Ionic Liquid Modified SPION@Chitosan as a Novel and Reusable Superparamagnetic Catalyst for Green One-Pot Synthesis of Pyrido[2,3-d]pyrimidine-dione Derivatives in Water

Round 1

Reviewer 1 Report

The TEM images are meaningless and must be redone.

Author Response

The TEM images are meaningless and must be redone.

• Dear reviewer. Thank you very much for your comment. We understood that the TEM images do not have sufficient quality. The TEM was changed and a high-quality image was added to the manuscript.

Reviewer 2 Report

The paper presents an application of SPION@Chitosan functionalized ionic liquid catalyst for one-pot synthesis of pyr-ido[2,3-d]pyrimidine-dione derivatives by using water as the solvent. It may be a topic of interest to the researchers in the related areas but the paper needs very significant improvement before acceptance for publication. My detailed comments are as follows：

1.    The title of the paper should be more specific and concise.

2.    Abbreviations should be used in standardized form. Such as, “MNPs” in line42, line48 and line49.

3.    The abbreviated journal titles should be carefully corrected. For example, “Dalt. Trans” in ref7, “Angew. Chemie Int. Ed” in ref8 and ref34.

4.    In line102, “superparamagnetic iron oxide nanoparticles @Chitosan” should be replaced by “SPION@CS”.

5.    In Fig.1, the feature of N signal is unobvious, why?

6.    A few charts in the present work not meet the specification. Such as, the necessary caption of abscissa and ordinate in FT-IR spectrum should be added.

7. In line242, removal “:” in line265, removal “,”

Comments for author File: Comments.pdf

Author Response

The paper presents an application of SPION@Chitosan functionalized ionic liquid catalyst for one-pot synthesis of pyr-ido[2,3-d]pyrimidine-dione derivatives by using water as the solvent. It may be a topic of interest to the researchers in the related areas but the paper needs very significant improvement before acceptance for publication. My detailed comments are as follows：

1. The title of the paper should be more specific and concise.

• Thank you very much for your comment. We understood that the title is too long. The title of the manuscript was shortened.

2. Abbreviations should be used in standardized form. Such as, “MNPs” in line42, line48 and line49.

• Thank you very much for your comment. The abbreviations were standardized as the suggestion.

3. The abbreviated journal titles should be carefully corrected. For example, “Dalt. Trans” in ref7, “Angew. Chemie Int. Ed” in ref8 and ref34.

• Thank you very much for your comment. The references were checked, and the abbreviations were corrected where required.

4. In line102, “superparamagnetic iron oxide nanoparticles @Chitosan” should be replaced by “SPION@CS”.

• Thank you very much for your comment. It was corrected in the manuscript.

5. In Fig.1, the feature of N signal is unobvious, why?

• Thank you very much for your comment. The signal for nitrogen (Kα) was observed at 0.392 keV, which was presented in Figure 1 in the manuscript.

6. A few charts in the present work not meet the specification. Such as, the necessary caption of abscissa and ordinate in FT-IR spectrum should be added.

• Thank you very much for your comment. The required information and the specific peaks were added to the FT-IR spectrum in the manuscript.

7. In line242, removal “:” in line265, removal “,”

• Thank you very much. It was corrected in the manuscript.

Reviewer 3 Report

The manuscript deals with the formulation of the of catalytic composite based on iron oxide, chitosan, and ionic liquids for the synthesis of pyrido[2,3‑d] pyrimidine‑dione derivatives. The synthesis and catalytic role of the composites were clearly confirmed. However, there are a number of issues that has to addressed:

- The colloidal stability of the composite and particle size is not mentioned. At what pH conditions was the reaction carried out? Since magnetite has an isoelectric point at pH 7, which will cause rapid aggregation?

- What is the mass ratio of the positively charged chitosan in the composite, since an isoelectric point can be reached in the SPION-CS composite resulting in unstable catalysts. Generally, a good hybrid catalyst shall have an overall high surface charge to remain well-dispersed during the catalytic action. No such related information was mentioned.

