2‑Acylamino- and 2,4-Bis(acylamino)pyrimidines as Supramolecular Synthons Analyzed by Multiple Noncovalent Interactions. DFT, X‑ray Diffraction, and NMR Spectral Studies

Intermolecular interactions of ten 2-acylamino and 2,4-bis­(acylamino)­pyrimidines
(7 of which are previously unknown) have been investigated by X-ray
structural, quantum chemical (DFT), and NMR spectral methods. Especially
the concentration dependencies of the 1H NMR chemical shifts
and titrations with other molecules capable of multiple hydrogen bonding
provided useful information regarding their association via triple
or quadruple hydrogen bonding, which is controlled by the conformational
preferences of 2-acylamino- and 2,4-bis­(acylamino)­pyrimidines. On
comparison of the properties of 2-acylamino- and 2,4-bis­(acylamino)­pyrimidines
with the corresponding pyridines, an additional nitrogen in the heterocyclic
ring is the crucial factor in explaining the stability of various
conformers and dimers of pyrimidines. Computational modeling of their
dimerization (self-association) and heteroassociation supports the
experimental findings. The substituent effects in 2-acylamino- and
2,4-bis­(acylamino)­pyrimidines are discussed via inter- and intramolecular
terms. The subtle balance between several structural factors and their
influence on the aggregation of studied pyrimidines was confirmed
also by variable-temperature NMR and NOE experiments. X-ray structures
of 2-methyl- and 2-adamantyl-CONH-pyrimidines revealed very different
intermolecular interactions, showing the importance of the substituent
size on the self-assembly process. As a whole NMR spectral, X-ray
structural, and computational data of 2-acylamino- and 2,4-bis­(acylamino)­pyrimidines
can be interpreted in terms of multiple intra-/intermolecular interactions.