Theoretical analysis and evaluation of reaction routes by “three-parameter difference”

How to choose a high-efficiency, green and inherent safety synthetic route is an important issue for the development of the chemical industry. “Three-parameter difference” is a complex parameter with the calculation of Gibbs free energy, atom utilization and inherent safety index, and can be used to comprehensively evaluate the thermodynamic feasibility, greenness and safety of chemical reactions. This parameter has been proposed and established, but the reliability has not been determined. In this study, the parameter has been corrected to make it more universal. It was calculated and studied in the synthesis of dimethyl carbonate and toluene diisocyanate, separately. The results showed that the reaction pathways for synthesizing dimethyl carbonate from the gas-phase oxidative carbonylation of methanol by a one-step process, and toluene diisocyanate from dimethyl carbonate-ionic liquid hydroxylamine have obvious advantages and future research prospects. They are consistent with the existing actual research, which can prove the reliability of the “three-parameter difference”. More importantly, the parameter provides a theoretical basis and has an adequate practical guidance significance to design and evaluate a new synthesis route.


Introduction
At present, the chemical industry is developing from the early single technical and economic index to the goal of paying equal attention to the triple indexes of engineering economy, environment-friendly and process safety. 1 The "three-parameter difference" parameter has been proposed and dened by our research group based on Gibbs free energy, atom utilization and inherent safety index as the theoretical basis for evaluating the thermodynamic feasibility, greenness and safety of chemical reactions. 2 However, there is a little introduction on the use of this parameter. In this study, the synthesis pathways of dimethyl carbonate and toluene diisocyanate, covering various of phase states and types of reaction routes, were comprehensively analyzed by using this parameter, and hence the optimal reaction route was designed. By comparing with the existing research results, the reliability of the "three-parameter difference" was veried, which provides examples for the synthesis of the chemical products, particularly the proposal of new processes.

Definition and correction of "threeparameter difference"
We dened the difference DR i between the three parameters (x DG 0 i , y AUi , z OSI 0 i ) of the chemical reaction i and the three parameters (À1, 1, 0) of the ideal chemical reaction as the "three-parameter difference", as shown in the following formula. That is, the degree of proximity to the ideal reaction was used to characterize the comprehensive performance of the reaction, and this was used as a criterion to provide a basis for the selection of the chemical reaction path. The smaller the DR i value is, the closer to the ideal chemical reaction; DR i ¼ 0, which represents the ideal chemical reaction.
.; RÞ where x DG 0 i is the ratio of the Gibbs free energy of reaction i to the absolute value of the minimum Gibbs free energy for all reactions, is the ratio of the inherent safety index of reaction i to the maximum inherent safety index of all reactions, Detailed calculations of Gibbs free energy, atomic utilization and inherent safety index mentioned above are provided in the ESI. † On this basis, the following provisions are recommended.
(1) The selection rules of reaction conditions are as follows: the reaction conditions of the industrialized process are actual reaction conditions. Due to the uncertainty and research goal for each reaction condition in the basic research, the reaction temperature was selected as 70-150 C; the reaction pressure as 5-25 bar; the reaction yield as 90-99%. (2) For a multi-step reaction system, the DR i of the total reaction is the average value of the steps. However, the reactions with smaller or larger of DR i should be paid more attention.

Analysis of the reaction route for the synthesis of dimethyl carbonate
Dimethyl carbonate (DMC) has excellent reactivity because there are various functional groups in the molecule, such as methyl, methoxy, and carbonyl group. Therefore, it can replace highly toxic phosgene and dimethyl sulphate as the carbonylation or methylation agent. At present, with the rapid development of the electric vehicle industry, the market demand of DMC in electrolytes is huge. Since the 1980s, numerous synthetic routes of DMC have been developed, mainly including phosgene process, 3 transesterication method, 4-6 gas-phase oxidative carbonylation of methanol (one-step process, 7,8 twostep process 9 ), methanol-urea alcoholysis method, 10,11 methanol-CO 2 method 12 and methanol-propylene oxide-CO 2 method. 13,14 In this section, the "three-parameter difference" was rst applied to the analysis and comparison of the reaction route for the "synthesis of DMC with methanol as the initial raw material", and then, the similar reaction paths with different raw materials were analyzed and compared to predict and evaluate the advantages and disadvantages. The material safety index (Table S1 †) and the process safety index (Table S2 †) of each reaction for the synthesis of DMC are shown in the ESI. †

