Review Reports - Unsupported Copper Nanoparticles in the Arylation of Amines

Round 1

Reviewer 1 Report

This manuscript reports a study of the arylation of primary and secondary amines with unsupported copper nanoparticles. In my opinion, this is a very important article, and it will be useful to a wide range of readers. An extensive set of results was presented and all products were characterized. The great advantage of the article is the use of commercially available copper nanoparticles and ligands.

I want to clarify a few concerns which may further improve the article and make it suitable for Catalysts.

1. I'm surprised that 25 nm copper nanoparticles oxidized less than 72 nm and 86 nm. Is there any explanation?

2. Why does Table 1 not contain a complete set of ligands (L0-L4) for any type of copper nanoparticles?

I believe that the submitted article should be published after minor revision.

Author Response

We are very grateful for your valuable comments, notes and proposals in order to improve the manuscript. We highly appreciate your interest, attention and time taken to carefully review our paper. We tried to follow all issues and made appropriate changes in the manuscript which are marked in green. Below are our answers.

I'm surprised that 25 nm copper nanoparticles oxidized less than 72 nm and 86 nm.Is there any explanation?

Indeed, it was equally surprising for us. In fact, initially taken Cu NPs 25 nm were found (by means of TEM and electronography) to be covered with a very thin layer of Cu₂O while two other nanoparticles, with the average sizes of 72 and 86 nm, were shown to be covered with thicker layers of both oxides, Cu₂O and CuO. All nanoparticles were purchased from SigmaAldrich in the argon-filled tightly closed glass vessels and were immediately transferred into argon-filled Schlenk vessels for further use. Nevertheless, initial Cu NPs 72 and 86 nm were notable more oxidized than Cu NPs 25 nm, and this difference was noted especially on exposition of these three samples on air. One may suppose that bigger nanoparticles contain some admixtures of other metals which accelerate oxidation.

Why does Table 1 not contain a complete set of ligands (L0-L4) for any type of copper nanoparticles?

In our previous publications ([48] Mendeleev Commun. 2022, 32, 91-93 and [49] Russ. J. Org. Chem. 2022, 58, 15-24) we have shown that L3 was quite efficient with Cu NPs 25 nm and L4 almost did not work. In the present paper we verified it also for other Cu NPs.

Reviewer 2 Report

The authors described an efficient protocol for unsupported copper nanoparticles-catalyzed arylation of amine. Commercially available CuNPs and CuO NPs nanoparticles was used as catalyst, and their true average size and composition was characterized by the TEM and electronography methods. This reaction features broad substrate scope and functional group tolerance that is applicable for alkyl amine and the NH-heterocycles. Moreover, the copper nanocatalysts had good catalytic efficiency and could be recycled up to four times, but the substrate scope of aryl moiety is limited to iodobenzene. If other aryl iodides or chlorobenzene bromobenzene could be compatible in this transformation, it will be better. In conclusion, there are some new discoveries in this work and should belong to an improved work. Therefore, the publication of this work may be recommended in Catalysts as an article after addressing the following issues:

1. The author should clearly indicate that the yields in the manuscript is isolated yields or NMR yields.

2. The ligands are very important for arylation of amines in this manuscript. What is the role of the ligands?

3. The copper nanoparticles catalyst could be recycled for many times. After multiple use, will the particle size, shape and composition of the nanoparticles change?

Author Response

The copper nanocatalysts had good catalytic efficiency and could be recycled up to four times, but the substrate scope of aryl moiety is limited to iodobenzene. If other aryl iodides or chlorobenzene bromobenzene could be compatible in this transformation, it will be better.

No doubt that these issues will be dealt with in our further research as the work is to be continued in many aspects. The conditions for involving much less active bromo- and chlorobenzenes in this process are to be additionally elaborated using our commercial nanocatalysts.

The author should clearly indicate that the yields in the manuscript is isolated yields or NMR yields.

In all tables the indications that given yields are calculated from ¹H NMR spectra have been added (marked in green)

The ligands are very important for arylation of amines in this manuscript. What is the role of the ligands?

