Toward a New Way for the Valorization of Miscanthus Biomass Produced on Metal-Contaminated Soils Part 2: Miscanthus-Based Biosourced Catalyst: Design, Preparation, and Catalytic Efficiency in the Synthesis of Moclobemide
Round 1
Reviewer 1 Report
Dear authors:
After reading, some comments are as follow:
1.The reason for using MM1? The full manuscript has never descript and explain why use MM1, and the purpose and benefit such treatment (supported on montmorillonite K10 to obtain 1.22 mmol Zn per g of support in dry methanol). The additional treatment will increae the cost of such catalyst derived from biochar.
2.The biochar is pyrolyzed at 500 degree C, as we know, some polycyclic aromatic hydrocarbon (PAHs) will be produced in biochar. As for biocatalyst, the purpose for using biochar is focused on their metal inclused, most importance is Fe and Mn; however, to the formation of moclobemide the co-existed PAHs in biochar could be or could not be affect the production or have risk ? I think the commercial pure metal chloride does not have PAHs.
Author Response
REVIEWER 1
The authors would like to thank the reviewer 1 for his interest in our research and comments to improve the quality of the manuscript.
Dear authors: After reading, some comments are as follow:
1.The reason for using MM1? The full manuscript has never descript and explain why use MM1, and the purpose and benefit such treatment (supported on montmorillonite K10 to obtain 1.22 mmol Zn per g of support in dry methanol). The additional treatment will increase the cost of such catalyst derived from biochar.
The authors thank the reviewer for this excellent remark. The following red sentence was added in the current manuscript (in the introduction section). Montmorillonite is one of the most common clay used to support metals in order to obtain clean catalyst that can be employed in organic synthesis as Lewis acids (we explained that in reference 15 : Hechelski et al., 2018).
Lewis acids are the most common and widely used in homogeneous and heterogeneous organic syntheses when they are supported on montmorillonite K10 [3,4,5].
I don’t understand really why the reviewer wrote biochar. In our study, there is no biochar. Our starting material are ashes from contaminated biomasses. The production of our catalyst was based on the reference 13 (Waterlot et al., 2000). In this reference, the authors have prepared the catalyst from zinc choride and montomorillonite (known as clayzic catalyst) whereas in the current study, a mixture of salt chlorides was used after its extraction from contaminated ashes using HCl.
I published some papers on the preparation of clayzic in organic synthesis (Waterlot et al., 2011; Waterlot et al., 2000a, 2000b) based on many study previously described (Cornélis et al., Clark et al., Pai et al…….. ) in which it was demonstrated that the maximum capacity is 1.22 mmol Zn par g of montmorillonite K10.
- Waterlot C.,* Couturier D., Rigo B., Ghinet A., De Backer M. (2011) – DFT calculations on the Friedel-Crafts benzylation of 1,4-dimethoxybenzene using ZnCl2-impregnated montmorillonite K10 – Inversion of the relative selectivities and reactivities of aryl halides. Chemical Papers, 65, 873-882. *Corresponding author.
- Waterlot C.,* Hasiak B., Couturier D. (2000a) – Friedel-Crafts benzylation of 1,4-dimethoxybenzenes - Cleavage and rearrangement of esters and methoxymethyl ethers in ZnCl2 montmorillonite K10 Journal of Chemical Research (S), 100-101. *Corresponding author.
- Waterlot C.,* Hasiak B., Couturier D. (2000b) – Friedel-Crafts benzylation of 1,4-dimethoxybenzenes - Cleavage and rearrangement of esters and methoxymethyl ethers in ZnCl2 montmorillonite K10 Journal of Chemical Research (M), 417-420. *Corresponding author.
Based on manuscripts published in the earlier 80’s – 90’, I prepared other catalysts like clayfen and MK10-Pd-Cu
- Waterlot C.,* Hasiak B., Couturier D. (2000b) – Friedel-Crafts benzylation of 1,4-dimethoxybenzenes - Cleavage and rearrangement of esters and methoxymethyl ethers in ZnCl2 montmorillonite K10 Journal of Chemical Research (M), 417-420. *Corresponding author.
- Waterlot C.,* Couturier D. (2010) – Reduction of dissolved oxygen in boiler water using new redox polymers. Journal of Applied Polymer Science, 118, 7-16. *Corresponding author.
- Waterlot C.,* Hasiak B., Couturier D., Rigo B. (2001) – On the synthesis of dimethoxybenzyl cinnamates monomers for electron transfer polymers. Tetrahedron, 57, 4889-4901. *Corresponding author.
- Waterlot C.,* Couturier D., Rigo B. (2000) – Montmorillonite-palladium-copper catalyzed cross-coupling of methyl acrylate with aryl amines. Tetrahedron Letters, 41, 317-319. *Corresponding author.
