Tao Shen,Bo Ouyang,2,Chao Qian,3, *,Xinzhi Chen

1 Zhejiang Provincial Key Laboratory of Advanced Chemical Engineering Manufacture Technology,College of Chemical and Biological Engineering,Zhejiang University,Hangzhou 310027,China

2 Zhejiang Garden Biochemical High-Tech Co.,LTD,Dongyan 322121,China

3 Research Institute of Zhejiang University-Quzhou,Quzhou 324000,China

Keywords:Tubular reactor Reaction kinetics Ethyl acetate Aminolysis

ABSTRACT The aminolysis of ethyl acetate was promoted significantly via continuous reaction in a tubular reactor.Npropylacetamide was thus synthesized without presence of solvent and catalyst.The optimum conditions were obtained as follows:the reaction temperature is 218°C,the reaction pressure is 3.5 MPa,the molar ratio(ethyl acetate:N-propylamine)is 1:1,and the residence time is 350 min.Accordingly,the conversion of ethyl acetate is up to 94.8%.Furthermore,the kinetics of the rapid reaction stage(when the conversion of ethyl acetate is 20%-80%)can be expressed as lnk=-4629.44 1/T+2.1366,and the apparent activation energy is Ea=38489 J·mol-1.

1.Introduction

Amides continue to serve as key intermediates for preparing versatile products like peptides,polymers,natural products and medicines[1,2];the synthesis of amides is thus attracting great attention[3-5].Acyl halides[6-8],anhydrides[9,10],esters[11-13]and carboxylic acids[14-16]are usually employed as substrates for the formation of amide.For example,the aminolysis of acyl halides is a typical addition-elimination process;here,the halogen atom is of strong electronwithdrawing ability and prone to accept electrophilic attack to afford an amide.Although the aminolysis of acyl halides is already a widely employed process in industry,it suffers from some well-known defects,e.g.inevitable using of organic solvent,coupling reagents and catalyst,as well as the emission of waste acid and harsh conditions[17].To solve these problems,an alternative route,i.e.aminolysis of esters was developed,producing alcohol as the only by-product.In addition,the aminolysis of esters does not only avoid emission of waste acid but also benefits from cheap raw materials and higher selectivity.However,catalyst and long reaction time were still required due to the inertness of esters[18].Despite the fact that considerable efforts have been made recently to promote the production of amides by using one-pot synthesis[19],various catalysts[20-22]or radiofrequency heating[23],the application of these strategies in scale-up processes is still limited due to the intervention of solvents or catalysts.Thus,the development of green and efficient process for aminolysis continues to be interesting and challenging.

On a different background,continuous flow reactor is an attractive alternative to batch reactor due to their fast mass transfer,safe access to high temperatures and pressures,as well as high surface area to volume ratio[24].In a continuous-flow tubular reactor,reactive reagents were pumped into a narrow-diameter pipeline under precisely controlled temperature and pressure.As a chemical strengthening process technology,tubular reactor can be applied to enhance reaction efficiency and has higher scale-up potential as compared to standard batch techniques[25-30].There exist several reports on process intensification performed in tubular reactors.For example,(a)Cantillo et al.[31]developed a continuous-flow protocol for the preparation of nitriles from carboxylic acids under high temperature and pressure without any catalyst or additives;(b)Ouchi et al.[32]reported a process intensification for hydrogenation of ethyl nicotinate using a trickle continuous flow bed reactor;(c)Kohl et al.[33]adapted a continuous-flow process for the amination reactions of aryl halides and esters;and(d)Rincon et al.[34]described a continuous-flow protocol to accomplish cycloaddition of nitrones,which is not easily achievable in conventional reactors.

Classical route to synthesize N-propylacetamide from ethyl acetate and N-propylamine uses methanol as solvent,disodium carbonate as catalyst,while the yield of product is only 65%at 60°C[35].The low boiling point of the solvent and the limit of pressure in a batch reactor make it hard to elevate the reaction temperature to reach a higher yield.This inspired us to improve the batch aminolysis to a continuous-flow process.In this paper,we report the aminolysis of ethyl acetate with N-propylamine performed in a continues-flow tubular reactor with the focus on industrially scale-up consideration.The reaction condition was explored and kinetics of the rapid reaction stage(ethyl acetate conversion rate of 20%-80%)was studied.

