Mechanochemistry through Extrusion: Opportunities for Nanomaterials Design and Catalysis in the Continuous Mode

Round 1

Reviewer 1 Report

The authors have developed a mechanochemical approach through extrusion for the preparation of chitin supported Pd catalytic materials used in Suzuki coupling reactions. The approach combines the potential of mechanochemistry to the benefits of continuous flow processes Therefore, I support the present manuscript for publication in Chemistry after considering the following comments.

1) The scope of aryl halide and aryl boronic acid should be explored.

2) What result is it if the same loading of Pd(OAc)2/Na2CO3 is used instead of Pd-chitin-500 under mechanochemistry conditions？

3）More Pd catalyzed Suzuki reaction can be cited, for example,

Angew. Chem., Int. Ed., 2022, 61, e202114146;

Org. Lett., 2022, 24, 2338;

J. Am. Chem. Soc. 2023, 145, 6823;

Chem. Sci. 2019, 10, 8202.

 Minor editing of English language required

Author Response

General. A point-by-point response to the Reviewer’s comments is listed below. Accordingly, all changes made in the revised version of the manuscript were highlighted in yellow.

Reviewer #1

Comments to Authors

The authors have developed a mechanochemical approach through extrusion for the preparation of chitin supported Pd catalytic materials used in Suzuki coupling reactions. The approach combines the potential of mechanochemistry to the benefits of continuous flow processes Therefore, I support the present manuscript for publication in Chemistry after considering the following comments.

Authors thanks this Reviewer for his/her positive and supportive comment  

Q1.1 The scope of aryl halide and aryl boronic acid should be explored.

R1.1 In response to this comment, new experiments were carried out by employing chlorobenzene in place of iodobenzene, and m-tolylboronic acid in place of phenylboronic acid, respectively. As was reported in the original ms, bromobenzene was inactive for the reaction. The same held true for chlorobenzene with which a negligible conversion (ca 5%) was reached. Only iodobenzene was successful in consistency with the leaving group ability of halides. Instead, m-tolylboronic acid showed a reactivity comparable to that of phenyl boronic acid. To account for these results, a new sentence was included on p. 6 of the revised version of the manuscript.

Q1.2 What result is it if the same loading of Pd(OAc)2/Na2CO3 is used instead of Pd-chitin-500 under mechanochemistry conditions?

R1.2 An additional test was carried out employing Pd(OAc)₂ and Na₂CO₃ instead of using Pd-chitin-500 as catalyst under standard reaction conditions of Table 2. Results were described in an additional sentence placed on p. 5 of the revised manuscript. Moreover, another experiment was performed to demonstrate the efficacy of the recycle of the heterogeneous Pd-chitin-500 catalyst.

Q1.3 More Pd catalyzed Suzuki reaction can be cited, for example,

Angew. Chem., Int. Ed., 2022, 61, e202114146; Org. Lett., 2022, 24, 2338; J. Am. Chem. Soc. 2023, 145, 6823; Chem. Sci. 2019, 10, 8202.

R1.3 The introduction section of the revised manuscript was updated by adding the suggested references (refs. #31-34).

Reviewer 2 Report

The work deals with the implementation of Suzuki-Miyaura reaction of iodobenzene and phenylboronic acid in an extruder. The authors have used several characterization techniques (XRD, surface and textural analysis, GC-FID/MS, ICP-MS) and some of the work is perhaps interesting, in particular that it gives an example of the utilization of mechanical energy in cross-coupling reaction, but the manuscript in its present form requires major revision.

1. In the manuscript, only 5. Conclusion is included, but 1. Introduction, 2. Materials and Methods, 3. Results and 4. Discussion sections are missing. This structuring of the text is absolutely necessary, as the reviewer wishes to draw attention to the importance of using the template provided by the journal!

2. Relevant technical data for the X-ray diffraction measurements are missing like the scanning speed, resolution, type of the cathode ray tube, meantime the parameters of the degassing pre-treatment used for the N₂ adsorption-desorption analyses are also key to the interpretation of the results!

3. It is not clear on what basis (experimental results, previous works perhaps) the appropriate parameters were chosen for the mechachemical preparation of the various Pd-chitin composites!

4. Because of its fundamental importance, the application of the Suzuki-Miyaura reaction needs to be discussed in the introduction section, with particular attention to economical and environmentally friendly examples that avoid the use of less expensive and rare precious metals (e.g. Ni and Cu).

