Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis

Round 1

Reviewer 1 Report

This manuscript by Averina group reports the CuAAC synthesis of specific cyclooctane- cored hydroxyalkyl triazoles and their abilities as copper ligand for further CuAAC catalysis. The detailed structural characterization and X-ray crystallographic analysis of new copper(II) complex bearing thus synthesized cyclooctanol triazole are also demonstrated in this study. The new copper catalysis report and usability of new triazole as ligand seem to be a enough scientific appeal to justify publication of this work in Catalysts journal.

On the other hand, the present manuscript somewhat provides only brief experiments for the key synthesis of cyclooctane triazoles and their application as copper catalysis ligand. Regarding the triazole synthesis, no kinetic study is provided. As these cyclooctane triazoles produced in situ might act as second copper ligand during the reaction, their effect for autocatalysis or reaction inhibition are a matter of important discussion in this work. Furthermore, their application as copper ligand in CuAAC is demonstrated with only two substrates, and this brief investigation cannot conclude the new ligand is more excellent over others. Once these points are suitably investigated and discussed, I recommend publication of this work as a Catalysts article.

Author Response

Dear Reviewer,

We thank you for the attention to our work and valuable remarks. We have revised the work, taking into account your suggestions, and the answers to your comments are included below. The revised manuscript with our corrections is uploaded.

 

Yours sincerely,

Dr. Elena B. Averina

 

This manuscript by Averina group reports the CuAAC synthesis of specific cyclooctane- cored hydroxyalkyl triazoles and their abilities as copper ligand for further CuAAC catalysis. The detailed structural characterization and X-ray crystallographic analysis of new copper(II) complex bearing thus synthesized cyclooctanol triazole are also demonstrated in this study. The new copper catalysis report and usability of new triazole as ligand seem to be a enough scientific appeal to justify publication of this work in Catalysts journal.

On the other hand, the present manuscript somewhat provides only brief experiments for the key synthesis of cyclooctane triazoles and their application as copper catalysis ligand.

• Answer: As required, we have tried to carry out the kinetic study on example of cycloaddition of azide 2a to phenyl acetylene, but the results were quite dubious. On the kinetic curve we observed an induction period of approximately 2 hours and then rapid increase of the reaction speed – that is, generally, in the accordance with autocatalytic action of the triazole product 3. Yet, as 50% conversion of starting azide 2a was achieved and the concentration of triazole 3 increased, the results of the analysis of probes became poorly reproducible and could not be approximated. At the same time the reaction mixture became visibly more heterogeneous, that may be connected with the complexing of triazole 3 with copper ions, troubling the quantitative analysis of the mixture.

Regarding the triazole synthesis, no kinetic study is provided. As these cyclooctane triazoles produced in situ might act as second copper ligand during the reaction, their effect for autocatalysis or reaction inhibition are a matter of important discussion in this work.

•  Answer: We thanks for your kind suggestions, but we would prefer not to describe these results, as they definitely need more profound investigations and some other design of the experiment.

Furthermore, their application as copper ligand in CuAAC is demonstrated with only two substrates, and this brief investigation cannot conclude the new ligand is more excellent over others. 

• Answer:  We have investigated in CuAAC reaction with benzyl azide in presence of compounds 3 and 9 four more alkynes with aromatic and aliphatic substituents. In the cases of EDG-containing alkynes there was no difference between triethylamine and compound 3 as ligand. But when less reactive starting compounds, containing COOR groups, were employed, we observed the increase of yields in the presence of compound 3. Corresponding data have been added to Table 3.

Once these points are suitably investigated and discussed, I recommend publication of this work as a Catalysts article.

• Answer:  We highly appreciate your positive feedback to our research.  We have carefully considered all the points you provided. Thanks again.
  

 

Reviewer 2 Report

1.     The Figure 4 is not clear, please also improve its quality; also, the authors have tried to discuss the H-bonded interaction, Please also list a table for the H-bonded parameter;

2.     Follow the Figure 4, the authors have to label the atoms and distance values in the Fig. 4B and C.

3.     The refs on the cycloaddition of readily available individual diastereomers of azidoalcohols or diazidodiols with phenylacetylene could be considered, such as Org. Chem. Front., 2020,7, 3515-3520; Chem. Commun., 2022, 58, 6653–6656; J. Org. Chem. 2019, 84, 14627−14635; Org. Lett. 2020, 22, 8086−8090 and Org. Chem. Front., 2021, 8, 4554–4559.

4.     IN the abstract section, I suggest the authors give more valuable description, the reader will get more information.

5.     Could you give some discussion on the cycloaddition for the similar reaction catalysis?

 

Author Response

Dear Reviewer,

We thank you for the attention to our work and valuable remarks. We have done most of suggested revisions, and the answers to your comments are included below. The revised manuscript with our corrections is uploaded.