2.Experimental and Characterization

2.1.Materials

Ethanol(AR),dimethylformamide(AR)were commercial products from Sinopharm Chemical Reagent Co.,Ltd.N-propylamine(99%purity)and N-propylacetamide(99.9%purity)were commercial products from Aladdin?.All regents were used without further purification.

2.2.Method

A schematic diagram of the tubular reaction device is shown in Fig.1.The tubular reaction device is composed of three parts:a feeding device,a reaction tube and a collector.In the feeding device,the substrates in the measuring cylinder were fed into the tubular reactor by a pump(LC-P100PHP,Shanghai Wufeng Scientific Instrument Co.,Ltd.).The length of the tube is 85 m with an outer diameter of 3 mm and a wall thickness of 0.5 mm.The reactor was heated with an oil bath(HH-S,Jintan Jairel Electric Co.,Ltd.).The collector consists of an autoclave(250 ml,30 MPa)and a collection tank,with a sample bypass between the autoclave and the collection tank.The autoclave was filled with nitrogen gas to ensure that the pressure of the reactor was higher than the bubble point pressure of the substrates.The pressure during the experiment was monitored by a high temperature pressure transmitter(MeiKong Control Co.,Ltd.).The aminolysis of ethyl acetate in the continuous-flow tubular reactor involved the following steps:

a.The reactor was purged with nitrogen gas through valve 12 until the pressure was 5.0 MPa and kept steady for 30 min to make sure it was sealed well.

b.The temperature of oil bath was set to the reaction temperature and the stirring paddle 5 was switched on to maintain a uniform temperature in the oil bath;the reactor was filled with nitrogen gas through valve 12 until reaching the reaction pressure.

c.Certain amount of ethanol and dimethylformamide was mixed before being added into the measuring cylinder 1.The mixed reactants were introduced into the tubular reactor via pump 3.

d.As the reaction proceeds,the pressure in the autoclave 7 raised,then valve 13 was open somewhat to keep pressure steady.

e.After 350 ml of reactants were pumped in the reactor,the pump 3 and the valves 10,11 were closed,and then a sample can be collected via valve 12 for analysis.

2.3.Analysis methods

The reaction solution sample was analyzed by gas chromatographymass spectrometry(Agilent 5973,GC-MS)firstly.The rest reaction solution sample was evaporated to dryness under reduced pressure to get the crude product,the crude product was purified by recrystallization using ethanol.And the purified product was obtained after filtration.1H NMR spectra were recorded using Bruker DRX-400 spectrometer using solvent peaks as CDCl3solutions after purification by recrystallization using ethanol.

Quantitative analysis of the products was carried out by external standard method using GC(Agilent 1790F series)analyses.The GC analysis of the standard solutions was carried out to get the Eq.(1)between the peak area A with N-propylacetamide concentration c.

The reaction liquid mixture sample was weighed of mass mi(g)before adding into a volumetric flask,and then the volume was adjusted to V.GC analysis was carried out to get Aiof the peak area of Npropylacetamide(average area by three times).The molar concentration of the product was used to characterize the concentration of the product.The sample mass molar concentration b was calculated as shown in the following Eq.(2);the reaction conversion x calculation was decided by the molar ratio of ethyl acetate to N-propylamine.When N-propylamine is excessive,the reaction conversion x was calculated using Eq.(3),M1and M2are the molar masses of ethyl acetate and n-propylamine,respectively,and n1and n2were the molar ratios of ethyl acetate and n-propylamine,respectively.When ethyl acetate is excessive,the reaction conversion x was calculated using Eq.(4).

2.4.Structure characterization of product

The analysis date of the product:1H NMR(400 MHz,CDCl3)δ:6.40-5.44(m,1H),3.22-2.97(m,2H),1.93(d,J=19.7 Hz,3H),1.44(dt,J=14.6,7.3 Hz,2H),0.85(t,J=7.4 Hz,3H).MS(EI,70 Ev),m/z(rel abundance):101(M+,59),86(39),72(35),58(12),43(92),30(100),15(7).

