1-(3-Isoselenocyanatopropyl)adamantane
Round 1
Reviewer 1 Report
The article entitled "1-(3-isoselenocyanatopropyl)adamantane" describes the synthesis of a new homologue of the isoselenocyanoadamantane derivative that contains an n-propyl chain between the adamantane moiety and isoselenocyanate. Indeed, the compound was not previously reported in the literature (Reaxy, Google Scholar), however, its close analogues like 1-isoselenocyanatoadamantane and 1- (2-isoselenocyanatoethyl)adamantane are already known, which reduces the scientific importance of the synthesis of another homologue without any additional bioactivity investigation or at least preparation of additional derivative such as selenourea.
The provided analysis is incomplete. There is no information about the form of the obtained compounds 2 and 3 (solid/liquid/oil and colour). If it is solid, there should be provided melting point. The IR analysis is also missed, and the GC-MS should be supplemented with additional data such as column type in the GC, separation method parameters, and retention time of the pick (the GC chromatogram should also be added to the SI). The Authors did not precise if compound 2 is already known or not. If compound 2 is unreported it should be characterized by the complete analysis like 3. If it is known or unstable after preparation just crude 1H and 13CNMR with GC-MS analysis should be provided. In this way, in the experimental part, the synthesis of compounds 2 and 3 should be separated by then. The essential issue is a lack of information about the yields of both steps to gain some conclusions about the efficiency of the proposed procedure. Another confusion is the chosen method of isonitrile preparation. The most common and efficient one is based on the formation of formamide from the starting amine that in subsequent steps undergoes dehydration by treatment with POCl3 or triphosgene. The Authors should add some comments on why they choose this particular method. I also recommend the Authors explain in more detail the quadrupole effect of nitrogen on the shape of signals since it is not a common phenomenon and the provided single-sentence comment is not clear.
The language of the manuscript is appropriate and correct. The style can be improved by unifying the size of drawings in schemes adding the numbers to all compounds and the modification of Figure 2, which looks like raw data taken from NMR spectra. Interestingly, those triplets mentioned in the main text for 1HNMR and 13CNMR are not observed or even marked in the NMR spectra in the SI. The reference part provided different types of citations style that should be unified.
In summary, the manuscript can be published in the Molbank Journal after major revisions with an essential expansion of the scientific impact.
Author Response
The article entitled "1-(3-isoselenocyanatopropyl)adamantane" describes the synthesis of a new homologue of the isoselenocyanoadamantane derivative that contains an n-propyl chain between the adamantane moiety and isoselenocyanate. Indeed, the compound was not previously reported in the literature (Reaxy, Google Scholar), however, its close analogues like 1-isoselenocyanatoadamantane and 1- (2-isoselenocyanatoethyl)adamantane are already known, which reduces the scientific importance of the synthesis of another homologue without any additional bioactivity investigation or at least preparation of additional derivative such as selenourea.
The provided analysis is incomplete. There is no information about the form of the obtained compounds 2 and 3 (solid/liquid/oil and colour). If it is solid, there should be provided melting point.
Form of compound 2 as well as 1H and 13C NMR and mass-spectra added to the experimental section. Form of compound 3 was mentioned in the initial manuscript (highlighted with green)
The IR analysis is also missed, and the GC-MS should be supplemented with additional data such as column type in the GC, separation method parameters, and retention time of the pick (the GC chromatogram should also be added to the SI).
Retention time for compounds 2 and 3 added to the experimental section with additional data concerning GC-MS analysis. Chromatograms of compounds 2 and 3 added to the SI.
The Authors did not precise if compound 2 is already known or not. If compound 2 is unreported it should be characterized by the complete analysis like 3. If it is known or unstable after preparation just crude 1H and 13CNMR with GC-MS analysis should be provided. In this way, in the experimental part, the synthesis of compounds 2 and 3 should be separated by then. The essential issue is a lack of information about the yields of both steps to gain some conclusions about the efficiency of the proposed procedure.
Compound 2 is a new one. Characterization of 2 added to the experimental section. Experimental part for compounds 2 and 3 was separated. Yield for compound 2 added.
