates that lower temperature will help to slow down the side reaction( cyclization of C=C). This might be due to the exponential dependency of kinetic constants on temperature (Arrhenius law). On the other hand, the quantity of group 3(N=N) remains almost constant during the cyclization reaction at both temperatures. These confirms our assumption that the group 3(N=N)


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serves as catalyst. The effect of sodium hydroxide dosage (1ml and 12ml) on the cyclization reaction at same temperature (30oC) is given in Figure 8. It is shown that the reaction rate of addition cyclization increases significantly with the increasing of sodium hydroxide dosage from 1 ml to 12 ml, similar to the behavior of addition cyclization reaction at different temperatures. This result indicates that the addition cyclization of C=C ( side reaction 5 ) can be controlled or suppressed by adjusting the dosage of sodium hydroxide and the reaction temperature.

Figure 7. Effect of temperature on the addition cyclization of group 7(C=C) at the sodium hydroxide dosage of 2 ml ( 50oC (a) , 25oC (b) )


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Figure 8. Effect of sodium hydroxide dosage on the addition cyclization of group 7 (C=C) at 30oC ( 12ml (a) , 1ml (b) ) The Effect of Reaction Conditions on Other Side Reactions. From above discussion, it has been know that the main reaction (Claisen-Schmidt condensation) will happen only when the dosage of sodium hydroxide is higher than 1 ml. So, the effect of sodium hydroxide dosage on other side reactions is investigated by varying the dosage of sodium hydroxide from 1 ml to 12 ml (Figure 9). From Figure 9, it can be seen that side reactions 3 and 4 will not happen while side reaction 1 and 2 will happen at the dosage of 2 ml sodium hydroxide. Nevertheless, when the dosage of sodium hydroxide was increased to 10ml, all side reactions of 1,2,3,4 will happen. It can be conclude that side reaction 3 and 4 can be suppressed by controlling the dosage of sodium hydroxide while side reaction 1 and 2 is unavoidable. The effect of temperature on the side reactions is shown in Figure 10 by varying the temperature from 10oC to 50oC with the dosage of sodium hydroxide of 1ml .From this figure, it can be seen that side reactions 1 and 2 happened at either temperature with the increase of the content of band 3 (N=N) and band 4 (-NH2) while side reactions 3 and 4 didn't happen at either temperature. Combining data from Figure 9 and figure 10, it can be concluded that the dosage of


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sodium hydroxide was the key factor which will significantly affect the side reactions 3 and 4. These two side reactions can be controlled by changing the dosage of sodium hydroxide.

Figure 9. Effect of sodium hydroxide dosage on side reactions 1, 2, 3 and 4 at 30oC (12ml (a) , 1ml (b) )

Figure 10. Effect of temperature on side reactions 1, 2, 3 and 4 at sodium hydroxide dosage of 2 ml ( 50oC (a) , 10oC (b) )


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Effect of Reaction Conditions on the Purity of Final BTNP Products. From above analysis, it has been known that the dosage of sodium hydroxide is the key factor which will affect not only the main reaction but also the side reactions. If the dosage of sodium hydroxide can be controlled appropriately, side reactions 3,4 and 5 can be suppressed although side reaction 1 and 2 will happen anyway. It has also been known that the reaction temperature will slightly affect the main reaction and side reactions. If temperature is too high, it will also promote the side reactions. To verify above conclusions and the proposed side reaction scheme, the effect of reaction conditions on the purity of the final BTNP products is shown in Table 2 and graphically shown in Figure 11 and 12. It can be seen from Figure 11 that the purity of BTNP reaches maximum value of 95.22% at dosage of sodium hydroxide 1-2 ml while starts to decrease to 57.12% when the sodium hydroxide dosage increases from 2 ml to 12 ml. This phenomenon indicates that high sodium hydroxide dosage will result in more side reactions, which is in accordance with the impact of sodium hydroxide dosage on side reactions which has been mentioned above.

