3,4-Diaminopyridine-2,5-dicarbonitrile
Round 1
Reviewer 1 Report
This short note focuses on a double cyanation of 2,5-dibromo-3,4-diaminopyridine with copper cyanide affording the corresponding 2,5-dicarbonitrile derivative that could be utilised as precursor of heterocyclic compounds. The preparation of this dicarbonitrile is not easy, and I suggest to improve the introduction part by adding the importance of cyanation methods. In this regard, the authors could add the following references: 1) Org. Lett. 2004, 6, 2837-2840; 2) Chem. Eur. J. 2007, 13, 6249-6254.
In the introduction, I suggest to use the term "ortho" for benzene derivatives. Properly, in the case of pyridines location numbers have to be used.
In the result and discussion part, at row 34 I suggest to change "cyanide and potassium" with cyanide or potassium".
In the table 1, it is convenient to specify how the yields have been calculated (isolated or by internal standard) and the molar ratio of reactants. The best yield is very moderate: did you try other solvents or conditions in order to improve the yield?
In the experimental section, could the authors specify the feature of the reactor used? In addition, how the authors remove the DMF from the crude? Please describe in the procedure.
In the supporting, the 1H NMR is not clean. Please reload a better spectrum. If possible also a more concentrated 13C with a better noise/signal ratio.
When suggested changes will be addressed, this manuscript could be suitable for publication in Molbank.
Author Response
Reviewer 1
The authors are grateful to the reviewer for a kind and highly professional review.
Point 1.
The preparation of this dicarbonitrile is not easy, and I suggest to improve the introduction part by adding the importance of cyanation methods. In this regard, the authors could add the following references: 1) Org. Lett. 2004, 6, 2837-2840; 2) Chem. Eur. J. 2007, 13, 6249-6254.
Response from authors.
The Introduction was corrected as suggested by the reviewer.
Point 2.
In the introduction, I suggest to use the term "ortho" for benzene derivatives. Properly, in the case of pyridines location numbers have to be used.
Response from authors.
Corrected to “1,2-diamines” as suggested by the reviewer.
Point 3.
In the result and discussion part, at row 34 I suggest to change "cyanide and potassium" with cyanide or potassium".
Response from authors.
Corrected as suggested by the reviewer.
Point 4.
In the table 1, it is convenient to specify how the yields have been calculated (isolated or by internal standard) and the molar ratio of reactants. The best yield is very moderate: did you try other solvents or conditions in order to improve the yield?
Response from authors.
The yields of the final compounds were determined using column chromatography, as described in the experimental part of the article. The molar ratio of the reactants was included in the title of the Table 1. The formation of the target product with a moderate yield occurred as a result of its decomposition during the course of a chemical reaction. The reaction was not carried out in other solvents.
Point 5.
In the experimental section, could the authors specify the feature of the reactor used? In addition, how the authors remove the DMF from the crude? Please describe in the procedure.
Response from authors.
The necessary information is added to the paper as suggested by the reviewer.
Point 6.
In the supporting, the 1H NMR is not clean. Please reload a better spectrum. If possible also a more concentrated 13C with a better noise/signal ratio.
Response from authors.
New 1H and 13C NMR spectra were obtained and included in the Supplementary Materials as suggested by the reviewer.
Reviewer 2 Report
In this contribution the authors described the synthesis of titled compound that could be used a precursor for molecular materials for optoelectronic. The title compound is effectively a new one (checked on Scifinder). and the structure elucidation is conclusive. Nevertheless there are few points that need to be adressed before acceptance of this short note
1- l 19/20 it is stated that "ortho-Diamine moiety in benzene or heterocyclic rings is often used to design fused 1,2,5-thia(selena)diazoles " This is correct but the authors should mention also that these precursors are also extensively used for the synthesis of quinoxaline, pyridopyrazine and related scafolds. Correpsonding litterature citations should be provided.