As homogeneous catalytic process is evidenced by leaching, great importance of a proper ligand can be easily understood because it is the ligand which contributes much to the realization of the catalytic cycle with multiple oxidation/reduction steps for copper. On the other hand, the role of ligands in the described reactions with nanoparticles is not the same as in purely homogeneous amination reactions catalyzed by CuI. In ref. [49] we demonstrated that CuI gave high yields of the amination products only in the presence of L1 ligand, while with L2 and especially L3 the yields dramatically diminished. This text is added on Page 13 (marked in green).

The copper nanoparticles catalyst could be recycled for many times. After multiple use, will the particle size, shape and composition of the nanoparticles change?

It was found that initial Cu NPs 25 nm transformed into CuO NPs (average size 50 nm with a smaller fraction 10-20 nm) (pages 14-15, Fig. 7 in our paper). Further investigations of the nanoparticles sizes after second, third and fourth cycles are to be fulfilled in our further studies.

Reviewer 3 Report

The authors here reported about Unsupported Copper Nanoparticles for C-N bond formation; the issue of C-N bond formation is very important for pharmaceutical compound formation, but from the practical point of view utilizing heterogeneous copper catalyst is favored.

unfortunately, the authors here use an unsupported nano copper with a ligand considered homogeneous catalysis, which suffers from limitations such as no good reusability and leaching of copper, but this is good to show the limitations of this method in a proper way. and can do one reaction utilizing the best commercial nano-copper catalyst used such CuO on inorganic support such as silica or alumina to clarify which is the best method

in addition some minor issues should be taken into consideration

1. NMR charts of some synthesized compounds should be added in supporting information to clarify the purity

2. the current reusability method is not clear how they put copper with ligand and then take the rest of the copper; especially they talk about 4 mg

3. author should clarify the limitation in the conclusion

4. authors should rewrite the introduction and clarify the aim of this study as to check the limitations of this method (unsupported nano copper)

Author Response

The authors can do one reaction utilizing the best commercial nano-copper catalyst used such CuO on inorganic support such as silica or alumina to clarify which is the best method.

Indeed we have conducted several reactions of n-octylamine with iodobenzene using supported nanoparticles, e.g. Cu (ca 2 nm)/C, Cu (ca 100 nm)/C, Cu (ca 100 nm)/Al₂O₃, CuO (ca 100 nm)/SiO₂-Al₂O₃, CuO (ca 100 nm)/TiO₂. Yields of the product ranged from to 43 to 83% and ligands were also important. Moreover, the influence of the ligands was in some cases different than with unsupported nanoparticles. This research needs further profound development as we need to obtain TEM images of the immobilized nanoparticles to know more precise their sizes, studying of leaching and recyclization is also very important. This will be done in continuation of our studies.

NMR charts of some synthesized compounds should be added in supporting information to clarify the purity

¹H and ¹³C NMR spectra of new compounds 3c, k, m have been added to the Supporting Information.

The current reusability method is not clear how they put copper with ligand and then take the rest of the copper; especially they talk about 4 mg

It is enough easy (from technical viewpoint) to centrifuge the reaction mixture just keeping it in a vial, collect the solution, then to wash the residue twice with 1 ml DMSO, again centrifuge it and obtain residual copper nanocatalyst for further catalytic experiments. We added some details to the description of the experiment (marked in green).

Author should clarify the limitation in the conclusion

The limitations (indispensable use of ligands and need for better reusability) are added in Conclusions (marked in green)

Authors should rewrite the introduction and clarify the aim of this study as to check the limitations of this method (unsupported nano copper)

Additional material has been added to the Introduction (marked in green)

Reviewer 4 Report

I am in general, favourably disposed towards this manuscript. The document is a substantial expansion of the authors’ earlier communication works, and (while not earth shattering) is a useful set of results. The inclusion of the actual measured nanoparticle sizes is also worthwhile. There are several individual matters to be addressed, but they are minor in nature and can be addressed under the minor revision category.

Are the any indications of diarylation of the amine? The authors often employ modest excesses iodoarene, and this can be an issue with Pd catalyzed haloarene aminations. Even if there is none (or only traces observed), it is worth noting this in the manuscript.

In footnote 1 to Table 2, I am recommending that the authors indicate the mol% of copper rather than the mole% of the catalyst itself. This matter gets a bit tough to decipher in the manuscript when the catalysts is Cu₂O.

