Swinton Darious Robert, Thomas Muthiah Packianathan, Perdih Franc
School of Chemistry, Bharathidasan University, Tiruchirappalli 620 024, Tamilnadu, India.
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna, pot 113, PO Box 537, SI-1000 Ljubljana, Slovenia.
Acta Crystallogr C Struct Chem. 2018 Apr 1;74(Pt 4):487-503. doi: 10.1107/S2053229618004072. Epub 2018 Mar 23.
Nine salts of the antifolate drugs trimethoprim and pyrimethamine, namely, trimethoprimium [or 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium] 2,5-dichlorothiophene-3-carboxylate monohydrate (TMPDCTPC, 1:1), CHNO·CHClOS, (I), trimethoprimium 3-bromothiophene-2-carboxylate monohydrate, (TMPBTPC, 1:1:1), CHNO·CHBrOS·HO, (II), trimethoprimium 3-chlorothiophene-2-carboxylate monohydrate (TMPCTPC, 1:1:1), CHNO·CHClOS·HO, (III), trimethoprimium 5-methylthiophene-2-carboxylate monohydrate (TMPMTPC, 1:1:1), CHNO·CHOS·HO, (IV), trimethoprimium anthracene-9-carboxylate sesquihydrate (TMPAC, 2:2:3), CHNO·CHO·1.5HO, (V), pyrimethaminium [or 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium] 2,5-dichlorothiophene-3-carboxylate (PMNDCTPC, 1:1), CHClN·CHClOS, (VI), pyrimethaminium 5-bromothiophene-2-carboxylate (PMNBTPC, 1:1), CHClN·CHBrOS, (VII), pyrimethaminium anthracene-9-carboxylate ethanol monosolvate monohydrate (PMNAC, 1:1:1:1), CHClN·CHO·CHOH·HO, (VIII), and bis(pyrimethaminium) naphthalene-1,5-disulfonate (PMNNSA, 2:1), 2CHClN·CHOS, (IX), have been prepared and characterized by single-crystal X-ray diffraction. In all the crystal structures, the pyrimidine N1 atom is protonated. In salts (I)-(III) and (VI)-(IX), the 2-aminopyrimidinium cation interacts with the corresponding anion via a pair of N-H...O hydrogen bonds, generating the robust R(8) supramolecular heterosynthon. In salt (IV), instead of forming the R(8) heterosynthon, the carboxylate group bridges two pyrimidinium cations via N-H...O hydrogen bonds. In salt (V), one of the carboxylate O atoms bridges the N1-H group and a 2-amino H atom of the pyrimidinium cation to form a smaller R(6) ring instead of the R(8) ring. In salt (IX), the sulfonate O atoms mimic the role of carboxylate O atoms in forming an R(8) ring motif. In salts (II)-(IX), the pyrimidinium cation forms base pairs via a pair of N-H...N hydrogen bonds, generating a ring motif [R(8) homosynthon]. Compounds (II) and (III) are isomorphous. The quadruple DDAA (D = hydrogen-bond donor and A = hydrogen-bond acceptor) array is observed in (I). In salts (II)-(IV) and (VI)-(IX), quadruple DADA arrays are present. In salts (VI) and (VII), both DADA and DDAA arrays co-exist. The crystal structures are further stabilized by π-π stacking interactions [in (I), (V) and (VII)-(IX)], C-H...π interactions [in (IV)-(V) and (VII)-(IX)], C-Br...π interactions [in (II)] and C-Cl...π interactions [in (I), (III) and (VI)]. Cl...O and Cl...Cl halogen-bond interactions are present in (I) and (VI), with distances and angles of 3.0020 (18) and 3.5159 (16) Å, and 165.56 (10) and 154.81 (11)°, respectively.
已制备了抗叶酸药物甲氧苄啶和乙胺嘧啶的九种盐，即甲氧苄啶鎓[或2,4 - 二氨基 - 5 - (3,4,5 - 三甲氧基苄基)嘧啶 - 1 - 鎓] 2,5 - 二氯噻吩 - 3 - 羧酸盐一水合物（TMPDCTPC，1:1），CHNO·CHClOS，(I)；甲氧苄啶鎓3 - 溴噻吩 - 2 - 羧酸盐一水合物（TMPBTPC，1:1:1），CHNO·CHBrOS·HO，(II)；甲氧苄啶鎓3 - 氯噻吩 - 2 - 羧酸盐一水合物（TMPCTPC，1:1:1），CHNO·CHClOS·HO，(III)；甲氧苄啶鎓5 - 甲基噻吩 - 2 - 羧酸盐一水合物（TMPMTPC，1:1:1），CHNO·CHOS·HO，(IV)；甲氧苄啶鎓蒽 - 9 - 羧酸盐倍半水合物（TMPAC，2:2:3），CHNO·CHO·1.5HO，(V)；乙胺嘧啶鎓[或2,4 - 二氨基 - 5 - (4 - 氯苯基)-6 - 乙基嘧啶 - 1 - 鎓] 2,5 - 二氯噻吩 - 3 - 羧酸盐（PMNDCTPC，1:1），CHClN·CHClOS，(VI)；乙胺嘧啶鎓5 - 溴噻吩 - 2 - 羧酸盐（PMNBTPC，1:1），CHClN·CHBrOS，(VII)；乙胺嘧啶鎓蒽 - 9 - 羧酸盐乙醇单溶剂合物一水合物（PMNAC，1:1:1:1），CHClN·CHO·CHOH·HO，(VIII)；以及双(乙胺嘧啶鎓)萘 - 1,5 - 二磺酸盐（PMNNSA，2:1），2CHClN·CHOS，(IX)，并通过单晶X射线衍射对其进行了表征。在所有晶体结构中，嘧啶N1原子被质子化。在盐(I) - (III)和(VI) - (IX)中，2 - 氨基嘧啶鎓阳离子通过一对N - H...O氢键与相应阴离子相互作用，生成稳定的R(8)超分子杂合成子。在盐(IV)中，羧酸盐基团不是形成R(8)杂合成子，而是通过N - H...O氢键桥连两个嘧啶鎓阳离子。在盐(V)中，羧酸盐的一个O原子桥连嘧啶鎓阳离子的N1 - H基团和一个2 - 氨基H原子，形成一个较小的R(6)环而非R(8)环。在盐(IX)中，磺酸盐O原子在形成R(8)环基序中模拟了羧酸盐O原子的作用。在盐(II) - (IX)中，嘧啶鎓阳离子通过一对N - H...N氢键形成碱基对，生成一个环基序[R(8)同合成子]。化合物(II)和(III)是同构的。在(I)中观察到四重DDAA（D = 氢键供体，A = 氢键受体）阵列。在盐(II) - (IV)和(VI) - (IX)中，存在四重DADA阵列。在盐(VI)和(VII)中，DADA和DDAA阵列共存。晶体结构通过π - π堆积相互作用[在(I)、(V)和(VII) - (IX)中]、C - H...π相互作用[在(IV) - (V)和(VII) - (IX)中]、C - Br...π相互作用[在(II)中]以及C - Cl...π相互作用[在(I)、(III)和(VI)中]进一步稳定。在(I)和(VI)中存在Cl...O和Cl...Cl卤键相互作用，距离和角度分别为3.0020 (18)和3.5159 (16) Å，以及165.56 (10)和154.81 (11)°。
