Synthesis, DFT and X-ray Studies of Trans CuCl₂L₂ with L Is (E)-(4-Chlorophenyl)-N-(3-phenyl-4H-1,2,4-triazol-4-yl)methanimine

Round 1

Reviewer 1 Report

The manuscript by Hassan H. Hammud and coworkers deals with the synthesis of a new Schiff base ligand substituted a by a triazole moiety and its coordination to a copper(II) center. Further theoretical calculations have been performed to optimize the structure in order to compare with the obtained crystallographic data.

If the synthesis of the ligands is relatively well described and the ligands characterized by NMR, the synthesis of the copper complex lacks details and characterization. No details on how the compound was isolated or purified (what is the green precipitate?), nor yield are given. The only technique used to determine the structure is X-ray diffraction crystallography on crystals obtained after a month (how was the solution kept during this time?). No elemental analysis, UV vis or other analytical data are given. As such, the claim that “the newly synthesized compounds are characterized by FTIR and NMR” in abstract and conclusions is not true.

As for the calculations, many data are redundant and are not essential to the research informed. Figures 6 and 7, as well as Table 2 do not provide important information.

The title must be modified as the name of the ligand is not correct as the thiol moiety is not considered. English language must be improved, and many typos should be corrected. For instance, the first sentence of the abstract is difficult to understand, as well as lines 52-55 in page 2.

Author Response

Reply to Reviewer 1 comments:

Referee 1

The manuscript by Hassan H. Hammud and coworkers deals with the synthesis of a new Schiff base ligand substituted a by a triazole moiety and its coordination to a copper(II) center. Further theoretical calculations have been performed to optimize the structure in order to compare with the obtained crystallographic data.

 

Comment 1: If the synthesis of the ligands is relatively well described and the ligands characterized by NMR, the synthesis of the copper complex lacks details and characterization. No details on how the compound was isolated or purified (what is the green precipitate?), nor yield are given. The only technique used to determine the structure is X-ray diffraction crystallography on crystals obtained after a month (how was the solution kept during this time?). No elemental analysis, UV vis or other analytical data are given. As such, the claim that “the newly synthesized compounds are characterized by FTIR and NMR” in abstract and conclusions is not true.

Response:

Thanks for referee comments, the following was updated in the text.

• The green precipitate is a side reaction product probably copper hydroxide complex.
• The yield was 40%
• The solution was left for slow evaporation at room temperature in a closed flask with a tiny hole. Crystallization can be fastened to four days if a larger hole is used to evaporate the solvent from the covered mixture flask.
• The sentence the newly synthesized compounds are characterized by FTIR and NMR is removed in abstract and conclusion and replaced by “the synthesized compounds were characterized by applying various spectroscopic techniques”

 

Comment 2: As for the calculations, many data are redundant and are not essential to the research informed. Figures 6 and 7, as well as Table 2 do not provide important information.

Response: Thanks for highlighting this point. Figures 6 and 7, and Table 2 have been removed from the main text of the manuscript as recommended by the reviewer and moved to supporting information. In addition, the relevant sections of the manuscript are updated accordingly. Such thorough information, at times, is essential to highlight the validity of the method used for the calculations. 

 

Comment 3: The title must be modified as the name of the ligand is not correct as the thiol moiety is not considered.

Response:

Thanks for the reviewer comment. However, the prepared complex (6) contains the triazole ligand without thiol.

Thus, we have added a clarification to the end of section 3.3:

The obtained ligand L, (E)-(4-chlorophenyl)-N-(3-phenyl-4H-1,2,4-triazol-4-yl)methanimine was formed in situ by the reaction of CuCl₂ with 4-(4-chlorobenzylideneamino)-5-phenyl-2H-1,2,4-triazole-3(4H)-thione (5) followed by the formation of complex (6)

Additionally, we have updated the name of compound (5) and ligand L.

 

Comment 4: English language must be improved, and many typos should be corrected. For instance, the first sentence of the abstract is difficult to understand, as well as lines 52-55 in page 2.

Response: Thanks for the comment. We have carefully revised the manuscript for linguistic aspects and incorporated the changes.

Author Response File: Author Response.pdf

Reviewer 2 Report

H.H. Hammud et al. in the manuscript "Synthesis, DFT and X-ray Studies of Trans CuCl2L2 with L is 4-2 (4-chlorobenzylidene)amino-5-phenyl-4H-1,2,4-triazole" presented the synthesis of the ligand and the copper complex based on it. 

The described ligand is not a new compound and has already been described in several publications: https://doi.org/10.1186/2191-2858-2-26; https://doi.org/10.1016/j.ejmech.2009.05.030; https://doi.org/10.1016/j.bmcl.2017.10.065.

The second important note to this study: why has the sulfur atom from the heterocyclic fragment disappeared from the structure of the complex? Thus, the crystal structure does not correspond to the original ligand.

Third, the article does not present the properties of the obtained complex, which reduces the interest in this work. It is necessary to show the application or physicochemical properties for this complex.