2.The biochar is pyrolyzed at 500 degree C, as we know, some polycyclic aromatic hydrocarbon (PAHs) will be produced in biochar. As for biocatalyst, the purpose for using biochar is focused on their metal inclused, most importance is Fe and Mn; however, to the formation of moclobemide the co-existed PAHs in biochar could be or could not be affect the production or have risk ? I think the commercial pure metal chloride does not have PAHs.
As previously said our starting materials were not biochars but ashes from contaminated biomasses. Consequently, the thermal process was not based on pyrolysis, thermal process from which PAHs can be produced. We have checked the absence of Cd and Pb in moclobemide. As detailed in Table 1, the Cd and Pb concentrations are two of the three lowest concentrations. Taking into account the percentage of extracted metal using 2M HCl, the percentage of Cd and Pb are 0.035% and 0.022%, respectively. Considering the general procedure, this means that 7 µg Cd and 4.5 µg Pb were introduced in the mixture. After purification of moclobemide, it has been analysed by ETAAS to highlight possible metallic traces due to the catalysts. The concentrations of Cd and Pb were below the limit of detection (LDCd = 0.02 µg/L; LDPb = 0.06 µg/L).
Author Response File: 
Author Response.pdf
Reviewer 2 Report
It is an interesting paper on the fine tunning a new way for the Valorization of Miscanthus 3 Biomass produced on Metal-Contaminated Soils, through Miscanthus-based Biosourced Catalyst.
This paper demonstrate the relevance to other studies or how to extend methodological approaches high concentration of some chemical elements-compounds. The experimental desing has been carried out with care and thoroughness.
I am not sure that the title is the most appropriate. It also takes two ::
The mineralization method used it is someone´s method or is it your owns?.
Please reduce the methodological extension and specially the conclusions
In my opinion this paper should preferably be published in a journal of environmental chemistry.
Author Response
REVIEWER 2
The authors would like to thank the reviewer 1 for his interest in our research and comments to improve the quality of the manuscript.
It is an interesting paper on the fine tunning a new way for the Valorization of Miscanthus Biomass produced on Metal-Contaminated Soils, through Miscanthus-based Biosourced Catalyst. This paper demonstrate the relevance to other studies or how to extend methodological approaches high concentration of some chemical elements-compounds. The experimental desing has been carried out with care and thoroughness.
I am not sure that the title is the most appropriate. It also takes two ::
The first part of the title is common to the first part of the manuscript that have been already published
The mineralization method used it is someone´s method or is it your owns?
The mineralization process was the same as the one used in the first part. It was adaped from the USEPA 3050 B method [11].
Please reduce the methodological extension and specially the conclusions
From the previous recommendation, section 2.1 and 2.2 in the initial version were mixed together as follows:
2.1. Mineralisation and analysis
The mineralization method was based in the procedure described in literature [10,11]. The concentration of heavy (Cd, Pb, Zn, Cu, Mn and Fe), alkali (Na and K) and alkaline earth (Ca and Mg) metals in ashes and as well as the HCl-extracted metals were determined by flame atomic absorption spectrometry (AA-6800, Shimadzu, Tokyo, Japan) following the recommendations described in the literature [11] to avoid potential spectra interferences. Details on characteristics of light source, limits of detection and quantification were given in Waterlot and Hechelski [11].
On the other, the section 2.3.3 title ‘Analysis of Moclobemide” was removed from the experimental since no data about analysis was reported in the current manuscript. By contrast, material used to determine the conversion rate of the reagents and the formation of moclobemide.
The conclusion was reduced in particular for the first half
Two bio-sourced catalysts (M1 and MM1) were successfully obtained from miscanthus biomass cultivated on metal-contaminated soils and were investigated in the synthesis of moclobemide.
Since many syntheses of moclobemide previously described have drawbacks, a review of all the procedures that allowed to obtain moclobemide with a yield greater than 75% was carried out (Figure 2). From this review, the test of the newly obtained biosourced catalysts demonstrated interesting catalytic activity and allowed to obtain moclobemide in good (79% for MM1) to excellent yield (90% for M1). The reaction proceeded in solvent-less conditions under heating at 100 °C for 18 hours and needed 0.05 equiv of catalyst only. Of interest, even if the catalyst MM1 induced decreased catalytic activity compared to M1, it had the advantage of being regenerable at the end of the reaction and was reused up to 5 runs.
