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6‐Propyl‐2‐thiouracil versus 6‐methoxymethyl‐2‐thiouracil: enhancing the hydrogen‐bonded synthon motif by replacement of a methylene group with an O atom
Author(s) -
Hützler Wilhelm Maximilian,
Egert Ernst,
Bolte Michael
Publication year - 2016
Publication title -
acta crystallographica section c
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.304
H-Index - 17
ISSN - 2053-2296
DOI - 10.1107/s2053229616011281
Subject(s) - synthon , cocrystal , chemistry , hydrogen bond , crystal engineering , methylene , molecule , stereochemistry , thiouracil , crystallography , acceptor , ionic bonding , medicinal chemistry , organic chemistry , ion , medicine , physics , thyroid , condensed matter physics
The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6‐propyl‐2‐thiouracil (PTU) with 2,4‐diaminopyrimidine (DAPY), and of 6‐methoxymethyl‐2‐thiouracil (MOMTU) with DAPY and 2,4,6‐triaminopyrimidine (TAPY), respectively, are reported. PTU and MOMTU show a high structural similarity and differ only in the replacement of a methylene group (–CH 2 –) with an O atom in the side chain, thus introducing an additional hydrogen‐bond acceptor in MOMTU. Both molecules contain an ADA hydrogen‐bonding site ( A = acceptor and D = donor), while the coformers DAPY and TAPY both show complementary DAD sites and therefore should be capable of forming a mixed ADA / DAD synthon with each other, i.e . N—H…O, N—H…N and N—H…S hydrogen bonds. The experiments yielded one solvated cocrystal salt of PTU with DAPY, four different solvates of MOMTU, one ionic cocrystal of MOMTU with DAPY and one cocrystal salt of MOMTU with TAPY, namely 2,4‐diaminopyrimidinium 6‐propyl‐2‐thiouracilate–2,4‐diaminopyrimidine– N , N ‐dimethylacetamide–water (1/1/1/1) (the systematic name for 6‐propyl‐2‐thiouracilate is 6‐oxo‐4‐propyl‐2‐sulfanylidene‐1,2,3,6‐tetrahydropyrimidin‐1‐ide), C 4 H 7 N 4 + ·C 7 H 9 N 2 OS − ·C 4 H 6 N 4 ·C 4 H 9 NO·H 2 O, (I), 6‐methoxymethyl‐2‐thiouracil– N , N ‐dimethylformamide (1/1), C 6 H 8 N 2 O 2 S·C 3 H 7 NO, (II), 6‐methoxymethyl‐2‐thiouracil– N , N ‐dimethylacetamide (1/1), C 6 H 8 N 2 O 2 S·C 4 H 9 NO, (III), 6‐methoxymethyl‐2‐thiouracil–dimethyl sulfoxide (1/1), C 6 H 8 N 2 O 2 S·C 2 H 6 OS, (IV), 6‐methoxymethyl‐2‐thiouracil–1‐methylpyrrolidin‐2‐one (1/1), C 6 H 8 N 2 O 2 S·C 5 H 9 NO, (V), 2,4‐diaminopyrimidinium 6‐methoxymethyl‐2‐thiouracilate (the systematic name for 6‐methoxymethyl‐2‐thiouracilate is 4‐methoxymethyl‐6‐oxo‐2‐sulfanylidene‐1,2,3,6‐tetrahydropyrimidin‐1‐ide), C 4 H 7 N 4 + ·C 6 H 7 N 2 O 2 S − , (VI), and 2,4,6‐triaminopyrimidinium 6‐methoxymethyl‐2‐thiouracilate–6‐methoxymethyl‐2‐thiouracil (1/1), C 4 H 8 N 5 + ·C 6 H 7 N 2 O 2 S − ·C 6 H 8 N 2 O 2 S, (VII). Whereas in (I) only an AA / DD hydrogen‐bonding interaction was formed, the structures of (VI) and (VII) both display the desired ADA / DAD synthon. Conformational studies on the side chains of PTU and MOMTU also revealed a significant deviation for cocrystals (VI) and (VII), leading to the desired enhancement of the hydrogen‐bond pattern within the crystal.