3.Results and Discussion

3.1.Optimization of reaction conditions

Fig.1.The tubular reactor schematic.1:measuring cylinder;2:filter head;3:pump;4:reaction pipeline;5:stirring paddle;6:oil bath;7:autoclave;8:collecting tank;9-13:valve;14-15:high temperature pressure transmitter.

Fig.2.Effect of reaction temperature on conversion of ethyl acetate(molar ratio of ethyl acetate to N-propylamine of 1:1,reaction pressure P=4.5 MPa).

Laminar and slug flow regimes commonly exist in a tubular reactor for liquid-liquid mixtures,especially in the laboratory scale[36].Aminolysis of ethyl acetate with N-propylamine was selected as a model reaction.In the batch reactor,the model reaction is typically mediated by some catalysts(e.g.SnCl2,FeCl3,AlCl3,and Na2CO3),using methanol as the solvent[37].As seen in Fig.1,the reactor was made of stainless steel(i.d.2 mm).Ethyl acetate and N-propylamine were firstly mixed in the measuring cylinder,and introduced into the reactor using the same pump.And then the mixture was quenched automatically once it flowed out from the oil bath due to drastically temperature reducing.

As mentioned above,due to the low activity of ethyl acetate,harsh conditions were required for this reaction if no catalyst is involved.Initially,the temperature was studied in Fig.2.As expected,when the temperature increased from 188°C to 228°C,the GC yield was improved.Significant improvement of the GC yield was not observed when the temperature was further increased to 228°C.

Subsequently,the effect of the molar ratio of ethyl acetate to Npropylamine on the conversion of ethyl acetate was showed in Fig.3.In the incipient stage of the reaction(when the conversion of ethyl acetate was less than 40%),when the excessive N-propylamine was subjected,the reaction rate increased.However,the molar ratio of the substrates exerts no significant influence on the conversion of ethyl acetate in general.It should be noted that any excess of a reagent is a waste of the raw material and will increase the post-processing.

Fig.3.Effect of molar ratio of ethyl acetate to N-propylamine on conversion of ethyl acetate(reaction temperature T=188°C，reaction pressure P=4.5 MPa).

Fig.4.Effect of reaction pressure on conversion of ethyl acetate(reaction temperature T=188°C,molar ratio of ethyl acetate to N-propylamine of 1:1,reaction time t=268 min).

We next turned our attention to the reaction pressure.According to the experiments,however,little effect on the ethyl acetate conversion rate caused by reaction pressure was observed,as shown in Fig.4.Table 1 shows the maximum bubble point calculated by NRTL-RK method using ASPEN PLUS software.The reaction pressure was selected to be higher than the maximum bubble point in the reactor,which was supposed to explain this phenomenon.

In summary,the optimal reaction conditions were as follows:the temperature is 218°C,the pressure is 3.5 MPa,molar ratio of ethyl acetate to N-propylamine is 1:1,350 min residence time,the conversion of ethyl acetate could reach up to 94.8%.

3.2.Apparent reaction kinetics

Flow process does not change the kinetics of the reaction[38].Moreover,mutually soluble property of the starting reagents ensured the Damkohler number(Da)＜1,which means that the process described by the measured kinetics was not controlled by mass transfer limitation.To obtain better understanding of this reaction,kinetics study was carried out.

In order to investigate the apparent kinetics,the concentration of Npropylacetamide was recorded at different temperature and molar ratio of ethyl acetate to N-propylamine,as seen in Fig.5.In the initial stage of the reaction,both the concentration of N-propylacetamide and the conversion of ethyl acetate increased from zero,and a smooth curve could be proposed in this stage according to Figs.2 and 5.Therefore,the concentration of N-propylacetamide in Fig.5 exhibited an“S”-type tendency with reaction time.In the initial stage of the reaction,little products existed,and the reaction proceeded slowly;later,both the concentration of N-propylacetamide and the reaction rate increased,possibly because the product N-propylacetamide could catalyze the reaction.In the late stage of the reaction,the reaction rate decreased mainly because of the low concentration of the reactants.

Table 1 The maximum bubble point pressure at different temperature(MPa)

Fig.5.Effect of reaction temperature and molar ratio of ethyl acetate to N-propylamine on concentration of N-propylacetamide(reaction pressure P=4.5 MPa).

