Forsyth, Craig M., Deacon, Glen B., and Junk, Peter C. (2026) Directing alendronate structures into 2-D layers with bulky quaternary phosphonium cations. CrystEngComm, 28 (14). pp. 2151-2163.

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Abstract

Bisphosphonates are an important class of therapeutic agents for the treatment of bone disorders. Herein, a new class of salts of (4-amino-1-hydroxybutylidine)-1,1-bisphosphonic acid (alendronic acid, LH<inf>5</inf>) with quaternary phosphonium counter ions [R<inf>4</inf>P][LH<inf>4</inf>]·x(H<inf>2</inf>O) have been synthesised by metathesis reactions of [Ag(LH<inf>4</inf>)(H<inf>2</inf>O)]·2H<inf>2</inf>O with [R<inf>4</inf>P]Br in water. The crystalline ion pair compounds [Ph<inf>4</inf>P][LH<inf>4</inf>]·6H<inf>2</inf>O (1), [Ph<inf>3</inf>MeP][LH<inf>4</inf>] (2), [Ph<inf>3</inf>EtP][LH<inf>4</inf>]·4H<inf>2</inf>O (3), [Ph<inf>3</inf>PrP][LH<inf>4</inf>]·H<inf>2</inf>O (4) and [Ph<inf>3</inf>BnP][LH<inf>4</inf>]·H<inf>2</inf>O·MeCN (5) were obtained in good yield. The tetraalkyl-phosphonium derivative [Bu<inf>4</inf>P][LH<inf>4</inf>]·2H<inf>2</inf>O 6 was similarly prepared, but was only isolated as an amorphous semi-solid which we were unable to crystallise. Compounds 1–6 were highly soluble in water and showed significant solubility in short chain alcohols. A second form of compounds 1 and 3 was obtained by the partial or complete removal of water yielding crystalline [Ph<inf>4</inf>P][LH<inf>4</inf>]·0.5H<inf>2</inf>O (1a), or water free [Ph<inf>3</inf>EtP][LH<inf>4</inf>] (3a). Detailed analyses of the crystal structures of the compounds showed discrete [R<inf>4</inf>P]⁺ cations arranged into 2-D layers, alternating with 2-D hydrogen bonded sheets of [LH<inf>4</inf>]⁻ anions and water molecules. The hydrogen bonding within the anion layers was complex but with a consistent head-to-tail pairing of [LH<inf>4</inf>]⁻ anions, linked by a cyclic R²<inf>2</inf>(16) hydrogen bonded motif. Within the cation layers, there is a strong supramolecular organisation of the phosphonium cations, mediated by edge-to-face (ef) and face-to-face (ff) phenyl–phenyl arrangements. In addition, there are potential weak cation–anion interactions involving non-classical C–H⋯O and C–H⋯π contacts.

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