 

Yours sincerely,

Dr. Elena B. Averina

 

1. The Figure 4 is not clear, please also improve its quality; also, the authors have tried to discuss the H-bonded interaction, Please also list a table for the H-bonded parameter;
2. Follow the Figure 4, the authors have to label the atoms and distance values in the Fig. 4B and C.

1-2) Concerning the representation of X-Ray analysis data.

- We improved the quality of Figure 4D (now Figure 4B), labeled the atoms on this Figure and pointed the largest distance between the corresponding atoms in the figure caption.

As for Figures 4B,C we were not able to find a better projection clearly illustrating molecular packing or H-bonds; and labeling the atoms made the figures too crowded. We removed them to Supplementary Materials.

- Also we have added table for the hydrogen bond parameters (Table 4), as required.

3. The refs on the cycloaddition of readily available individual diastereomers of azidoalcohols or diazidodiols with phenylacetylene could be considered, such as Org. Chem. Front., 2020,7, 3515-3520; Chem. Commun., 2022, 58, 6653–6656; J. Org. Chem. 2019, 84, 14627−14635; Org. Lett. 2020, 22, 8086−8090 and Org. Chem. Front., 2021, 8, 4554–4559.

3) We would like to ask the Reviewer to check whether the references are correct, as we have found no data on cycloaddition in the abovementioned works.

4. IN the abstract section, I suggest the authors give more valuable description, the reader will get more information.

4) We have expanded the abstract, adding information to background and description of the present work.

5. Could you give some discussion on the cycloaddition for the similar reaction catalysis?

5) We have inserted comments and additional references to reviews on this topic.

Reviewer 3 Report

The paper describes the preparation of triazoles in the reaction of copper-catalyzed azide-alkyne cycloaddition CuAAC. The synthesis is not complicated, nor is it completely original. An analogous method of obtaining hydroxytriazoles from previously obtained hydroxyazides (after opening epoxides) was described by Couty in Chem Commun 2017, 53, 321-323. Although Couty used a different solvent and a different amine (TBTA), he also obtained yields of triazoles in the range of 60-99%.

In the presented manuscript only a few yields obtained after screening were cited, the best being 82%. Unfortunately, the authors do not even cite the 2017 paper in their manuscript (!).

I also have reservations about interpreting the performed experiments documenting the catalytic applications of the obtained compounds (3, 9-12). All results (reaction yields) were based on the analysis of the 1HNMR spectrum, as I understand it by comparing the integration of the emerging signal from gr. CH₂ of the product (triazole) with the integration of the decaying signal from the gr. CH₂ substrate (azide). Unfortunately, I have the impression that the chosen method is not appropriate, and is even unreliable. In the spectrum from the "comparison" reaction (with Et₃N), the peak at 4.34 ppm was assigned to the substrate, while in the other spectra after catalysis, the same peak was assigned to the ligand (with 3, 11, and 12 as a ligand) or not at all (with 9 as a ligand). In the latter case, I do not understand where the 0.5:1 (14:15) ratio came from?

In my opinion, the authors should definitely choose another method of quantitative interpretation of catalysis results.

 

In its current form, the manuscript is unsuitable for publication.

Author Response

Dear Reviewer,

We thank you for the attention to our work and valuable comments. We have revised the work, taking into account your remarks, and the answers to your comments are included below. The revised manuscript with our corrections is uploaded.

 

Yours sincerely,

Dr. Elena B. Averina

 

The paper describes the preparation of triazoles in the reaction of copper-catalyzed azide-alkyne cycloaddition CuAAC. The synthesis is not complicated, nor is it completely original. An analogous method of obtaining hydroxytriazoles from previously obtained hydroxyazides (after opening epoxides) was described by Couty in Chem Commun 2017, 53, 321-323. Although Couty used a different solvent and a different amine (TBTA), he also obtained yields of triazoles in the range of 60-99%.

In the presented manuscript only a few yields obtained after screening were cited, the best being 82%. Unfortunately, the authors do not even cite the 2017 paper in their manuscript (!).

I also have reservations about interpreting the performed experiments documenting the catalytic applications of the obtained compounds (3, 9-12). All results (reaction yields) were based on the analysis of the 1HNMR spectrum, as I understand it by comparing the integration of the emerging signal from gr. CH₂ of the product (triazole) with the integration of the decaying signal from the gr. CH₂ substrate (azide). Unfortunately, I have the impression that the chosen method is not appropriate, and is even unreliable. In the spectrum from the "comparison" reaction (with Et₃N), the peak at 4.34 ppm was assigned to the substrate, while in the other spectra after catalysis, the same peak was assigned to the ligand (with 3, 11, and 12 as a ligand) or not at all (with 9 as a ligand). In the latter case, I do not understand where the 0.5:1 (14:15) ratio came from?

In my opinion, the authors should definitely choose another method of quantitative interpretation of catalysis results.

 In its current form, the manuscript is unsuitable for publication.

