Phosphorus‐Nitrogen Compounds. Part 85. Design and Synthesis of Novel Hybrid Multiheterocyclic <i>spiro</i> ‐ and 2‐ <i>cis</i> ‐4‐ <i>ansa</i> ‐Ferrocenyl‐(N/O)‐cyclotetraphosphazene Conjugates Bearing Piperonal Pendant Arms: Structural Characteriza

ABSTRACT The reaction of octachlorocyclotetraphosphazene, N 4 P 4 Cl 8 , OCCP ‐( 1 ), with sodium‐3‐( N ‐ferrocenylmethylamino)‐1‐propanoxide‐( L1 ) in an equimolar ratio of 1:1 led to the formation of the starting compounds, mono‐ferrocenyl‐ spiro ‐( spiro ‐2 ) and 2‐ cis ‐4‐dichloro‐ ansa ‐ ( ansa‐ 3 ) (N/O)cyclotetraphosphazenes. The piperonal pendant armed cyclotetraphosphazenes were prepared from the reactions of spiro‐ 2 and ansa‐ 3 with bidentate ligands, N ‐(piperonalyl)‐ N ′‐methyl‐1,3‐diamino‐propane‐( L2 ) and sodium‐3‐(piperonalylamino)‐1‐propanoxide‐( L3 ). Spiro‐ 2 was separately reacted with L2 and L3 to afford trispiro ‐2a ( ctt ‐2a and tct ‐2a; c : cis and t : trans ) and tetraspiro ‐2a ( cctt‐ 2a and tctc‐ 2a ), and tetraspiro ‐2b ( cctt ‐2b ) cyclotetraphosphazenes, respectively. However, the reactions of ansa‐ 3 with excess L2 and L3 resulted in the formation of ansa‐dispiro ‐3a ( ctt ‐3a ) and ansa‐dispiro ‐ 3b ( ctt ‐3b ) cyclotetraphosphazenes, respectively. These novel products were synthesized to investigate their spectroscopic, stereogenic, crystallographic and bioactivity properties. The structures of piperonalyl‐cyclotetraphosphazenes were evaluated by elemental analysis, ESI‐MS, FTIR, 1 H, 13 C{ 1 H} and 31 P{ 1 H} NMR techniques. The compounds had two ( ansa‐ 3 , cctt ‐2a/ tctc ‐2a and cctt ‐2b ), three ( ctt ‐2a ) and four ( ctt‐ 3a and ctt‐ 3b ) stereogenic P‐centers. The molecular and crystal structures of ctt ‐3a were confirmed by X‐ray crystallography and its Hirshfeld surface ( HS ) analysis was performed. Thus, the crystal structure of ctt‐ 3a revealed the absolute configuration of one enantiomer ( RS'R′S″ ). Carbonic anhydrase activator and antioxidant activities of the cyclotetraphosphazenes were evaluated. Based on the in vitro activator effects of these compounds on the esterase activities of hCA I and hCA II isoenzymes, trispiro‐ 2a was found to have the strongest activator ( K A = 17.53 ± 2.63 μM ) . Additionally, among the derivatives evaluated, trispiro‐ 2a (91.3% ± 0.2%) and tetraspiro‐ 2b (89.3% ± 0.1%) demonstrated exceptionally high free radical scavenging ( antioxidant ) activities ( FRSAs ), approaching those of standard antioxidants ( BHA 94.0% ± 0.3% and α‐tocopherol 97.1% ± 0.1%).