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

Abstract

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 (1)H 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.

The influence of CH bond polarization on the self-association of 2-acylaminopyrimidines by NH/CH···O/N interactions: XRD, NMR, DFT, and AIM study

“…This conformational freedom is restricted in 2,6-bis(acylamino)pyridines preventing their dimerization via quadruple hydrogen bonding while the conformational flexibility is maintained in related pyrimidines [10,18] possessing an additional nitrogen in the ring when compared with pyridine. The same is realized in comparison of the solid-state structure of 2-acetylaminopyridine [9] versus 2-acetylaminopyrimidine [16] (Fig. 1).…”

“…It has been shown [16] that 2-acetylaminopyrimidine exists in E conformation in crystals as dimers stabilized by two NHÁÁÁN and two CHÁÁÁO interactions (Fig. 1).…”

“…An increased flexibility of the 2-acylamino substituent in pyrimidine is argued to be due to electron lone pair repulsions between N-3 and carbonyl oxygen [16]. This was confirmed by comparison of the heteroassociation of 2,2 0 -dipyridylamine versus 2-acetylaminopyrimidine which both contain ADA hydrogen bond motifs with DAD counterparts capable for triple hydrogen bonding [12].…”

“…2) was performed as described before [16]. Their dimerization constants were determined by 1 H NMR dilution studies fitted to BenesiHildebrand equation [42].…”

“…It has been shown how hydrogen bonding can be used in designing the shape of aggregate [5][6][7] in solution and in solid state [8]. Generally, non-covalent intermolecular interactions are influenced by steric effects [9][10][11][12], electronic repulsion [11,13], position of the heteroatoms in the ring [14][15][16], and cooperative effects [17]. The atoms able to compete for hydrogen bonds (basic or acidic centers) are responsible for the conformational flexibility of NH-CO bond in amides [18][19][20].…”