Encouraged by the catalytic activity of M1 and MM1, additional studies to find the metal species responsible for their catalytic activity have been carried out. Among the tested pure commercial metal chlorides, some of them resulted in better conversion rate (MnCl2, FeCl2 and AlCl3 induced respectively 56%, 53% and 54% yield) compared to others (ZnCl2, CuCl2, NaCl, KCl, CaCl2 and MgCl2 providing respectively 36%, 39%, 43%, 43%, 42% and 44% yield). No pure species has equaled the performance of bio-based catalysts M1 or MM1 and highlighted the importance of the synergy of metallic species. Binary equimolar mixtures of commercial metal chlorides were also tested in the same synthesis to obtain moclobemide. The best efficiency was obtained with a mixture of MnCl2 and FeCl2 but did not exceed the performance induced by M1 or MM1 (54% versus 90% and 79%, respectively). This allowed to conclude that the equimolar mixture is not representative of the composition of the biosourced salts. Different ratios of MnCl2 and FeCl2 were finally studied and highlighted the importance of the proportion of MnCl2 compared to that of FeCl2. While a small excess of FeCl2 compared to MnCl2 (0.03:0.02 equiv.) allowed to reach 78% yield equivalent to that of MM1, the reverse ratio FeCl2:MnCl2 0.02/0.03 equiv. considerably inhibited the chemical transformation and provided moclobemide in only 20% yield. This corroborated well with the composition of the biosourced catalyst, iron being detected in a greater concentration than that of manganese. Therefore, iron and manganese species proved their important role to the catalytic activity induced by the biosourced catalysts M1 and MM1 in the synthesis of moclobemide.
Finally, previously and newly described procedures to access moclobemide were all compared in terms of green chemistry metrics (AE, RME and E-Factor) to evaluate their environmental impact. The biosourced catalysts, especially M1 (AE of 89.3%, RME of 80.4% and E-Factor of 0.243), have led to one of the greenest synthetic routes described to date to produce moclobemide. This study therefore opens new perspectives for the use of bio-based catalysts obtained from plants as substitutes for products from the petrochemical industry. Moreover, their use can be further considered in various chemical transformations using Lewis acids and consequently contribute to the circular economy.
Author Response File: Author Response.pdf
Reviewer 3 Report
The requested clarifications have been made but the comment concerning the reaction test still needs modification.
- A figure with the reactants and product should be added in table 3 to help the readers (line 184).
- The comparison of green chemistry metrics is again questionable since different starting products are used and green chemistry metrics for these starting products are not taking into account (i.e. benzaldehyde vs methyl benzoate vs benzoyl chloride). However, three references (ref 17, 25, and 27) are using the same starting product, i.e. methyl 4-chlorobenzoate, and thus green chemistry metrics could be useful to compare the methods. The authors should focus only on these three references (and in each case green chemistry metrics are worse !).
- A discussion about the publication of Olivier Riant et al in “Synthetic Communications” 44 (2014) 2364-2376, DOI:10.1080/00397911.2014.898072 is (still) also necessary. I have noticed that a Cl in para position is missing but it is also known that Cl in para position will, at minima, activate the substitution. Thus, citation and comment are necessary.
- The problem of contamination by toxic metal traces need to be discussed. In their answer, the authors discussed the problem of Cd and Pb contamination (response to question C). Their answer should be added to the manuscript.
Author Response
REVIEWER 3
The authors would like to thank the reviewer 2 for his interest in our research and comments to improve the quality of the manuscript.
The requested clarifications have been made but the comment concerning the reaction test still needs modification.
- A figure with the reactants and product should be added in table 3 to help the readers (line 184).
The Figure 1 was added in the current revised manuscript is as follows:
Figure 1. Synthesis of Moclobemide from methyl-4-chlorobenzoate and 4-(2-aminoethyl)morpholine.
- The comparison of green chemistry metrics is again questionable since different starting products are used and green chemistry metrics for these starting products are not taking into account (i.e. benzaldehyde vs methyl benzoate vs benzoyl chloride). However, three references (ref 17, 25, and 27) are using the same starting product, i.e. methyl 4-chlorobenzoate, and thus green chemistry metrics could be useful to compare the methods. The authors should focus only on these three references (and in each case green chemistry metrics are worse !).
Due to the review of methods from which it is possible to obtain moclobemide with a yield greater than 75%, the authors think that the consideration of only three references could be restrictive even if in the other references the starting reactants are different.
If we consider references 17, 25 and 27 (now 18, 26 and 28), I well understand the greater rate conversion obtained by the authors compared to our results but green chemistry metrics are not limited to yield but include others like AE, RME and the others listed in the current manuscript.
- A discussion about the publication of Olivier Riant et al in “Synthetic Communications” 44 (2014) 2364-2376, DOI:10.1080/00397911.2014.898072 is (still) also necessary. I have noticed that a Cl in para position is missing but it is also known that Cl in para position will, at minima, activate the substitution. Thus, citation and comment are necessary.