 

 

- Regretfully, we did overlooked the abovementioned article (Chem Commun 2017). In the revised version of manuscript we have cited that reference. Besides, we have applied the conditions, described in that work to our model compound 2a and least reactive tertiary azide 2b, but it did not allow increasing the yields.

As for originality, we would like to mention that we are dealing with quite interesting cores – 1,2- or 1,5-substituted cyclooctane or oxabicyclononanes, which provide a specific spacial arrangement of substituents, including two triazolyl moieties. We believe that the obtained compounds are attractive for their further investigation as complexing agent.

- We agree that the chosen method should not be used as a proper characterization of the reaction results, as it reflects only one parameter – the ratio of starting compound and product. We have revisited the results of the experiments on catalysis, using for quantitative characterization the product yield, estimated by ¹H NMR spectra in relation to external standard (p-xylene, 10 mol.% in relation to starting azide). That method of interpretation was definitely much more correct and illustrative than our previous description, particularly, in the case of reaction of benzyl azide and phenylacetylene (Table 2).

- As for the previous interpretation of results of the experiments of cycloaddition of phenylacetylene and benzyl azide, we can reliably distinguish the signal at 4.34 ppm assigned to CH₂-N₃ group in starting benzyl azide and close peaks corresponding to CH₂-triazolyl groups in ligands 3,10 or 12. The latter are accompanied with characteristic low-field signals of triazolyl moieties of taken ligand, particularly, a singlet at approx. 8.00 ppm. As for ligands 9,11 we do not observe a singlet signal in the region 4.30-4.40 ppm, as the diastereotopic protons of their CH₂-triazolyl groups are characterized with AB-systems in NMR ¹H spectra. Spectra for the compounds 10 and 11 as ligands meant to be vice versa; now we have corrected the mistake.

- There was no 0.5:1 (14:15) ratio in Table 2, describing the reaction between phenylacetylene and benzyl azide. Presumably, Table 3, Entry 2 is mentioned here – it describes the reaction between benzyl azide and propargyl alcohol and ratio 14:16. The numbering relates to the previous version of manuscript: in the revised manuscript former number 15 is 15a and former number 16 is 15b. 

Round 2

Reviewer 1 Report

I have re-reviewed the revised manuscript, and confirmed that the authors have conducted suitable revisions considering the comments by all reviewers. The quality of the manuscript is surely improved by adding the further information about the key synthesis of cyclooctane triazoles and their application in CuAAC catalysis ligand for more extended series of substrates with electron-donating and withdrawing group. The synthesis of these cyclooctanol triazole ligands as well as characterization and X-ray crystallographic structure determination of new copper(II) complex have enough scientific appeal to justify publication of this work in Catalysts journal. I recommend acceptance of the present manuscript after minor revision; the authors should guarantee the reaction yield by direct isolation of the product, and some of one example should be compared with the NMR result.

The kinetic study for triazole ligand synthesis and further CuAAC application is an important work in their future study. I look forward to meeting such investigation for this work as a separate paper, with further new application of the copper catalysts.

Author Response

I have re-reviewed the revised manuscript, and confirmed that the authors have conducted suitable revisions considering the comments by all reviewers. The quality of the manuscript is surely improved by adding the further information about the key synthesis of cyclooctane triazoles and their application in CuAAC catalysis ligand for more extended series of substrates with electron-donating and withdrawing group. The synthesis of these cyclooctanol triazole ligands as well as characterization and X-ray crystallographic structure determination of new copper(II) complex have enough scientific appeal to justify publication of this work in Catalysts journal. I recommend acceptance of the present manuscript after minor revision; the authors should guarantee the reaction yield by direct isolation of the product, and some of one example should be compared with the NMR result.

The kinetic study for triazole ligand synthesis and further CuAAC application is an important work in their future study. I look forward to meeting such investigation for this work as a separate paper, with further new application of the copper catalysts.

 

Dear Reviewer!

We thank you again for the attention to our work and valuable remarks.

As required, we have isolated compound 15a from the reaction in presence of ligand 3 and included the isolated yield to Table 2.

Sincerely yours,

Prof. E.B. Averina

Reviewer 2 Report

accept

Author Response

Dear Reviewer,

We thank you again for the attention to our work and valuable remarks.

Sincerely yours,

Prof. E.B. Averina

Reviewer 3 Report

After the additions, I rate the manuscript slightly better, but still no "evidence" for the results of catalysis has been presented.
The Supplementary Materials do not contain 1HNMR spectra with a standard, which would confirm the calculations of the results of catalytic reactions.

Author Response

After the additions, I rate the manuscript slightly better, but still no "evidence" for the results of catalysis has been presented.
The Supplementary Materials do not contain 1HNMR spectra with a standard, which would confirm the calculations of the results of catalytic reactions.

 

Dear Reviewer,

We thank you again for the attention to our work and valuable remarks.

We have included all the ¹H NMR spectra with a standard to the Supplementary materials, as required.

Sincerely yours,

Prof. E.B. Averina