5,8-Di-tert-butyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione—A New Lipophilic N-oxyl Radical Precursor
Round 1
Reviewer 1 Report
This is a fine report of a potentially useful compound. The authors are able to demonstrate the utility of the title compound versus existing methods.
The manuscript would benefit from only some small edits:
- synthesis is misspelled on p2 line 59
- Please note what was used to reference the NMR spectra in the general experimental section.
- tabulated NMR data should be included for intermediates 2 and 3
- Selected FTIR resonances are not the most pertinent to the structure of the compound. The resonances related to the C=O and O–H stretches are present in the SI spectra but not listed.
- 2D spectra such as HSQC and HMBC would be useful for a compound with so few hydrogen atoms, but not required.
Author Response
Dear Reviewer,
Thank you for the careful evaluation of our manuscript and your comments. The manuscript was corrected accordingly, the track-changes version of the manuscript file is attached to the submission. The step-by-step answers to the comments of Reviewer 1 are listed below. Answers to all Reviewers are attached as pdf file.
Reviewer’s comment:
This is a fine report of a potentially useful compound. The authors are able to demonstrate the utility of the title compound versus existing methods.
Answer: Thank you for your careful reading and positive evaluation of our work.
Reviewer’s comment:
The manuscript would benefit from only some small edits:
- synthesis is misspelled on p2 line 59
Answer: The misprint was corrected
Reviewer’s comment: - Please note what was used to reference the NMR spectra in the general experimental section.
Answer: The text “The residual signal of CHCl3 in CDCl3 (7.26 ppm) was used as a chemical shift reference in 1H NMR spectra. The central line of CDCl3 signal (77.16 ppm) was used as a chemical shift reference in 13C NMR spectra.” was added in the 3. Materials and Methods, General.
Reviewer’s comment: - tabulated NMR data should be included for intermediates 2 and 3
Answer: 1H and 13C NMR data for the compounds 2 and 3 are added in the main text (3. Materials and Methods), and the images of the corresponding spectra are added to the Supplementary information.
Reviewer’s comment: - Selected FTIR resonances are not the most pertinent to the structure of the compound. The resonances related to the C=O and O–H stretches are present in the SI spectra but not listed.
Answer: FTIR spectrum description is corrected. Characteristic O-H, C-H and C=O vibrations are listed for product 4.
Reviewer’s comment:
- 2D spectra such as HSQC and HMBC would be useful for a compound with so few hydrogen atoms, but not required.
Answer: 1H–13C HSQC and 1H–13C HMBC spectra for the compound 4 confirming its structure are added to the supplementary information.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
In the communication “5,8-Di-tert-butyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione – a new lipophilic N-oxyl radical precursor” the authors reported synthesis of a new lipophilic radical precursor that can be used for radical C-O coupling and for in redox organocatalysis. In the introduction the authors have presented a case for the discovery of a new organocatalyst for liquid phase reactions as the currently used NHPI, suffers from solubility issues with low-polarity solvents. The titled compound was chosen for the study as its unsubstituted analog, N-hydroxynaphthalimide is believed to have higher NO-H BDE than NHPI but lower solubility in low polarity solvents.
There are certain explanations I would expect from the authors to include in the manuscript,
If NHPI has solubility issues, why not to derivatize it and try to make better oxidant rather than NHNI? Is there any study reported on NHPI and how are the results?
The BDE of the compound 5 was calculated using DFT calculations and there is no study was reported in this paper. What new information/inference the authors were able to derive other than the solubility based on the synthesized compound?
Have the authors deduced NO-H BDE (reported in table 1) for compound using EPR or is it only based DFT calculations?
Other minor changes:
The way the results are presented, it gives the impression that, compound 3 is new. Add reference for compound 3.
Consider citing additional Reference,
Chem. Eur. J. 2017, 23, 2149 – 2156
J. Chem. Soc. 1942, 562-565
Table 1.: In the footnote 1, use either employing or using.
Author Response
Dear Reviewer,
Thank you for the careful evaluation of our manuscript and your comments. The manuscript was corrected accordingly, the track-changes version of the manuscript file is attached to the submission. The step-by-step answers to the comments of Reviewer 2 are listed below. Answers to all Reviewers are attached as pdf file.
Reviewer’s comment:
In the communication “5,8-Di-tert-butyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione – a new lipophilic N-oxyl radical precursor” the authors reported synthesis of a new lipophilic radical precursor that can be used for radical C-O coupling and for in redox organocatalysis. In the introduction the authors have presented a case for the discovery of a new organocatalyst for liquid phase reactions as the currently used NHPI, suffers from solubility issues with low-polarity solvents. The titled compound was chosen for the study as its unsubstituted analog, N-hydroxynaphthalimide is believed to have higher NO-H BDE than NHPI but lower solubility in low polarity solvents.
Answer: Thank you for your careful reading of the manuscript.
Reviewer’s comment:
There are certain explanations I would expect from the authors to include in the manuscript,
If NHPI has solubility issues, why not to derivatize it and try to make better oxidant rather than NHNI? Is there any study reported on NHPI and how are the results?
Answer: Thank you for this question. There were several reasons for choice of di-t-Bu-NHNI as a synthetic target: 1) its lipophilicity increasing the solubility in organic medium, 2) its high O-H BDE that should correspond to high oxidative (hydrogen-abstracting) properties of the corresponding N-oxyl radical, 3) the catalytic properties of NHNI are much less studied than that of NHPI, NHNI derivatives were not studied as redox organocatalysts at all. We have added the comment to the introduction: Several catalytically effective lipophilic NHPI derivatives were reported [21–23]. However, BDE values for these derivatives were very close to that of parent NHPI [23].
Reviewer’s comment:
The BDE of the compound 5 was calculated using DFT calculations and there is no study was reported in this paper. What new information/inference the authors were able to derive other than the solubility based on the synthesized compound?
Answer: The high O-H BDE of synthesized compound 4 allows us to expect that corresponding N-oxyl radical 5 can be used for hydrogen atom abstraction from unactivated CH-reagents. This information is highlighted in conclusion: “The high NO–H BDE (92.5 kcal/mol according to ωB97M-D3BJ/def2-TZVPP calculation) in 4 and relatively slow self-decay of the corresponding N-oxyl radical 5 make 4 perspective N-oxyl radical precursor for CH-functionalization of unactivated substrates by hydrogen atom abstraction.”.
Reviewer’s comment:
Have the authors deduced NO-H BDE (reported in table 1) for compound using EPR or is it only based DFT calculations?
Answer: NO-H BDE were calculated by DFT method (note 1 to Table 1). A good agreement of our calculations with literature values was observed. In particular, significantly higher BDE for NHNI 6 compared to NHPI was reported previously.
Reviewer’s comment:
Other minor changes:
The way the results are presented, it gives the impression that, compound 3 is new. Add reference for compound 3.
Consider citing additional Reference,
Chem. Eur. J. 2017, 23, 2149 – 2156
- Chem. Soc.1942, 562-565
Answer:
Missing references were added (see refs. 35, 36).
Reviewer’s comment:
Table 1.: In the footnote 1, use either employing or using.
Answer: The word “using” was excluded.
Author Response File: Author Response.pdf