In this version, I cannot recommend this work for publication in Inorganics.

Author Response

Reply to Reviewer 2 comments:                        revision  inorganics-2065400

Referee 2

Comment 1: The described ligand is not a new compound and has already been described in several publications: https://doi.org/10.1186/2191-2858-2-26; https://doi.org/10.1016/j.ejmech.2009.05.030; https://doi.org/10.1016/j.bmcl.2017.10.065.

Response: Thanks to the referee for highlighting this point and sharing valuable references. We have updated the revised manuscript accordingly and cited the relevant references as 56 (b), (c) and (d) where appropriate in the experimental section. We have also removed the word new when describing the compound.

Comment 2: The second important note to this study: why has the sulfur atom from the heterocyclic fragment disappeared from the structure of the complex? Thus, the crystal structure does not correspond to the original ligand.

Response: The referee has mentioned a valid point regarding the loss of sulfur atom during the complexation with copper chloride (CuCl2).

Related to this point, we have added a paragraph to the revised manuscript at the end of section 3.3:

Regarding the loss of sulfur atom during the complexation with CuCl₂. We are still investigating this experimental observation to fully understand the mechanism involved. One of the plausible explanations could be related to the complexation with copper chloride that could facilitate this rearrangement as reported for other system, where copper chloride was involved in the rearrangement of ampicillin containing sulfur moiety.[Ref 72] Thus, the obtained ligand L: (E)-(4-chlorophenyl)-N-(3-phenyl-4H-1,2,4-triazol-4-yl)methanimine was formed in situ by the reaction of CuCl₂ with 4-(4-chlorobenzylideneamino)-5-phenyl-2H-1,2,4-triazole-3(4H)-thione  (5) followed by the formation of the complex CuCl₂L₂ (6)

Comment 3: Third, the article does not present the properties of the obtained complex, which reduces the interest in this work. It is necessary to show the application or physicochemical properties for this complex.

Response:

Thanks to referee who asked to mention possible application of the prepared complex in order to elaborate the importance of this work, the synthesis of complex (6).

The following was added to the end of section 3.3:

It is also expected that the Schiff base complex CuCl2L2 (6) should show better anticancer activity than its ligand based on cytotoxicity studies for related copper complexes. [Ref 70,71,73,74] Thus, studying the anticancer behavior of copper complex (6) will be carried in a future work.

The following was also added to abstract and conclusion:

The Schiff base 1,2,4-triazole copper chloride complex is expected to have high anticancer activity.

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Despite the corrections, I still have concerns about the preparation and characterization of the copper complex. For instance, how is the complex purified and the green precipitate eliminated? UV-vis and IR spectroscopies are not sufficient to confirm the structure and purity of the compounds. At least elemental analysis and mass-spectrometry data must be added. With a yield of 40 %, this method can hardly be considered as an efficient approach to the synthesis of such derivatives as claimed in the abstract. As for the reaction to form L from 5 (in the copper complex How is the complex purifier and the green precipitate eliminated?), what is the faith of the sulfur atom?

Author Response

Reply to reviewer 1:                                                                      10-12-2022

 

- Minor spell check required

Reply:

• Minor English spell check is done

1 - Comment:

Despite the corrections, I still have concerns about the preparation and characterization of the copper complex. For instance, how is the complex purified and the green precipitate eliminated? UV-vis and IR spectroscopies are not sufficient to confirm the structure and purity of the compounds. At least elemental analysis and mass-spectrometry data must be added.

Reply:

Thanks a lot for the reviewer to point out these comments.

The following was added to the experimental section:

“The green precipitate was separated by filtration and the obtained filtrate consisted of clear violet solution”. Finally, the “violet filtrate” solution was left for slow evaporation………..”

We have done single crystal X-ray structure and the structure of the final copper complex was confirmed. Unfortunately, we do not have access to elemental analysis and mass spectrometry, and it is impossible at this stage to do these measurements. We apologize for not being able to do additional measurements.

2- Comment:

With a yield of 40 %, this method can hardly be considered as an efficient approach to the synthesis of such derivatives as claimed in the abstract. As for the reaction to form L from 5 (in the copper complex How is the complex purifier and the green precipitate eliminated?), what is the faith of the sulfur atom?

Reply:

We thank again the reviewer for mentioning these comments.

In the abstract. The “word” efficient was replaced by “novel” approach to prepare trans-CuCl₂L₂ complex.

The following was added to discussion:

The yield was only 40 % because a side product green precipitate was also obtained, and some of the desired complex was still in solution. Forcing precipitation to increase the yield (such as stirring and overheating) will cause precipitation of unwanted starting materials or side products and can also cause precipitation of the desired product copper complex (6) as a powder rather than pure crystals.

The following was added to discussion:

As mentioned in the experimental section, filtration technique was used in order to remove the side product green precipitate before crystallization of desired copper complex. The violet filtrate was left for slow evaporation and violet pure crystals were then obtained. Obtaining the product in a crystalline form is considered as a way of purifying the product. Since, it is well known that crystalline product should have much higher purity compared to amorphous product. Also, the morphology of the crystals was checked using a microscope. The crystals appeared as perfect crystalline transparent violet cubes of high purity with no amorphous materials adsorbed on them.