As seen in Fig.5,the ammonization of ethyl acetate in the tubular reactor can be assumed as a zero-order reaction in the rapid reaction stage(ethyl acetate conversion 20%-80%),which means that the reaction rate was irrelevant with the concentration of ethyl acetate and Npropylamine.Thus,the concentration of N-propylacetamide b should satisfy Eq.(5).And Eq.(6)is its integrated form.

Next,the initial stage of the reaction was also assumed to be a zeroorder reaction,but an“induction time”was required to achieve the desired reaction rate.The“induction time”t0was determined by Eq.(7).

Fitting results were shown in Tables 2 and 3.The correlation coefficient R2were all above 0.9925,indicating that Eq.(5)fitted well to experimental results.

As seen from Table 2,at fixed molar ratio of ethyl acetate to Npropylamine,reaction rate r increased from 2.2320 to 4.9755 as reaction temperature ranged from 188°C to 228°C.And the reaction“induction time”t0decreased rapidly when temperature increased.

As seen from Table 3,at fixed reaction temperature,reaction rate r also increased from 1.7790 to 2.0489 as the molar ratio of ethyl acetate to N-propylamine increased.We ascribe this variation to the factors such as mass transfers and solution properties changing.It should be noted that no solvent was added in this experiment,the changing of molar ratio of ethyl acetate to N-propylamine had an influence on the properties of the solution like viscosity,density and diffusion coefficient.

Table 2 The reaction rate and the R2 of the reaction at different temperature①

Table 3 The reaction rate and the R2 of the reaction at different molar ratio of ethyl acetate to Npropylamine①

Swedish physical chemist Arrhenius summed the Arrhenius empirical equation by lots of experimental results,after which the equation was confirmed with the thermodynamic method.Eq.(8)was the integral expression of the Arrhenius empirical equation.

The relationship between the reaction rate constant k and the reaction rate r was determined by Eq.(9).

In this reaction,α was 0.And the reaction rate constant k was numerically equal to the reaction rate r.Thus,Eq.(10)was obtained by combining Eqs.(8)and(9).Obviously,ln r was a linear function to 1/T,and the slope was-Ea/R.

To obtain further insight between reaction rate r and temperature t.The reaction rate r unit was converted into mol·kg-1·s-1,and the temperature unit was converted into K,respectively.Then the relationship between ln k and 1000/T could be revealed in Fig.6.

Finally,Eq.(11)was obtained by Fig.6,which indicated the activation energy Ea=38489 J·mol-1,the parameter C=2.1366 and the pre-exponential factor A=8.4709.

Fig.6.The relationship between ln k and 1000/T.

4.Conclusions

Aminolysis of ethyl acetate was performed without any solvent or catalyst in a continuous-flow tubular reactor.Significant improvements in process intensity for aminolysis of ethyl acetate was achieved by using continuous-flow tubular reactor in this work,which allowed safe handling of reagents under high temperature and pressure.Under the optimal conditions of reaction temperature 218°C,reaction pressure 3.5 MPa,molar ratio of ethyl acetate to N-propylamine of 1:1,the conversion of ethyl acetate was up to 94.8%at 350 min residence time.The kinetic equations and activation energy were obtained by apparent reaction kinetics in the continuous-flow tubular reactor.Compared to traditional batch methods,this work focused on industrial interest,such as solvent and catalyst free process,cheap raw materials,few side reactions,high conversion,simple and safe operation.Such a protocol is of high potential to be applied for industry scale-up.

Nomenclature

C Arrhenius empirical equation parameters

Eaactivation energy,J·mol-1

f correlation coefficient in the external standard curve equation of N-propylacetamide

K reaction rate constant,mol·kg-1

M the mass of the sampled reaction solution,g

M1,M2molecular molar masses of ethyl acetate and N-propylamine,respectively

P reaction pressure,MPa

R reaction rate,mol·kg-1·min-1

T reaction temperature,°C

t reaction time,min

V the volume of the reaction solution,ml

Acknowledgments

The authors are grateful for the financial support from the National Natural Science Foundation of China(21476194)and the National Key Research and Development Program of China(2016YFB0301800).