- The role is chitosan and iron oxide should be specifically mentioned, which one plays the catalytic role? The authors did not mention such information.

- The description of the structure of the catalyst is confusing. Is it a chitosan-functionalized MNPs or nanoparticles in polymer matrix? A graphical scheme demonstrating the detailed structure of the composite must be added.

What is the purpose of the ionic liquid?

- In the IR section, as well as other characterization sections, the authors shall compare results with literature values. Numerous works in the literature deals with chitosan-functionalized MNPs.

- The TEM image provides no clear description of the composite morphology. The authors shall provide more TEM images with the components clearly marked. Also, a TEM image for SPION alone is needed.

- The TLC is not defined, and procedure is not described. The authors shall add experimental section providing the details of monitoring the reaction. Was it done using TLC with NMR and/or MS? The experimental section provides no information about NMR and MS as described in section 2.1. Both sections shall be modified accordingly.

- In the title of Table 1, the term 4g should be replaced with the exact R, since 4g is first defined in Table 2. 

- Also, if applicable, the authors shall compare the catalytic performance to other catalyst catalyzing similar reactions. 

Language and style:

- The authors shall clearly provide the role of each component. In in the introduction implies that both chitosan and SPION are both catalysts.

- The description of the structure of the catalyst in the abstract is confusing. The introduction shall be modified. For example: Line 101: “The SPIONs were then functionalized with chitosan to” while in the abstract it implies the opposite.

 

- In line 61, chitosan is functionalized with ionic liquid, not the opposite?

- The authors used SPION (superparamagnetic iron oxide nanoparticles) and iron oxide MNPs, what is the difference. Also, the authors use SPIONs on some occasions? The use should be uniform?

- MNPs and CS are not defined

- Other irregularities such as Table 1 footnote: non-superscripted c, line 265, and other unnecessary capitalization.

The authors shall revise the manuscript and correct such typos?

Author Response

The manuscript deals with the formulation of the of catalytic composite based on iron oxide, chitosan, and ionic liquids for the synthesis of pyrido[2,3‑d] pyrimidine‑dione derivatives. The synthesis and catalytic role of the composites were clearly confirmed. However, there are a number of issues that has to addressed:

- The colloidal stability of the composite and particle size is not mentioned. At what pH conditions was the reaction carried out? Since magnetite has an isoelectric point at pH 7, which will cause rapid aggregation?

• Thank you very much for your comment. As you mentioned, the pH changes affect the stability of the nanoparticles. The SPION nanoparticles were synthesized in aqueous media in basic conditions. The next step, the synthesis of SPION@CS was also performed in basic conditions in the presence of NaOH in water. The final step ((the synthesis of SPION@CS-IL) was performed in DMF as a nonprotic solvent. As could be seen, and based on your comment, all the synthesis steps were performed at pH above 7.

- What is the mass ratio of the positively charged chitosan in the composite, since an isoelectric point can be reached in the SPION-CS composite resulting in unstable catalysts. Generally, a good hybrid catalyst shall have an overall high surface charge to remain well-dispersed during the catalytic action. No such related information was mentioned.

• Thanks for your comment. Based on the TGA results, a weight loss of 40% was observed, which could be correlated to the decomposition of the organic materials in the structure of SPION@CS-IL catalyst. As you mentioned, the catalyst showed very good dispersion in the reaction mixture during the reaction time. Detailed information was added to the manuscript.

- The role is chitosan and iron oxide should be specifically mentioned, which one plays the catalytic role? The authors did not mention such information.

• Thank you very much for your comment. We believe that the ionic liquid functionalized chitosan acts as the catalyst and iron oxide helps the recovery and separation of the catalyst from the reaction mixture by their magnetic properties. Regarding the magnetic properties of the SPIONs, the catalyst, which is modified by superparamagnetic nanoparticles is easily separated from the reaction mixture using an external magnet.

