2-Chloropyrimidine is a useful reagent in the preparation of antivirals and other biologically active compounds. 2-Chloropyrimidine was first synthesized in the early 20th century, though specific details on its initial discovery are less documented. It has been widely used in pharmaceutical and agrochemical industries, particularly in the synthesis of biologically active compounds and as a building block for the production of various heterocyclic compounds. It is also used in the manufacture of herbicides and insecticides. 2-Chloropyrimidine is produced synthetically by chlorination of pyrimidine, typically using chlorine or phosphorus trichloride as the chlorinating agent. The compound does not occur naturally and is entirely synthetic.

Palladium Catalysis or SNAr in Green Solvents

The formation of aryl C–N bonds is a fundamental process within organic chemistry, and the product N-arylamines are present in various natural products and pharmaceutical molecules. Precious metals are expensive and dwindling resources, and although the success of palladium-catalysed reactions has revolutionised N-arylation chemistry, there is a risk that they are used without due consideration of alternatives. For instance, 2-chloropyrimidine is 1014–1016 times more reactive than chlorobenzene in terms of its ability to undergo SNAr reactions; however, an examination of the recent literature reveals that even such reactive substrates are subjected to palladium-catalysed amination reactions. Some recent examples of the palladium-catalysed amination of 2-chloropyrimidine and chloropyrazine are shown and although these reactions, some of which are performed under fairly forcing conditions with non-trivial ligands, proceed in good yield, it does beg the question as to whether palladium is really needed for such highly activated substrates. Organic solvents were found to be generally ineffective for chloropyrazine reactions, although they are better in the reaction of 2-chloropyrimidine and yield 2-morpholinopyrimidine (data shown in the Supporting Information).[1]

However, for both the chloroheterocycles, the best result was obtained by using water as a solvent, which gave both the highest yield and the cleanest reaction mixtures.As expected, reactions with the more reactive 2-chloropyrimidine generally produced higher yields (2-chloropyrimidine is ≈100 times more reactive than chloropyrazine) and reacted in moderate to excellent yield with primary and secondary amines. In the case of α-methylbenzylamine (entry 5), HPLC demonstrated that there was no loss of enantiomeric excess in the final product (ee>98). In addition, the coupling of 2-chloropyrimidine with imidazole and benzimidazole performed under copper catalysis resulted in 90 % and 100 % yield, respectively, which are comparable to the slightly poorer yields of 62 % and 83 % obtained under our conditions. From this list of amines, seven examples were chosen to be tested against other pyrimidines in comparison to 2-chloropyrimidine. Unsurprisingly, 2-bromopyrimidine showed similar reactivity; however, the reactions with 4-chloro-2,6-diaminopyrimidine resulted in unpredictable yields, possibly as a result of solubility issues.

Cross-Section Calculations for Electron-Impact Ionization

A detailed and deep understanding of electron scattering from atoms and molecules is crucial for the interpretation the relevant phenomena occurring in many different environments, including natural and technological ones. The total cross-sections for the single electron-impact ionization of pyrimidine (C4H4N2), 2-chloropyrimidine (2-C4H3ClN2), 5-chloropyrimidine (5-C4H3ClN2), 2-bromopyrimidine (2-C4H3BrN2) and 5-bromopyrimidine (5-C4H3BrN2) molecules have been calculated with the binary-encounter-Bethe model from the ionization threshold up to 5 keV. Pyrimidine (1,3-diazine) is a six-membered, aromatic, heterocyclic organic compound in which two CH groups of the benzene molecule are replaced by nitrogen atoms. The objective of the present work is to provide carefully and precisely calculated electron-impact ionization cross-sections for pyrimidine and its simple halogenated derivatives i.e., 2-chloropyrimidine, 5-chloropyrimidine, 2-bromopyrimidine and 5-bromopyrimidine.[2]

Within BEB approximation, the total cross-sections for electron-impact ionization of pyrimidine, 2-chloropyrimidine, 5-chloropyrimidine, 2-bromopyrimidine and 5-bromopyrimidine are presented and compared. For all the studied compounds, a maximum of the ICS is located at around 80 eV. For 2-chloropyrimidine and 5-chloropyrimidine, the maximum ICS value is similar and amounts to 13.84×10?20 m2 and 13.73×10?20 m2, respectively. This tendency in the dependencies between the cross-section values for these compounds is visible from almost the ionization threshold up to 500 eV. In the case of 2-chloropyrimidine and 5-chloropyrimidine, their respective ionization cross-sections almost coincide at incident electron energies above 500 eV. The BEB method was used to calculate the ionization cross-sections for ionization induced by collisions with electrons of pyrimidine and its halogenated derivatives. All parameters necessary for the BEB method were carefully determined using quantum chemical methods.

References

[1]Walsh K, Sneddon HF, Moody CJ. Amination of heteroaryl chlorides: palladium catalysis or SN Ar in green solvents? ChemSusChem. 2013 Aug;6(8):1455-60. doi: 10.1002/cssc.201300239. Epub 2013 Jun 21. PMID: 23794470; PMCID: PMC3792620.

[2]?ywicka B, Mo?ejko P. Cross-Section Calculations for Electron-Impact Ionization of Pyrimidine Molecule and Its Halogenated Derivatives: 2-Chloropyrimidine, 5-Chloropyrimidine, 2-Bromopyrimidine and 5-Bromopyrimidine. Molecules. 2024 Dec 24;30(1):6. doi: 10.3390/molecules30010006. PMID: 39795064; PMCID: PMC11721976.