2- Nothing is said about the mechanism of the reaction: I suppose this is a nucleophilic aromatic substitution, isn't it? In this case the reactivity of both bromine atoms should be significantly different (Bromine atom in position 2 should be much more reactive than bromine in position 5. The later should react only after substitution of the bromine in position 2). Did the authors observed the formation of monocyanated derivative in some cases?
3- If the mechanism of the reaction is a nucleophilic aromatic substitution as I suppose, difluoropyridine (or dichloropyridine) starting material would be more reactive (both are known in the litterature). Why starting from bromo derivative?
4- How do you explain the difference in reactivity between potassium and copper salt?
5- Similarly the absence of reactivity in EtOH is explained by its protic charactec ofrsimply because the boiling point is lower?
6- l 42: dipolar aprotic DMF: you meaned polar aprotic DMF I suppose.
4- In experimental part, please provide only the data corresponding to selected IR bands that can be attributed. Same remark for mass spectrum. Are you sure you can provide the molar absorption coefficient with such accurancy (4 significant digits?)
5- In ESI for each spectra(NMR, UV), please specify the solvent.
Author Response
Reviewer 2
The authors are grateful to the reviewer for a kind and highly professional review.
Point 1.
l 19/20 it is stated that "ortho-Diamine moiety in benzene or heterocyclic rings is often used to design fused 1,2,5-thia(selena)diazoles " This is correct but the authors should mention also that these precursors are also extensively used for the synthesis of quinoxaline, pyridopyrazine and related scafolds. Correpsonding litterature citations should be provided.
Response from authors.
Corrected as suggested by the reviewer.
Point 2.
Nothing is said about the mechanism of the reaction: I suppose this is a nucleophilic aromatic substitution, isn't it? In this case the reactivity of both bromine atoms should be significantly different (Bromine atom in position 2 should be much more reactive than bromine in position 5. The later should react only after substitution of the bromine in position 2). Did the authors observed the formation of monocyanated derivative in some cases?
Response from authors.
The cyanation reaction of aryl and hetaryl halides is not a pure nucleophilic substitution reaction and requires either severe conditions or catalysis by palladium or other metals, as indicated in the revised version of our article. Indeed, the reactivity of two bromine atoms in the pyridine ring should be different, but this can be offset by the influence of two amino groups. Therefore, a positive result was achieved under harsh conditions - heating in DMF at high temperature. No other compounds than 2, including monocyanated derivative, were observed for all other entries. Obviously, additional research is needed to obtain a monocyanated derivative.
Point 3.
If the mechanism of the reaction is a nucleophilic aromatic substitution as I suppose, difluoropyridine (or dichloropyridine) starting material would be more reactive (both are known in the litterature). Why starting from bromo derivative?
Response from authors.
We used 2,5-dibromo-3,4-diaminopyridine as it is easily prepared from commercially available 3,4-diaminopyridine in one step (see Reference 13).
Point 4.
How do you explain the difference in reactivity between potassium and copper salt?
Response from authors.
Since the reaction of cyanation of aryl and hetaryl halides is not a pure nucleophilic substitution reaction, we used severe conditions described in the literature - heating with copper cyanide in DMF at high temperature.
Point 5.
Similarly the absence of reactivity in EtOH is explained by its protic charactec ofrsimply because the boiling point is lower?
Response from authors.
We attribute the absence of reaction in ethanol to the dipolarity and aprotonicity of DMF and the high reaction temperature.
Point 6.
l 42: dipolar aprotic DMF: you meaned polar aprotic DMF I suppose.
Response from authors.
Usually DMF is called an aprotic dipolar solvent.
Point 7.
In experimental part, please provide only the data corresponding to selected IR bands that can be attributed. Same remark for mass spectrum. Are you sure you can provide the molar absorption coefficient with such accurancy (4 significant digits?)
Response from authors.
Corrected as suggested by the reviewer. The accuracy of the molar absorption coefficient is correct.
Point 8.
In ESI for each spectra(NMR, UV), please specify the solvent.
Response from authors.
The necessary information is added to the paper as suggested by the reviewer.
Round 2
Reviewer 2 Report
l 46: Iconfirm that the correct term is polar aprotic DMF instead of dipolar protic.