Mechanistic study of an improved Ni precatalyst for Suzuki-Miyaura reactions of aryl sulfamates: Understanding the role of Ni(I) species, J. Am. Chem. Soc., 139 (2017) 922-936
Mechanochemically modified hydrazine reduction method for the synthesis of nickel nanoparticles and their catalytic activities in the Suzuki-Miyaura cross-coupling reaction, Reac. Kinet. Mech. Cat., 126 (2019) 857-868
Copper-facilitated Suzuki-Miyaura coupling for the preparation of 1,3-dioxolane-protected 5-arylthiophene-2-carboxaldehydes, Tetrahedron, 74 (2018) 2002-2008
Tannic acid: A green and efficient stabilizer of Au, Ag, Cu and Pd nanoparticles for the 4-Nitrophenol reduction, Suzuki-Miyaura coupling reactions and click reactions in aqueous solution, J. Colloid Interface Sci., 604 (2021) 281-291
Copper-functionalized silica-coated magnetic nanoparticles for an efficient Suzuki cross-coupling reaction, ChemistrySelect, 6 (2021) 359-368

5. An essential part of a catalytic work is to carry out catalyst re-use tests, this needs to be completed!

6. Similarly, it is necessary to characterize the stability of the spent catalyst, in particular with regard to the possible leaching of Pd.

Author Response

General. A point-by-point response to the Reviewer’s comments is listed below. Accordingly, all changes made in the revised version of the manuscript were highlighted in yellow.

Reviewer #2

Comments to Authors

The work deals with the implementation of Suzuki-Miyaura reaction of iodobenzene and phenylboronic acid in an extruder. The authors have used several characterization techniques (XRD, surface and textural analysis, GC-FID/MS, ICP-MS) and some of the work is perhaps interesting, in particular that it gives an example of the utilization of mechanical energy in cross-coupling reaction, but the manuscript in its present form requires major revision.

Q2.1 In the manuscript, only 5. Conclusion is included, but 1. Introduction, 2. Materials and Methods, 3. Results and 4. Discussion sections are missing. This structuring of the text is absolutely necessary, as the reviewer wishes to draw attention to the importance of using the template provided by the journal!

R2.1 I understand the point raised and may agree with it. However, I take the liberty to underline that the ms is intended as a communication and as such, it is quite usual, at least for a variety of scientific journals (an example for all, is Chemical Communication edited by RSC), that a distinction into different sections is not carried out. Except, but not always, for the conclusion section.  That said, I recognise that the Chemistry (MDPI) template asks for a different article structuring which has been followed for the revision of the ms. According to this and the Referee comment, in the revised ms, four different sections (Introduction, Materials and Methods, Results and Discussion, and Conclusions) were indicated.  It should be noted that the “Materials and Methods” section was moved from the “supplementary materials” where it was originally placed to the main text of the article.

Q2.2 Relevant technical data for the X-ray diffraction measurements are missing like the scanning speed, resolution, type of the cathode ray tube, meantime the parameters of the degassing pre-treatment used for the N₂ adsorption-desorption analyses are also key to the interpretation of the results!

R2.2 The information required by the reviewer was already provided in the “Materials and Methods” section, originally placed in the supporting information. This section has now been moved into the revised version of the ms (see point R2.1).

Q2.3 It is not clear on what basis (experimental results, previous works perhaps) the appropriate parameters were chosen for the mechachemical preparation of the various Pd-chitin composites!

R2.3 The strategy for the continuous flow mechanochemical synthesis of supported nanoparticles was designed based on the experience of some of us in the mechanochemical preparation of nanomaterials. Some of the related references are:

10. Muñoz-Batista, M.J.; Rodriguez-Padron, D.; Puente-Santiago, A.R.; Luque, R. Mechanochemistry: Toward Sustainable Design of Advanced Nanomaterials for Electrochemical Energy Storage and Catalytic Applications. ACS Sustain. Chem. Eng. 2018, 6, 9530–9544, doi:10.1021/acssuschemeng.8b01716. (This was already quoted as Ref. #1 in the original ms);
11. Martín-Perales, A. I., Rodriguez-Padron, D., Garcia Coleto, A., Len, C., de Miguel, G., Munoz-Batista, M. J., & Luque, R. Photocatalytic Production of Vanillin over CeO x and ZrO2 Modified Biomass-Templated Titania. Ind Eng Chem Res 2020, 59(39), 17085-17093;

• Rodríguez-Padrón, D., Zhao, D., Carrillo-Carrion, C., Morales-Torres, C., Elsharif, A. M., Balu, A. M., Luque, R., & Len, C. Exploring the potential of biomass-templated Nb/ZnO nanocatalysts for the sustainable synthesis of N-heterocycles. Catal Today, 2021, 368, 243-249.