Another confusion is the chosen method of isonitrile preparation. The most common and efficient one is based on the formation of formamide from the starting amine that in subsequent steps undergoes dehydration by treatment with POCl3 or triphosgene. The Authors should add some comments on why they choose this particular method.
A large number of works on the synthesis of isonitriles are described in the literature [10.1039/D0GC02722G]. One common method is one that is based on the formation of formamide from the starting amine, which in subsequent steps is dehydrated by treatment with POCl3 or triphosgene [10.3390/molecules27206850]. However, POCl3, and even more so triphosgene, are highly toxic substances, the handling of which requires special care.
Another common method is the method in which isonitrile is obtained by reacting an amine with chloroform and an aqueous solution of alkali in dichloromethane in the presence of phase transfer catalysts such as Aliquat 336 or Adogen 464 [10.1055/s-0035-1560481], bypassing the stage of obtaining an intermediate formamide , and without the use of highly toxic substances such as POCl3 and triphosgene, which is more attractive from a technological point of view.
Although this approach gives good yields, it is characterized by the complexity of the isolation step due to contamination of the product with phase transfer catalysts and its fragments. At the same time, data on the use of alcohols for the homogenization of this reaction are described in the literature. For example, Biddle [10.1002/jlac.19003100102] recommends avoiding the use of ethyl alcohol as a solvent for KOH, as formamide is formed under these conditions. However, Lindemann [10.1002/cber.19300630705] reports that without the addition of a small amount of ethanol, the reaction stops quickly.
We investigated a range of alcohols: methanol, ethanol, isopropanol, tert-butanol, and 1-octanol as replacements for the Aliquat 336 phase transfer catalyst. It is important to note that without Aliquat 336 or alcohol, isonitrile formation does not occur. The best results have been achieved with tert-butyl alcohol [10.1007/s11172-022-3675-z]. By excluding water from the reaction, using dry alkali, it was possible to increase the yield of isonitrile to 90%.
Tert-butyl alcohol is a low-toxic, readily available compound that can be easily removed from the reaction mass during the synthesis of isonitrile by washing with water.
Thus, we have optimized a one-stage method for the preparation of adamantyl-containing isonitrile by reacting an amine with chloroform and NaOH in a dichloromethane medium, excluding the presence of water from the reaction mass and replacing the Aliquat 336 phase transfer catalyst with easily accessible and low-toxic tert-butyl alcohol.
Comments and citations added to the results and discussion part.
I also recommend the Authors explain in more detail the quadrupole effect of nitrogen on the shape of signals since it is not a common phenomenon and the provided single-sentence comment is not clear.
More detailed description of the observed effect was added.
The language of the manuscript is appropriate and correct. The style can be improved by unifying the size of drawings in schemes adding the numbers to all compounds and the modification of Figure 2, which looks like raw data taken from NMR spectra. Interestingly, those triplets mentioned in the main text for 1HNMR and 13CNMR are not observed or even marked in the NMR spectra in the SI.
Drawings were unified. Figure 2 was moved to SI Figure S5 as it is part of NMR data. Figure S5 show the reported triplets. SI was revised.
The reference part provided different types of citations style that should be unified.
Reference part was revised.
In summary, the manuscript can be published in the Molbank Journal after major revisions with an essential expansion of the scientific impact.
Thank you for the review.
Round 2
Reviewer 1 Report
The Authors provided missed information and corrected the issues noted by the reviewer in the revised manuscript. Analytical data from NMR and GC-MS are now adequately provided. Unfortunately, the IR spectrum, which is also essential for a complete analysis, was still skipped even without any comments from the Authors. Other mentioned editorial errors have been fixed more or less.
There are still several issues to be revised.
- After explaining the choice of isocyanide preparation method, there is mentioned condition screening (various solvent tests) – the table with the solvent variation and the yields obtained will significantly increase the importance of the work.
- Please add the yield for scheme 1
- Start with the compound numbering from Figure 1
- Page 2, line 33 - Change to 'in preparation of isoselenocyanates is a synthesis'
- Page 2, line 42 - Change to 'for the homogenisation of the first type of reaction involving CHCl3 and aqueous NaOH'
- The quadrupole effect is now nicely described, but in this particular example it is observed for 1H and not 13C based on the data provided in the SI.