Figure 11. Effect of sodium hydroxide dosage on the purity of BTNP at 30oC


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From Figure 12, it can be seen that the purity of BTNP varies slightly with the increasing of reaction temperature. The purity of BTNP increases from 89.47% to 95.81% as the temperature increases from 10oC to 25oC then slightly decreases as the temperature increases from 25oC to o

50 C. From Figure 6 and 10, the main reaction and side reactions 1, 2, 3, 4 will be accelerated slightly when temperature increases from 10oC to 50oC. However, from Figure 7, the reaction rate of side reaction 5 will increase significantly as the temperature increases from 25oC to 50oC. Through the above analysis, it can be inferred that the main reason for the decreasing of the purity of BTNP at higher temperature is the significant intensification of side reaction 5 when temperature is increased. So there should be a optimum reaction temperature. In this case, the optimum temperature will be around 25 oC .

Figure 12. Effect of temperature on the purity of BTNP at the sodium hydroxide dosage of 2ml Through the analysis of the mechanism of main reaction and side reactions of the synthesis process of BTNP, the effect of temperature and sodium hydroxide dosage on the Claisen– Schmidt condensation reaction and side reactions is well understood. By experiments and process analysis, it was found that the purity of BTNP can reach 96.88 % when the synthesis conditions of BTNP are well controlled. .


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■ CONCLUSIONS BTNP (1-(5-bromothiophen-2-yl)-3-(4-nitrophenyl) prop-2-en-1-one) was successfully synthesized from 2-acetyl-5-bromothiophene and 4-nitrobenzaldehyde by Claisen–Schmidt condensation reaction. The synthesis process of BTNP was in situ monitored by Raman Spectroscopy to investigate the mechanism of main reaction and side reactions. The effect of reaction conditions (temperature and sodium hydroxide dosage) on the Claisen–Schmidt condensation reaction and side reactions was investigated and discussed by using Raman spectroscopy data and HPLC data. The mechanism of side reactions was discovered and verified. It was found that the side reactions 1 and 2 are not avoidable although it could be affected slightly by temperature and dosage of sodium hydroxide. The carbon-carbon double bond (C=C) formed by the Claisen–Schmidt condensation reaction could result in further addition cyclization under the catalysis of photoinitiators (N=N) which is produced by another side reaction. Moreover, the sodium hydroxide dosage was the key factor for causing the side reactions. By controlling the dosage of sodium hydroxide, side reactions 3, 4 and 5 could be suppressed. Furthermore, the effect of temperature and sodium hydroxide dosage on the purity of BTNP products was analyzed. The results are consistent with the conclusions from the proposed side reaction scheme. The purity of obtained BTNP can reach 96.88% under well designed reaction conditions. ■ EXPERMENTAL SECTION Reagents and Materials.2-acetyl-5-bromothiophene (99%) and 4-nitrobenzaldehyde (99%) used to synthesize BTNP was purchased from Shanghai Fortunebio-tech Company (Shanghai, China). For the experiments of reaction, sodium hydroxide (Tianjin-guangfu, Tianjin, China) and


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the solvents (ethanol, methanol, acetone, pure water) were used as received. They are analytical grade with purity higher than 99.5% . The Synthesis Process of BTNP .The synthesis of BTNP was carried out in a 150 ml cylindrical jacketed round-bottom glass reactor equipped with a stainless steel agitator. The reactants, 2-acetyl-5-bromothiophene (0.005 mol) and 4-nitrobenzaldehyde (0.005 mol), were added into ethanol (100 ml) under continuous agitation. After the complete dissolution of the reactants, sodium hydroxide (w/w, 1%) was added into the solution at a dosing rate of 500 µl/min and then allowed to agitate for 1.5 h. The agitation speed and temperature were precisely controlled and recorded using a Mettler Toledo EasyMax reactor system . Thereafter, the crude product (sediment) which contained the BTNP was collected by filtration and dried for 24 hours. The synthetic scheme of BTNP is presented in Scheme 1. The conditions of all experiments performed along the synthesis process are listed in Table 2. Several experiments were conducted by varying the temperature (in the range of 5-50 oC) and the sodium hydroxide dosage ( 0.2 to 12 ml). Online Analysis Methods. All the synthesis processes of BTNP under different reaction conditions were in situ monitored by Raman spectroscopy. A 785 nm Raman RXN2TM HYBRID Analyzer from Kaiser Optical Systems, Inc. (Ann Arbor ,U.S.A with an immersion fiber-coupled MR probe together with iC Raman software was used to in situ monitor the reactions. The Raman spectra were collected at an intervals of 1 min while the total exposure time was set at 10 seconds. The Pearsons correction was applied to the spectrum to reduce the baseline drift impact. The relative Raman intensity of each of the peaks was tracked to investigate the BTNP synthesis process. The Raman peak height to 0 baseline was used to generate the relative Raman intensity.


