Crystallographic and Computational Analysis of Oxyma B Cocrystals with Nitrogen-Containing Coformers: The Relevant Role of n → π* Interactions in Their Diverse Supramolecular Architectures

Mahdi Jemai; Rafael Barbas; Miquel Barceló-Oliver; Houda Marouani; Fernando Albericio; Antonio Frontera; Rafel Prohens

doi:10.1021/acs.cgd.5c00884

Crystallographic and Computational Analysis of Oxyma B Cocrystals with Nitrogen-Containing Coformers: The Relevant Role of n → π* Interactions in Their Diverse Supramolecular Architectures

Cryst Growth Des. 2025 Sep 25;25(20):8503-8515. doi: 10.1021/acs.cgd.5c00884. eCollection 2025 Oct 15.

Authors

Mahdi Jemai^{1

2}, Rafael Barbas³, Miquel Barceló-Oliver⁴, Houda Marouani², Fernando Albericio^{5

6}, Antonio Frontera⁴, Rafel Prohens¹

Affiliations

¹ Laboratory of Organic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Avda. Joan XXIII Barcelona 08028, Spain.
² Laboratory of Material Chemistry, LR13ES08, Faculty of Sciences of Bizerte, University of Carthage, Bizerte 7021, Tunisia.
³ Unitat de Polimorfisme i Calorimetria, Centres Científics i Tecnològics, Universitat de Barcelona, Baldiri Reixac 10, Barcelona 08028, Spain.
⁴ Department of Chemistry, University of Balearic Islands, Palma 07122, Spain.
⁵ Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, Barcelona 08028, Spain.
⁶ School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa.

Abstract

Three new cocrystals of Oxyma-B, an important racemization suppressor for peptide synthesis, with 6-methylquinoline (I), 2,3,5,6-tetramethylpyrazine (II), and 1,10-phenanthroline (III) were synthesized and their single crystal structures analyzed. They show a rich network of noncovalent interactions, including classical and nonclassical hydrogen bonds (CH···O, OH···N, CH···N), CH···π, π-stacking, and, notably, lone pair···π (n → π*) interactions. Distinctive supramolecular synthons were identified, including the R₂ ²(7) motif found in both 6-methylquinoline/Oxyma-B and 2,3,5,6-tetramethylpyrazine/Oxyma-B cocrystals. In 1,10-phenanthroline/Oxyma-B, larger ring motifs such as R₄ ⁴(20) and R₅ ⁵(24) were observed, further supported by additional synthons of types R ₁ ²(5) and R ₁ ²(6). Hirshfeld surface analysis and density functional theory (DFT) calculations, including MEP surface, QTAIM, and NCIplot analyses, were carried out to quantify the intermolecular contributions and rationalize the experimental findings with a focus on the cooperative role of hydrogen bonding, π-stacking, and lone pair···π (n → π*) interactions in stabilizing and shaping the architectures of these new multicomponent crystalline materials.