- The flow rate of the He carrier gas in GC-MS should be provided.
- preparation of compound 2 - 258 mg (2.16 mmol) of CHCl3 - do the Authors measure the weight of chloroform or put the appropriate volume? I recommend adding equivalents of the reagents to the synthetic procedures.
- What about C14 at 13CNMR. Is it detectable or not (what about signals around 120 ppm on both 13CNMR in the SI)?
- Add the ending pages to References 6 - 10
- Change the page separator in reference 17
In summary, the manuscript still required major revision before publishing in the Molbank Journal.
Author Response
The Authors provided missed information and corrected the issues noted by the reviewer in the revised manuscript. Analytical data from NMR and GC-MS are now adequately provided. Unfortunately, the IR spectrum, which is also essential for a complete analysis, was still skipped even without any comments from the Authors. Other mentioned editorial errors have been fixed more or less.
Unfortunately, it is not possible to provide IR spectra of isonitrile and isoselenocyanate due to the absence of these substances. Isonitrile was completely consumed for the synthesis of isoselenocyanate and GC-MS, 1H and 13C NMR analyses. Isoselenocyanate was used for GC-MS, 1H and 13C NMR analyses, and was also sent for tests against oncology. Moreover, during the synthesis of isonitrile, the starting materials was also completely consumed, which does not allow synthesizing isonitrile and isoselenocyanate again in a short time.
In our opinion, 1H and 13C NMR, GC-MS, and elemental analysis are sufficient to confirm the structure.
There are still several issues to be revised.
- After explaining the choice of isocyanide preparation method, there is mentioned condition screening (various solvent tests) – the table with the solvent variation and the yields obtained will significantly increase the importance of the work.
Table added
- Please add the yield for scheme 1
Added
- Start with the compound numbering from Figure 1
Corrected
- Page 2, line 33 - Change to 'in preparation of isoselenocyanates is a synthesis'
Corrected
- Page 2, line 42 - Change to 'for the homogenisation of the first type of reaction involving CHCl3 and aqueous NaOH'
Corrected
- The quadrupole effect is now nicely described, but in this particular example it is observed for 1H and not 13C based on the data provided in the SI.
It is not uncommon to observe that 13C signals of isonitriles do not always show splitting on 15N nuclei. For instance, in the study [10.1134/S1068162021040166], the carbon signal with a D-glucose fragment is observed as a singlet, and in the study [10.1039/D2GC01398C], the alpha-isonitrile derivative of phenylalanine also appears as singlets.
- The flow rate of the He carrier gas in GC-MS should be provided.
Flow rate of carrier gas He in GC-MS is 1 ml/min. Added to the manuscript.
- preparation of compound 2 - 258 mg (2.16 mmol) of CHCl3 - do the Authors measure the weight of chloroform or put the appropriate volume? I recommend adding equivalents of the reagents to the synthetic procedures.
Reagent equivalents added to synthesis description.
Chloroform was weighed on an analytical balance. Since the dosage of the volume, taking into account the temperature and the accuracy of the dispensers, does not give the desired accuracy.
- What about C14 at 13CNMR. Is it detectable or not (what about signals around 120 ppm on both 13CNMR in the SI)?
According to literary sources, the carbon signal of the isonitrile group should be detected in the chemical shift range of 155 ppm. However, in our experimental practice, we sometimes encounter the absence of the carbon signal associated with the isonitrile group (-NC). This is explained by the long relaxation time, the absence of the Overhauser effect, and the need to use large quantities of the substance (200 μl). The signal at 120 ppm is a structural feature of the nuclear magnetic resonance spectrometer used in our experiments.
- Add the ending pages to References 6 – 10
Ref 7 – corrected
Articles in these journals (ref 6,8,9,10) do not have continuous numbering of pages, but are marked with the serial number of the article.
- Change the page separator in reference 17
Corrected
In summary, the manuscript still required major revision before publishing in the Molbank Journal.
Thank you for the review.