These three references were added in the revised version of the ms at the beginning of the “Results and Discussion” section (#1, 39, and 40) along with a brief explanatory sentence. 

An additional reference was also placed on the use of ethylene glycol as a reducing agent (ACS Sustainable Chem Eng 2017, 5(12), 11584-11587). This was quoted as ref #35 in the revised ms.

This Referee is also kindly asked to consider that this contribution reports preliminary results on an extrusion-based synthesis of nanomaterials which is an emerging new topic. Hence further optimizations and studies will need to be carried out in the future.

Q2.4 Because of its fundamental importance, the application of the Suzuki-Miyaura reaction needs to be discussed in the introduction section, with particular attention to economical and environmentally friendly examples that avoid the use of less expensive and rare precious metals (e.g. Ni and Cu).

Mechanistic study of an improved Ni precatalyst for Suzuki-Miyaura reactions of aryl sulfamates: Understanding the role of Ni(I) species, J. Am. Chem. Soc., 139 (2017) 922-936

Mechanochemically modified hydrazine reduction method for the synthesis of nickel nanoparticles and their catalytic activities in the Suzuki-Miyaura cross-coupling reaction, Reac. Kinet. Mech. Cat., 126 (2019) 857-868

Copper-facilitated Suzuki-Miyaura coupling for the preparation of 1,3-dioxolane-protected 5-arylthiophene-2-carboxaldehydes, Tetrahedron, 74 (2018) 2002-2008

Tannic acid: A green and efficient stabilizer of Au, Ag, Cu and Pd nanoparticles for the 4-Nitrophenol reduction, Suzuki-Miyaura coupling reactions and click reactions in aqueous solution, J. Colloid Interface Sci., 604 (2021) 281-291

Copper-functionalized silica-coated magnetic nanoparticles for an efficient Suzuki cross-coupling reaction, ChemistrySelect, 6 (2021) 359-368

R2.4 In response to the Referee comment, a new paragraph and new references (refs. 26-30) have been included in the introductory section of the revised manuscript (lines 56 to 68)

Q2.5 An essential part of a catalytic work is to carry out catalyst re-use tests, this needs to be completed! Similarly, it is necessary to characterize the stability of the spent catalyst, in particular with regard to the possible leaching of Pd.

R2.5 In response to the Referee comment, a recycle test was performed using Pd-chitin-500 as a model catalyst. It was demonstrating that the chosen sample could be recycled without any loss of performance. The result was described on p. 6 of the revised ms. Also, the metal leaching was explored by comparing the Pd content in the fresh and used catalyst. ICP-OES analyses proved that leaching was negligible (<5%). Results were briefly discussed on p. 6 of the revised manuscript.

Once again, this Referee is kindly asked to consider that this work is intended as a communication. The reported results, albeit promising, reliable, and reproducible, will be the object of further future investigations. These will also include an expanded study on the recycle of the prepared catalysts which is beyond the scope of the present paper.

Reviewer 3 Report

The authors report on the employment of continuous flow mechanochemical reactor to prepare Pd-based nanoparticles, and implementation of the resulting Pd cat to catalyze the Suzuki-Miyaura cross-coupling of phenyl boronic acid with iodobenzene in the mini-extruder. Despite the work expand the applications of continuous flow mechanochemistry in heterogeneous catalysis, it provided very preliminary information in this field: 1) the tested reaction scope was very limited while this type of reaction in solution chemistry very good results can be obtain by both homogeneous and heterogeneous catalysis; 2) the reaction selectivity issue should be further addressed since side-reaction as self-coupling of phenyl boronic acid could also give the target product biphenyl, thus different substituted substrates should be involved; 3) the recyclability of supported Pd nanocat. was not given; 4) the robustness and the catalytic efficiency of the Pd-based nanoparticles need further proved by more detailed experiments. Overall, the manuscript is not appropriated for publishing currently.

Other technique issues:

- In Figure 2, XRD pattens of the comparative palladium acetate, chitin and Na2CO3 should be added.

- In the manuscript, the text “.…… are limited to batch conditions where the control of the temperature is not accurate” is not a very accurate description. Several precise temperature control batch mechanochemical reaction have been reported (10.1002/anie.201805263; 10.1002/anie.202210508; 10.1021/acssuschemeng.2c00914; 10.26434/chemrxiv-2022-2326c-v2).

