*Article* **Bis-Citrullinato Copper(II) Complex: Synthesis, Crystal Structure, and Non-Covalent Interactions**

**Diego Ramírez-Contreras 1, Amalia García-García 1,2, Brenda L. Sánchez-Gaytán 1, Laura E. Serrano-de la Rosa 3, Francisco J. Melendez 4, Duane Choquesillo-Lazarte 5, Antonio Rodríguez-Diéguez 2, María Eugenia Castro 1,\* and Enrique González-Vergara 1,\***


**Abstract:** Citrulline (C6H13N3O3) is a non-protein amino acid found in watermelon. In physiological conditions, it is almost entirely present as a zwitterion, so its carboxylic and amine groups can act as Lewis donors, chelating metallic cations. In addition, Citrulline possesses a terminal ureide group of the aliphatic chain, which appears to be non-innocent. Although Citrulline is similar to other classical amino acids, only one coordination complex has been reported in the Cambridge Crystallographic Database. As part of our search for Casiopeina® analogs, we synthesized and characterized the copper bis-citrullinato complex, [Cu(Citr)2]n. The compound was described using UV-Vis, Infrared, and Raman spectroscopy, together with single-crystal X-ray diffraction. Computational tools were also used. The optimized structure, MEP map, IR and Raman spectra, and 1H and 13C chemical shifts were obtained with functional mPW1PW91 using 6-31G(d) basis set for N, O, C, and H atoms, and LANL2DZ basis set and ECP=LANL2DZ for the Cu atom. TD-mPW1PW91 calculations generated the UV-Vis spectrum. Finally, AIM and Hirshfeld surface analysis were used to examine noncovalent interactions. Previous investigations suggest Casiopeina®-like complexes can interact with DNA/RNA, creating potential anticancer chemicals. The [Cu(Citr)2]n complex's polymeric nature and insolubility make it difficult for such purposes. However, the facile synthesis of D-Citrulline could be a novel way to find new applications for this interesting amino acid.

**Keywords:** Citrulline; copper; DFT calculations; Hirshfeld surface analysis; non-covalent interactions