Reaction route for DMC synthesis from methanol as the initial raw material
The reaction equations are as follows: According to the Gibbs free energy, atom utilization and inherent safety index (Table S3 †) of each reaction for the DMC synthesis obtained above, DR i was calculated, and the results are shown in Table 1. It can be seen that the order of the OSI 0 is R2 > R1 ¼ R5 > R3 > R4, indicating that the methanol-CO 2 method (R4) is the safest with the lowest inherent safety index. However, the Gibbs free energy of this method is greater than 0 (Fig. S1 †) in the temperature range (298-1000 K), that is, it cannot proceed spontaneously in thermodynamics, so DR 4 is relatively large. The gas-phase oxidative carbonylation of methanol by the one-step process (R2) is less than 0, and the atom utilization rate is high, and DR 2 (1.014) is the minimum, indicating that it is the most favorable. Moreover, this method has certain advantages, such as easily available raw materials, low toxicity, simple process and low cost. It is a promising method, which is consistent with the existing research status. 7 13 propylene oxide 15,16 and cyclohexane oxide 17 as raw materials, respectively. The reaction equations are as follows: The Gibbs free energy, atom utilization and inherent safety index (Table S4 †) of the above-mentioned reactions were calculated, and the "three-parameter difference" DR i of each reaction are shown in Table 2. It can be seen that the trans-esterication (cyclohexenyl carbonate) (R8-2) is the most prone to occur thermodynamically, and the DR 8-2 (0.860) is the smallest. However, the Gibbs free energy of cyclohexene oxide-CO 2 (R8-1) is greater than 0 (Fig. S2 †) within the temperature range, and the DR 8-1 (3.639) is the largest. The average of the three-parameter difference of the two-step reaction is signicantly larger than the other two reaction paths. The intrinsic safety index OSI 0 of transesterication (propylene carbonate) (R7-2) is the lowest and the intrinsic safety is the highest. Considering comprehensively, the DR 7 (1.303) of transesterication (propylene oxide) is relatively small, which indicates that the reaction route for synthesizing DMC from propylene oxide as the raw material is the most favorable.
3.2.2. Comparison of the two-step process and the one-step process for the gas-phase oxidative carbonylation of methanol. The reaction equations for the synthesis of DMC by the gasphase oxidative carbonylation of methanol are as follows: According to the Gibbs free energy, atom utilization and inherent safety index (Table S5 †) of the above-mentioned reactions, DR i was calculated, and the results are shown in Table 3. It can be seen that the DR 2 (0.962) of the gas-phase oxidative carbonylation of methanol by the one-step process is smaller than that of two-step process DR 9 (1.160), and the Gibbs free energy is lower in the investigated temperature range, making it easier to proceed thermodynamically (Fig. S3 †). The DR i of the multi-step reaction is positively correlated with the number of reaction steps, that is, the more reaction steps, the greater is the mean value. Integrating multiple reactions can reduce the reaction steps, thereby decreasing the DR i , which is the target direction of developing the reaction path.
3.2.3. Comparison of the two-step method with propylene glycol as a recycling agent and methanol-urea alcoholysis. The reaction equations for the synthesis of DMC by the two-step method with propylene glycol as the circulating agent 18 and the methanol-urea alcoholysis method are as follows: The Gibbs free energy, atom utilization and inherent safety index (Table S6 †) of the above-mentioned reactions were calculated, and the "three-parameter difference" DR i of each reaction are shown in Table 4. It can be seen that the methanol-urea alcoholysis method DR 3 (1.379) is smaller than the two-step method with propylene glycol as the circulating agent. It is veried again that the DR i of the multi-step reaction is positively correlated with the number of reaction steps. Transesterication (propylene carbonate) (R7-2) has the lowest OSI 0 and the highest intrinsic safety, but it is not feasible in thermodynamics within the temperature range investigated (Fig. S4 †), that is why DR 7-2 (2.109) is larger.

Analysis of the reaction route for the synthesis of toluene diisocyanate from toluene as the initial raw material
Toluene diisocyanate (TDI) is an important organic intermediate used in the manufacturing of polyurethane foams. Polyurethane produced by TDI has excellent properties, such as wear resistance, low temperature resistance, oil resistance and ozone resistance, and is widely used in foam plastics, elastomer wear-resistant materials and coatings. 19,20 The industrial production methods of TDI mainly include: phosgene process, 21 reduction carbonylation method, 22 oxidative carbonylation method, 23 carbon dioxide (R10-1) (R7-2)  [25][26][27] and urea method. 28 On this basis, we proposed the dimethyl carbonate-ionic liquid hydroxylamine method. The specic reaction equations are as follows. The material safety index (Table S7 †) and the process safety index (Table S8 †  According to the Gibbs free energy, atom utilization and inherent safety index (Table S9 †) of each reaction for TDI synthesis obtained above, DR i was calculated, and the results are shown in Table 5. It can be seen that the order of the OSI 0 is R14 > R12 ¼ R15 > R17 > R16 > R11 > R20 ¼ R21 > R13 > R18 ¼ R19, which indicates that the synthesis of TDI by the carbon dioxide method (R18) or dimethyl carbonate method (R19) is the safest and has the highest inherent safety. However, these two reactions cannot occur spontaneously in thermodynamics (Fig. S5 †), which is the reason for the larger DR 18 and DR 19 . Considering the overall reaction safety, the order of the OSI is indicates that the synthesis of TDI by the dimethyl carbonate-ionic liquid hydroxylamine method has the highest inherent safety. And DR 21 (0.898) is the minimum, which shows that it is the most advantageous (pre-development process) and lays a theoretical foundation for the development of a new process. The order of the DR i mean value is DR VIII > DR V > DR VII > DR VI > DR III > DR II > DR IV > DR I , basically positively correlated with the number of the reaction steps. That is, by integrating multiple reactions and reducing reaction steps, the value of DR i can be obviously decreased, making it closer to the ideal chemical reaction. That is to say, one-step reaction not only simplies the reaction steps, but also breaks the thermodynamic limitation, removes the safety hazards from the source, and improves the atomic economy.

Conclusion
The "three-parameter difference" based on Gibbs free energy, atom utilization and inherent safety index can evaluate the thermodynamic feasibility, atomic economy and inherent safety of chemical reactions comprehensively. The smaller the "threeparameter difference" is, the closer it is to the ideal reaction. In this study, the synthesis of DMC and TDI were taken as examples, and the DR i of each reaction was calculated and analyzed. The synthesis of DMC by the gas-phase oxidative carbonylation of methanol by a one-step process (DR 2 ¼ 1.104) and the synthesis of TDI by the dimethyl carbonate-ionic liquid hydroxylamine method (DR VIII ¼ 1.122) had more potential. The results were consistent with the existing actual research, which proves the reliability of the "three-parameter difference". The model has an adequate practical guidance signicance to evaluate new synthesis routes.

Conflicts of interest
There are no conicts to declare.