- The description of the structure of the catalyst is confusing. Is it a chitosan-functionalized MNPs or nanoparticles in polymer matrix? A graphical scheme demonstrating the detailed structure of the composite must be added.

• Thank you very much for your comment. As per your comment, the presence of a graphical scheme of the catalyst helps the readers to better see the catalyst structure. Therefore, the structure of the catalyst was added to the manuscript in Scheme 3.

- What is the purpose of the ionic liquid?

• We believe that IL acts as the catalyst in the reaction.

- In the IR section, as well as other characterization sections, the authors shall compare results with literature values. Numerous works in the literature deals with chitosan-functionalized MNPs.

• Thank you very much for your comment. The comparison of the FTIR spectrum with previously reported chitosan functionalized SPION was added to the manuscript and appropriate citations were added.

- The TEM image provides no clear description of the composite morphology. The authors shall provide more TEM images with the components clearly marked. Also, a TEM image for SPION alone is needed.

• Thanks for your comment. The TEM image was changed and a clearer image was added to the manuscript. SPION nanoparticles, which are observed as dark spots in the image were marked in the TEM image.

- The TLC is not defined, and procedure is not described. The authors shall add experimental section providing the details of monitoring the reaction. Was it done using TLC with NMR and/or MS? The experimental section provides no information about NMR and MS as described in section 2.1. Both sections shall be modified accordingly.

• Thank you for the comment. TLC was defined and the conditions, including the ratio of the solvent mixtures, were added to the materials and methods section. The reaction performance was followed by TLC and after the reaction completion, the products were isolated and purified by recrystallization from ethanol. The pure products were characterized by NMR, MS, and FTIR. The detailed procedure was added to the manuscript in the materials and methods section.

- In the title of Table 1, the term 4g should be replaced with the exact R, since 4g is first defined in Table 2. 

• Thanks for your comment. R was defined in the description of Table 1.

- Also, if applicable, the authors shall compare the catalytic performance to other catalyst catalyzing similar reactions. 

• Thank you very much for your comment. It was added to the manuscript.

Language and style:

- The authors shall clearly provide the role of each component. In in the introduction implies that both chitosan and SPION are both catalysts.

• Thanks for your comment. The role of each component was added to the manuscript in the conclusion section.

- The description of the structure of the catalyst in the abstract is confusing. The introduction shall be modified. For example: Line 101: “The SPIONs were then functionalized with chitosan to” while in the abstract it implies the opposite.

• Thanks for your comment. We understood that the abstract is not clear to the readers. The first sentence of the abstract was rewritten to be more clear.

- In line 61, chitosan is functionalized with ionic liquid, not the opposite?

• Thanks for your comment. It was corrected in the manuscript.

- The authors used SPION (superparamagnetic iron oxide nanoparticles) and iron oxide MNPs, what is the difference. Also, the authors use SPIONs on some occasions? The use should be uniform?

• According to the characterizations, we have superparamagnetic iron oxide. Therefore, all the iron oxides were mentioned as superparamagnetic iron oxide in the manuscript.

- MNPs and CS are not defined

• Thanks for your comment. The abbreviations were defined in the manuscript.

- Other irregularities such as Table 1 footnote: non-superscripted c, line 265, and other unnecessary capitalization.

• Thank you very much for your comment. The issues were corrected in the manuscript.

The authors shall revise the manuscript and correct such typos?

• Thank you very much for your helpful comments. The manuscript was revised according to the comments and the changes were highlighted in the manuscript for your kind reference.

 

Round 2

Reviewer 2 Report

Accept

Reviewer 3 Report

I thank the authors for the adequate answering for the issues raised. I consider the article suitable for publication after the following issue is fixed:

There is a mistake in numbering of figures. Figure 7 should be Figure 6, it should be fixed.