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Page 24 of 27

The dried samples from the series of synthesis process were analyzed by HPLC on an Agilent 1100 HPLC-DAD system with a Kromasil-C18-5u column (250mm×4.6mm i.d., 5µm) at room temperature. Methanol–water (90:10, v/v) was used as the mobile phase. The flow rate was set at 1.0ml min-1, and the effluents were monitored at 254nm. The purity of BTNP in dried sediment was determined by LC area percentage. The analyzing results of BTNP products are included in Table 2. Table 2 Experimental conditions for different runs and the corresponding HPLC results of BTNP products T (oC)

VNaOH(1%) (ml)

t (h)

PurityBTNP（relative area%）

5

2

1.5

89.47

10

2

1.5

91.04

15

2

1.5

92.50

20

2

1.5

93.61

25

2

1.5

95.86

30

2

1.5

94.73

40

2

1.5

92.11

50

2

1.5

90.07


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30

0.2

1.5

0

30

0.5

1.5

81.77

30

1

1.5

95.23

30

2

1.5

94.73

30

3

1.5

72.09

30

5

1.5

69.85

30

8

1.5

63.54

30

12

1.5

57.12

40

5

10

0

25

1

1.5

96.88

■ ASSOCIATED CONTENT Supporting Information Available The supporting information is available free of charge via the Internet at http://pubs.acs.org. ■ AUTHOR INFORMATION


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Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest. ■ ACKNOWLEDGMENTS This research is financially supported by National Natural Science Foundation of China (No. 21376165) and Key Project of Tianjin Science and Technology Supporting Programme (No. 13ZCZDNC08900). The authors also would like to thank Kaiser Optical Systems, Inc. for providing the Raman RXN2 system. ■ REFERENCES

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(3) For recent reviews on reaction process via in situ techniques see: (a) Brun, N.; Youssef, I.; Chevrel, M.-C.; Chapron, D.; Schrauwen, C.; Hoppe, S.; Bourson, P.; Durand, A. J. Raman Spectrosc. 2013, 44, 909-915. (b) Yang, X.; Lu, J.; Wang, X.; Ching, C. B. J. Raman Spectrosc. 2008, 39, 1433-1439. (c) Alb, A. M.; Reed, W. F. Macromol. 2008, 41, 2406-2414. (d) Assirelli, M.; Xu, W.; Chew, W. Org. Process Res. Dev. 2011, 15, 610-621. (4) For the book which contained the raman date of Table 1 see:Tieying P.; Yulan Z.; Keman S. Spectrum analytical method; East China University Of Science and Technology Press: Shanghai, CN., 2009. (5) For the recent review on transformation reaction involved the groups 5(-NO2) see: (a) Cann, K.; Cole, T.; Slegeir, W.; Pettit, R. J. Am. Chem. Soc. 1978, 100, 3969-3971. (b) Galbraith, H. W.; Degering, E. F.; Hitch, E. J. Am. Chem. Soc. 1951, 73, 1323-1324. (6) For the recent review on substitution reaction involved the groups 2(-Br) see: (a) Facchetti, A.; Mushrush, M.; Katz, H. E.; Marks, T. J. Adv. Mater. 2003, 15, 33-38. (b) Yanmao, D.; Lu, J.; Xu, Q.; Yan, F.; Xia, X.; Wang, L.; Hu, L. Synth. Met. 2010, 160, 409-412. (7) For the recent review on weak acid of phenolic group (-OH) see: Saunders, B. B.; Kaufman, P. C.; Matheson, M. S. J. Phys. Chem. 1978, 82, 142-150. (8) For the recent review on radical addition cyclizations see: (a) Yorimitsu, H.; Wakabayashi, K.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1999, 40, 519-522. (b) Tsuritani, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2003, 68, 3246-3250. (c) Kita, Y.; Nambu, H.; Ramesh, N. G.; Anilkumar, G.; Matsugi, M. Org. Lett. 2001, 3, 1157-1160. (d) Li, C.-J. Chem. Rev. 2005, 105, 3095-3166. (e) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449-1484.


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Investigation on Main Reaction and Side Reaction Mechanism in the

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