Design of two series of 1:1 cocrystals involving 4-amino-5-chloro-2,6-dimethylpyrimidine and carboxylic acids

Abstract

Two series of a total of ten cocrystals involving 4-amino-5-chloro-2,6-dimethylpyrimidine with various carboxylic acids have been prepared and characterized by single-crystal X-ray diffraction. The pyrimidine unit used for the cocrystals offers two ring N atoms (positions N1 and N3) as proton-accepting sites. Depending upon the site of protonation, two types of cations are possible [Rajam et al. (2017). Acta Cryst. C73, 862-868]. In a parallel arrangement, two series of cocrystals are possible depending upon the hydrogen bonding of the carboxyl group with position N1 or N3. In one series of cocrystals, i.e. 4-amino-5-chloro-2,6-dimethylpyrimidine-3-bromothiophene-2-carboxylic acid (1/1), 1, 4-amino-5-chloro-2,6-dimethylpyrimidine-5-chlorothiophene-2-carboxylic acid (1/1), 2, 4-amino-5-chloro-2,6-dimethylpyrimidine-2,4-dichlorobenzoic acid (1/1), 3, and 4-amino-5-chloro-2,6-dimethylpyrimidine-2-aminobenzoic acid (1/1), 4, the carboxyl hydroxy group (-OH) is hydrogen bonded to position N1 (O-H...N1) of the corresponding pyrimidine unit (single point supramolecular synthon). The inversion-related stacked pyrimidines are doubly bridged by the carboxyl groups via N-H...O and O-H...N hydrogen bonds to form a large cage-like tetrameric unit with an R(20) graph-set ring motif. These tetrameric units are further connected via base pairing through a pair of N-H...N hydrogen bonds, generating R(8) motifs (supramolecular homosynthon). In the other series of cocrystals, i.e. 4-amino-5-chloro-2,6-dimethylpyrimidine-5-methylthiophene-2-carboxylic acid (1/1), 5, 4-amino-5-chloro-2,6-dimethylpyrimidine-benzoic acid (1/1), 6, 4-amino-5-chloro-2,6-dimethylpyrimidine-2-methylbenzoic acid (1/1), 7, 4-amino-5-chloro-2,6-dimethylpyrimidine-3-methylbenzoic acid (1/1), 8, 4-amino-5-chloro-2,6-dimethylpyrimidine-4-methylbenzoic acid (1/1), 9, and 4-amino-5-chloro-2,6-dimethylpyrimidine-4-aminobenzoic acid (1/1), 10, the carboxyl group interacts with position N3 and the adjacent 4-amino group of the corresponding pyrimidine ring via O-H...N and N-H...O hydrogen bonds to generate the robust R(8) supramolecular heterosynthon. These heterosynthons are further connected by N-H...N hydrogen-bond interactions in a linear fashion to form a chain-like arrangement. In cocrystal 1, a Br...Br halogen bond is present, in cocrystals 2 and 3, Cl...Cl halogen bonds are present, and in cocrystals 5, 6 and 7, Cl...O halogen bonds are present. In all of the ten cocrystals, π-π stacking interactions are observed.

Quantitative Investigation of Halogen and Hydrogen Bonding in 2‐Chloro, 4‐X‐Benzoic Acids

“…The crystal structures of 2 [40,41] and 4 [25] were already reported in the literature whereas the crystal structures of 1 and 3 were determined for the first time. However, it is interesting to note that cocrystals of 3 with different coformers such as 4-amino-5-chloro-2,6-dimethylpyrimidine [42] and Lproline [43] were known. The compounds 1 and 2 have isomorpous structures and crystallize in the monoclinic, P2 1 /n space group with Z = 4 (Table 1).…”

Insights on structure and interactions of 2-amino-4-methoxy-6-methylpyrimidinium salts with 4-aminosalicylate and 5-chlorosalicylate: a combined experimental and theoretical charge–density analysis

“…Pyrimidine derivatives have also been developed as antiviral agents, such as AZT, which is the most widely used anti-HIV drug, and in biology they have many applications in the areas of pesticides and pharmaceutical agents (Jeevaraj et al, 2018). Furthermore, the pyrimidine group offers two protonation sites (the two ring N atom) and the site of protonation depends on the nature of the substituent (Rajam et al, 2018;Odiase et al, 2015). 4-Aminosalicylic acid (4AMSA) is a well-known antibiotic used for the treatment of tuberculosis and is also an encouraging anticancer drug (Montis & Hursthouse, 2012;Goswami et al, 2016).…”

Insights into the interactions between salt molecules: A combined experimental and computational study

“…Pyrimidine derivatives also developed as the antiviral agents such as AZT, which is the most widely used anti-HIV drug and in biology it has many applications in the areas of pesticides and pharmaceutical agents [18]. Furthermore, the pyrimidine group offers two protonation sites (the two ring nitrogen) and the site of protonation depends on the nature of the substituent [19,20]. 4-Amino salicylic acid (4AMSA) is a well-known antibiotics for tuberculosis treatment and also encouraging anticancer drug [1,21].…”

“…[18,23,49,55]. In the cation, one of the pyrimidine nitrogen atoms (N1) is protonated and this is con rmed from the increase of bond angle at N1 [C2-N1-C1: 121.7 (2)°], and this angle is comparable with the unprotonated atom N2 [C4-N2-C1: 116.17(19)°] and this also further con rmed from the corresponding reported bond angle of neutral 2-amino-4-methoxy-6-methylpyrimidine[17, 18], which is signi cantly high [116.0(18)°]. An intramolecular O4 − H4•••O3 hydrogen bond in the 5-chlorosalicyclic acid anion generates a S(6) ring motif [56, 57].…”