ORIGINAL ARTICLE Synthesis of new water-soluble phosphonate calixazacrowns and their use as drug solubilizing agents Mevlu ¨ t Bayrakci • S ¸ eref Ertul • Mustafa Yilmaz Received: 11 November 2011 / Accepted: 17 January 2012 / Published online: 29 February 2012 Ó Springer Science+Business Media B.V. 2012 Abstract This study presents the selective chloromethy- lation of calix[4](aza)crown ethers 2a–c, using chloro- methyl n-octyl ether and SnCl 4 in chloroform at room temperature in good yield for the first time. Chlorome- thylated products 2a–c are used as key intermediates to synthesize new water-soluble p-phosphonato calix[4] (aza)crown ethers 5a–c. Liquid–liquid phase extraction and phase solubility studies with poor water soluble drug molecules such as nifedipine, niclosamide and furosemide are performed to evaluate their binding properties. Among the studied drugs, furosemide was the most effectively dissolved drug by p-phosphonato calix[4](aza)crown ethers 5a–c in water. Keywords Calixarene  Chloromethylation  Niclosamide  Furosemide  Nifedipine Introduction The importance of calixarenes has been entirely recognized since the pioneering studies of Gutsche [1, 2]. Calixarenes are cyclic oligomers made of several phenolic units bound with methylene bridges, which can adopt various confor- mations and form hydrophobic cavities. Calixarenes can be decorated with a wide variety of functional groups on the aromatic rings and/or the O-centres of the phenolic groups, the so-called upper (or wide) and lower (or narrow) rims of the calixarenes, respectively [3, 4]. Calixarenes are spar- ingly soluble in aqueous media and this property is the major problem for calixarene use in biopharmaceutical applications. To overcome these limitations, water-soluble groups containing positive or negative charges, such as amine [5], phosphonate [6] and sulphonate [7] groups, or with neutral groups, such as sulfonamides [8], sugars [9] and polyoxyethylene [10], can be located on the lower or upper rim of the calixarene skeleton. The first example of a water-soluble calixarene introduced by four carboxy methyl groups on the phenolic oxygen of p-tert-butylca- lix[4]arene was reported by Ungaro and co-workers in 1984 [11]. In the same year, Shinkai reported the prepa- ration of p-sulfonato calix[6]arene [12]. Although the most widely studied water soluble calixarenes are the p-sulfo- nato derivatives that show solubility greater than 0.1 M in aqueous solutions, the least studied are p-phosphonato- calixarene derivatives, especially due to the concerned synthetic procedures required to bind phosphonate groups directly to para position of calixarene via bromination [13]. To overcome this, a synthetic method was reported by Ungaro and co-workers in 1989 by introducing chloro- methyl groups onto the para position of calixarene (tetra- mer, hexamer or octamer) [6]. These chloromethylated compounds are useful intermediates for introducing useful functional groups at this position. A number of researchers have carried out the chloromethylation of calixarenes but no selective product has been observed until now [14–17]. Calix(aza)crown ether derivatives have been extensively used in chemical applications such as cations, anions and neutral recognitions [18–23]. Therefore, selective chlo- romethylated calix(aza)crown ethers may be useful pre- cursors to obtain several new p-substituted calixcrown ethers. M. Bayrakci  S ¸ . Ertul  M. Yilmaz (&) Department of Chemistry, Selcuk University, 42031 Konya, Turkey e-mail: myilmaz42@yahoo.com M. Bayrakci Department of Chemistry, Nigde University, 51100 Nigde, Turkey 123 J Incl Phenom Macrocycl Chem (2012) 74:293–303 DOI 10.1007/s10847-012-0115-y