We have added a short discussion about the synthesis of non-chlorinated congener of moclobemide, as requested. Indeed, in the case of Moclobemide bearing a chloro substituent in the para position of the phenyl ring, the amidation reaction should be favored compared to unsubstituted analogue described by Alalla et al. (Synth. Commun. 2014, 44, 2364-2376) since the intermediate carbocation is less stable and consequently more reactive when para-chloro substituted.
The discussion added in the current revised manuscript is as follows:
“A similar efficient synthetic pathway was described by Alalla et al. [43] but was applied to access the non-chlorinated analogue of Moclobemide. For this reason, it was not considered for comparison in terms of green metrics in this study. The method used vinyl benzoate (3 equiv.) and amine at room temperature in solvent less conditions and quantitatively yielded the target amide. Since Moclobemide is para-chloro substituted, we can assume that the same methodology applied with vinyl 4-chlorobenzoate, more reactive than vinyl benzoate in this amidation reaction thanks to the chloro substituent, should also provide quantitatively the title compound. This method deserves further investigation in due course.”
- The problem of contamination by toxic metal traces need to be discussed. In their answer, the authors discussed the problem of Cd and Pb contamination (response to question C). Their answer should be added to the manuscript.
The following section was added in the current revised manuscript:
As detailed in Table 1, the Cd and Pb concentrations are two of the three lowest concentrations; Taking into account the percentage of extracted metal using 2M HCl, the percentage of Cd and Pb are 0.035% and 0.022%, respectively. Considering the general procedure, this means that 7 µg Cd and 4.5 µg Pb were introduced in the mixture. After purification of moclobemide, it has been analysed by ETAAS to highlight possible metallic traces due to the catalysts. The concentrations of Cd and Pb were below the limit of detection (LDCd = 0.02 µg/L; LDPb = 0.06 µg/L).
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
All the comments and suggestions that I mentioned have been responded and revised; then the paper should be accepted for publication now.
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
The paper of C. Waterlot et al of valorization of miscanthus biomass could not be accepted in Sustainability. It should be corrected before resubmission (see below)
A Production of biocatalyst
What is the mass of miscanthus transformed into ashes to get 1.90 g of white solid? This could be an important point to evaluate the greenness of this technology.
B Reaction test:
i) The choice of the reaction test was also questionable. Without catalyst, the conversion was 25%. Using 0.05eq of catalyst (see B ii), as expected, the conversion was increased. By simply increasing the reaction temperature, a better conversion could be obtained. This could be also seen in table 4, where 5mol% of NaCl (!) increasing the conversion from 25% to 43%. Maybe by using sea salt, the same result could be obtained.
It should be noticed that using vinyl benzoate as acyl donors instead of methyl 4-chlorobenzoate, the synthesis of N-[2-(morpholin-4-yl)ethyl]benzamide (same molecule than moclobemide without the Cl in para position) could be obtained with a yield of 100% in 40 min without solvent nor catalyst (see Green Synthesis of Benzamides in Solvent- and Activation-Free Conditions; Alalla, Affef, et al; Synthetic Communications, 44(16), 2364-2376; 2014; see entry 17, Table 3). This methodology should be discussed.
ii) 0.05 eq of catalyst M1 or MM1 was used (section 2.3.2). What is the mass of catalyst used? 0.05 eq of 0.5g of methyl 4-chlorobenzoate i.e. 25 mg of M1 and MM1? In table 4, 0.05 eq of pure metal chloride were used … so what is the mass of catalyst M1 and MM1 used? Eq is never appropriate in catalytic studies. The authors should better describe their reaction test.
ii) It was claimed by the authors that an optimum multimetallic composition of the catalyst was necessary to increase the conversion. They were lucky that an optimum composition was reached using these ashes. However, a modification of the composition of the soil, of the growing conditions will have an impact on the composition of the catalyst. How could the authors take into account this variability?
C Presence of toxic metal traces
i) In table 1, one could see that ashes contained potential Lewis acid (Zn, Fe, Mn, …) but also toxic metal like Cd and Pb. Since the catalyst contained Cd and Pb, contamination of the drug must be evaluated.
This typical problem of biosourced catalyst must be discussed in the manuscript.
D Comparison with described methods
i) Green metrics comparison with different substrates is questionable. The waste generated to synthesize the starting material is neglected (compared bromochlorobenzene and 4-chlorobenzoyl chloride). As such the comparison of green metrics may lead to erroneous results.
Reviewer 2 Report
In my opinion it is a conscientious work, with an exhaustive and exquisite analytical methodology. But I think it is rather a work that should be published in a journal of another nature. I really do not enter into its assessment, so I encourage the authors to send it to another more appropriate journal.