In contrast to the discussion on lines 168-170, I do not see 5 mol% helping in entry 13 vs 12 (Table 2).

In the cases where the nanoparticles are reused, (Lines 338-340 and lines 370-373), it would be useful to know how much of the copper nanoparticles were recovered. In principle, it cannot be 100% recovery, and so when they are resubjecting the recovered catalysts for further reaction, is it truly the same loading as in the initial run?

I have some issues with the experimental section. The new compounds, 3k and 3m, do not have HMRS within 5 ppm of theoretical. This is not good enough. Secondly, in most synthetic journals, pdf’s of the 1H and 13C NMR spectra of certainly new compounds, but also know compounds made by a new method, are included in the Supporting/Supplementary Information/Material. They are not present here. I am leaving it up to the editors how rigorously they want to adhere to this, but certainly for the new compounds this is of importance.

Minor issues: The language is mostly OK…a few suggestions.

Line 12….The catalytic amine arylation

Line 39-40…the sentence just needs rephrasing

Line 107 … 25 nm NPs….

Line 135….were noted…..

Line 160….for amine and amide arylation….

Line 200….with a model iodobenzene…..

Line 232. A new sentence should start at …The use of a 1.5- fold excess…..

Line 338…the residual copper nanoparticles…

Ref 14 doesn’t use the standard, recognized abbreviation for this journal

Author Response

No evidence for N,N-diarylation by-products was got from our experiments. In other research we specially used 10-fold excess of iodobenzene in Cu-catalyzed amination reactions and did not obtain N,N-diaryl derivatives. We added this note to the text (marked in green).

The recommended changes have been done (marked in green).

In contrast to the discussion on lines 168-170, I do not see 5 mol% helping in entry 13 vs 12 (Table 2).

More precise formulation has been provided (marked in green)

We did not weigh the copper which was introduced in subsequent runs after centrifugation (it is very difficult technically). As the leaching of copper is well established, it is obvious that the loading of copper in subsequent runs was smaller and smaller with each cycle. Maybe rough calculations could have helped to adjust the amount of the reagents, ligand and base and the data on recycling could be better…

I have some issues with the experimental section. The new compounds, 3k and 3m, do not have HMRS within 5 ppm of theoretical. This is not good enough.

We use MALDI-TOF mass spectra with inner calibration (PEGs). Absolute error being similar in the range 200-1000 Da, for compounds with greater molecular masses relative error becomes smaller. Our compounds possess too small masses to fit well 5 ppm range.

Secondly, in most synthetic journals, pdf’s of the 1H and 13C NMR spectra of certainly new compounds, but also know compounds made by a new method, are included in the Supporting/Supplementary Information/Material. They are not present here. I am leaving it up to the editors how rigorously they want to adhere to this, but certainly for the new compounds this is of importance.

¹H and ¹³C NMR spectra of new compounds 3c, k, m have been added to the Supporting Information.

Minor issues: The language is mostly OK…a few suggestions.

Line 12….The catalytic amine arylation

Line 39-40…the sentence just needs rephrasing

Line 107 … 25 nm NPs….

Line 135….were noted…..

Line 160….for amine and amide arylation….

Line 200….with a model iodobenzene…..

Line 232. A new sentence should start at …The use of a 1.5- fold excess…..

Line 338…the residual copper nanoparticles…

Ref 14 doesn’t use the standard, recognized abbreviation for this journal

All needed corrections have been done in the text.

Round 2

Reviewer 3 Report

The authors responded to the comments carefully but with just a minor revision, in which the author respond to reusability by

"It is enough easy (from technical viewpoint) to centrifuge the reaction mixture just keeping it in a vial, collect the solution, then to wash the residue twice with 1 ml DMSO, again centrifuge it and obtain residual copper nanocatalyst for further catalytic experiments. We added some details to the description of the experiment (marked in green)."

but this is not technically correct, I suggest a minor revision

the authors must remove this part (reusability).

Author Response

In accordance with the suggestion of Reviewer we have withdrawn all materials dealing with reusability of the catalysts (from Abstract, Introduction, Results and Discussion and Experiment).