- The ref 22-23 are not related to “preparation of supported metal nanoparticles”, the C-C bond formation in ref 22-23 were catalyzed by NiCl₂(PPh₃)₂.

- Since the authors showed that K2CO3 was necessary for the Suzuki-Miyaura cross-coupling reaction, this referee wondered that if the catalytic efficiency would be enhanced by replacing Na2CO3 with K2CO3 when preparing the supported Pd cat.?

- Why is the extrusion temperature set to 200 ℃ (which is slightly higher than the boiling point of ethylene glycol), explain it or list the results while extruding under different temperature. 

Author Response

REVIEWER’S REPORT

General. A point-by-point response to the Reviewer’s comments is listed below. Accordingly, all changes made in the revised version of the manuscript were highlighted in yellow.

Reviewer #3

Comments to Authors

The authors report on the employment of continuous flow mechanochemical reactor to prepare Pd-based nanoparticles, and implementation of the resulting Pd cat to catalyze the Suzuki-Miyaura cross-coupling of phenyl boronic acid with iodobenzene in the mini-extruder. Despite the work expand the applications of continuous flow mechanochemistry in heterogeneous catalysis, it provided very preliminary information in this field.

Q3.1 The tested reaction scope was very limited while this type of reaction in solution chemistry very good results can be obtain by both homogeneous and heterogeneous catalysis.

R3.1 In response to this comment, new experiments were carried out by employing chlorobenzene in place of iodobenzene, and m-tolylboronic acid in place of phenylboronic acid, respectively. As was reported in the original ms, bromobenzene was inactive for the reaction. The same held true for chlorobenzene with which a negligible conversion (ca 5%) was reached. Only iodobenzene was successful in consistency with the leaving group ability of halides. Instead, m-tolylboronic acid showed a reactivity comparable to that of phenyl boronic acid. To account for these results, a new sentence was included on p. 6 of the revised version of the manuscript.

Q3.2 The reaction selectivity issue should be further addressed since side-reaction as self-coupling of phenyl boronic acid could also give the target product biphenyl, thus different substituted substrates should be involved;

R3.2 An additional experiment has provided insights into this subject (see also point Q3.1). In particular, the reaction of iodobenzene with m-tolylboronic acid in place of phenylboronic acid proved that at a conversion of 75%, the selectivity towards the desired coupling product, 3-methyl-1,1'-biphenyl, was 95%. The occurrence of secondary reactions, such as the homocoupling of aryl boronic acids, was not significant.

Q3.3 The recyclability of supported Pd nanocat. was not given;

R3.3 A recycle test was performed using Pd-chitin-500 as a model catalyst. It was demonstrated that the chosen sample could be recycled without any loss of performance. The result was described on p. 6 of the revised ms. Also, the metal leaching was explored by comparing the Pd content in the fresh and used catalyst. ICP-OES analyses proved that leaching was negligible (<5%). Results were briefly discussed on p. 6 of the revised manuscript.

Q3.4 The robustness and the catalytic efficiency of the Pd-based nanoparticles need further proved by more detailed experiments. Overall, the manuscript is not appropriated for publishing currently.

R3.4 To reply to the Reviewer’s comment: i) additional tests were performed to extend the reaction scope by using a different aryl halide and a different aryl boronic acid; ii) the catalyst stability was explored by performing not only by a recycle test but also by the ICP-OES characterization of the used catalyst, and iii) a not negligible update of the cited literature was carried out to highlight the novelty and the potential of the mechanochemical-assisted approach.

This Referee is also kindly asked to consider that this work is intended as a communication. As such, it reports new results on an innovative emerging topic and, therefore, it cannot provide a comprehensive/exhaustive treatment of the subject. Some aspects go necessarily beyond the scope of the present communication. We strongly believe that through this revision process, the impact of our contribution was further improved and do hope the Reviewer understands and share this point.

Other technique issues:

Q3.5 In Figure 2, XRD pattens of the comparative palladium acetate, chitin and Na2CO3 should be added.