The following was added to discussion section:

Sulfur was likely lost in the form of H₂S gas due to compound (5) rearrangement, while using NaOH then HCl to neutralize the medium, assisted by copper complexation as observed in other similar system [72]. The detailed mechanism is still under investigation.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

After changes have been made, the manuscript may be recommended for publication after the list of references has been corrected. Many of the references are to the period 2000-2005. Please refresh the references on the chemistry of Schiff bases. To that end, I also recommend mentioning the following recent papers that address Schiff base chemistry:  10.3390/molecules27238233; 10.3390/molecules27227894; 10.3390/molecules27030758; 10.1016/j.mencom.2018.03.032; 10.3390/cryst11050483

Author Response

Reply to reviewer 2:                                                                                                    10-12-20222

Comment:

After changes have been made, the manuscript may be recommended for publication after the list of references has been corrected. Many of the references are to the period 2000-2005. Please refresh the references on the chemistry of Schiff bases. To that end, I also recommend mentioning the following recent papers that address Schiff base chemistry:  10.3390/molecules27238233; 10.3390/molecules27227894; 10.3390/molecules27030758;  10.1016/j.mencom.2018.03.032; 10.3390/cryst11050483

Reply:

Thanks for the reviewer for recommending publication of the paper after updating some suggested references. We did abide to his suggestion and updated the references accordingly;

Thus, the following references are updated as such:

Ref 5:

N. Raman, J. Joseph, S.M. Kumar, S. Sujatha and K. Sahayaraj, Insecticidal activity of the schiff - base derived from anthranilic acid and acetoacetanilide and its copper complex on Spodoptera litura (Fab.), Journal of Biopesticides, 2008, 1(2), 206- 209

Ref 6:

E.A. Buvaylo, O.V. Nesterova, E.A. Goreshnik, H.V. Vyshniakova, S.R. Petrusenko, D.S. Nesterov, Supramolecular Diversity, Theoretical Investigation and Antibacterial Activity of Cu, Co and Cd Complexes Based on the Tridentate N,N,O-Schiff Base Ligand Formed In Situ, Molecules, 2022, 27(23), 8233; https://doi.org/10.3390/molecules27238233

Ref 7:

M. Badea, M.C. Chifiriuc, Metal Complexes—A Promising Approach to Target Biofilm Associated Infections, R. Olar, Molecules, 2022, 27(3), 758, https://doi.org/10.3390/molecules27030758

Ref 12:

G. Matela, Schiff Bases and Complexes: A Review on Anti-Cancer Activity, Anticancer Agents Med Chem. 2020, 20(16), 1908-1917. https://doi.org/10.2174/1871520620666200507091207.

Ref 23:

D.N. Bazhin, Y.S. Kudyakova, P.A. Slepukhin, Y.V. Burgart, N.N. Malysheva, A.N. Kozitsina, A.V. Ivanova, A.S. Bogomyakov, V.I. Saloutin, Dinuclear copper(ii) complex with novel N,N',N'',O-tetradentate Schiff base ligand containing trifluoromethylpyrazole and hydrazone moieties, Mendeleev Commun., 2018, 28, 202–204, https://doi.org/10.1016/j.mencom.2018.03.032

Ref 25:

R. Mazzoni, F. Roncaglia, L. Rigamonti, When the Metal Makes the Difference: Template Syntheses of Tridentate and Tetradentate Salen-Type Schiff Base Ligands and Related Complexes, Crystals, 2021, 11(5), 483, https://doi.org/10.3390/cryst11050483

 

Author Response File: Author Response.pdf

Round 3

Reviewer 1 Report

Unfortunately, without more analytical data the structure of the compound cannot be assessed unequivocally, as one crystal used for X-ray diffraction is not representative of the whole sample. Elemental analysis is particularly important to determine the purity of the sample. This should be stated at some point.

Author Response

Reply to reviewer 1                                                                                                             17-12-2022                                                                              

Comments and Suggestions for Authors

Unfortunately, without more analytical data the structure of the compound cannot be assessed unequivocally, as one crystal used for X-ray diffraction is not representative of the whole sample. Elemental analysis is particularly important to determine the purity of the sample. This should be stated at some point.

Reply:

Thank for the reviewer comment, the following was stated to the end of purification discussion as for the reviewer suggestion:

Finally, elemental analysis is particularly important to determine the purity of the sample. The theoretical % elemental analysis for complex (6) C₃₀H₂₂Cl₄CuN₈ (699.88 g/mol) is: %C, 51.48%; %H, 3.17%; %Cl, 20.26%; %Cu, 9.08%; %N, 16.01%. While the X-ray single structure CIF file is in CCDC No. 2217976 which contains the supplementary crystallographic data for complex (6), Table S1.

 

Author Response File: Author Response.pdf