R3.5 Authors appreciate the Reviewer comment. However, we would like to highlight that XRD data for chitin, (Clark, G. L., & Smith, A. F. (2002). X-ray Diffraction Studies of Chitin, Chitosan, and Derivatives J Phys Chem, 40(7), 863-879.), palladium acetate (Kirik, S. D., Mulagaleev, R. F., & Blokhin, A. I. [Pd (CHCOO)] from X-ray powder diffraction data. Acta Crystallographica Section C Crystal Structure Commun, 60(9).) and Na₂CO₃ (Masood, M. H., Haleem, N., Shakeel, I., & Jamal, Y. (2020). Carbon dioxide conversion into the reaction intermediate sodium formate for the synthesis of formic acid. Res Chem Intermediates, 46, 5165-5180.) are extensively documented in existing literature. We believe that this information was redundant in the manuscript. However, in response to the issue raised by this Referee, a brief sentence was placed in the revised ms to indicate that the XRD pattern of commercial chitin was included in the supporting information file, while appropriate references were quoted where both XRD data of Pd-acetate and Na₂CO₃ were reported and discussed.

Q3.6 In the manuscript, the text “.…… are limited to batch conditions where the control of the temperature is not accurate” is not a very accurate description. Several precise temperature control batch mechanochemical reaction have been reported (10.1002/anie.201805263; 10.1002/anie.202210508; 10.1021/acssuschemeng.2c00914; 10.26434/chemrxiv-2022-2326c-v2).

R3.6 We thank the Reviewer for this comment. The related sentence of the original ms was modified and reformulated in the revised version of the ms (lines 34 to 39). Also, the suggested references were added in the introduction section (refs. #19-21].

Q3.7 The ref 22-23 are not related to “preparation of supported metal nanoparticles”, the C-C bond formation in ref 22-23 were catalyzed by NiCl2(PPh3)2.

R3.7 The mistake was corrected. Refs. 22-23 were replaced with ref. #25 in the revised manuscript.

Q3.8 Since the authors showed that K₂CO₃ was necessary for the Suzuki-Miyaura cross-coupling reaction, this referee wondered that if the catalytic efficiency would be enhanced by replacing Na₂CO₃ with K₂CO₃ when preparing the supported Pd cat.?

R3.8 In response to this comment, the catalyst preparation was modified using K₂CO₃ instead of Na₂CO₃. Despite this change, the catalytic activity of the newly prepared sample remained as low as that of Pd-chitin-Na₂CO₃-500. This result has been described by an additional sentence on the placed at the bottom of p. 5 of the revised ms.

Q3.9 Why is the extrusion temperature set to 200 ℃ (which is slightly higher than the boiling point of ethylene glycol), explain it or list the results while extruding under different temperature.

R3.9 The selected parameters for extrusion were based on the previous experience of some of us in the mechanochemical synthesis of nanomaterials. This has been specified by adding three references (#1, 39, and 40) at the beginning of the “Results and Discussion” section of the revised version of the ms, along with a brief explanatory sentence. Also, experimental conditions for the use of ethylene glycol as a reducing agent were chosen according to a selected reference (ref. #35 in the revised ms): the extruding temperature was set to 200 °C to promote an efficient Pd reduction. Once again, a systematic study on the effect of the extruding temperature was well beyond the scope of the present communication. Hope these considerations may help the Referee understand the point.   

Round 2

Reviewer 1 Report

Accept in present form. 

Moderate editing of English language required.

Author Response

I thank the Referee for his/her supportive comment

Reviewer 2 Report

The manuscript has been much improved and can now be accepted in a revised form.

Author Response

I thank the Referee for his/her supportive comment

Reviewer 3 Report

The manuscript has been revised substantially according to the referee’ comments, and it was more suitable for publishing at this time. However, there are still some small issues that need to be addressed.

1. A detailed expression should be given to explain why additional base (K2CO3) was necessary for the cross-coupling reaction.

2. The recycle times of the supported cat. should be point out. 

Author Response

REVIEWER’S REPORTS #2

General. A point-by-point response to the Reviewer #3 comments is listed below. Accordingly, all changes made in the revised version were highlighted in light-blue.

Reviewer #3

Comments to Authors

The manuscript has been revised substantially according to the referee’ comments, and it was more suitable for publishing at this time. However, there are still some small issues that need to be addressed.

Authors thanks this Reviewer for his/her positive and supportive comment.

Q3.1 A detailed expression should be given to explain why additional base (K2CO3) was necessary for the cross-coupling reaction.

R3.1 An additional sentence was placed on p. 6 to provide insights about the role of the base (K₂CO₃ in this work) for the Suzuki-Miyaura cross-coupling reaction.

Q3.2 The recycle times of the supported cat. should be point out. 

R3.2 An additional sentence was placed on p. 6 to confirm that the catalyst recycle was run under the same conditions (entry 5 in Table 2) used for the fresh catalyst.