A problem has arisen in using chiral shift reagents (CSR) and chiral solvating agents (CSA) to determine meso and racemic forms of diastereoisomers in which the stereogenic centers of the molecules are separated by achiral spacers. It is found that NMR signals of both meso and racemic forms of diastereoisomers may exhibit doubling on addition of CSR/CSA, which means that unequivocal assignments cannot be made without characterizing the effects for separate meso and racemic forms; this is particularly important for additions of CSR/CSA at relatively low concentrations, which always result in the splitting of some NMR signals of diastereoisomers. The phenomenon is demonstrated in the (31)P NMR spectra of meso and racemic forms of three spermine-bridged gem-disubstituted cyclotriphosphazatrienes, 1a-c, and compared with analogous achiral molecules, the per-substituted spermine-bridged cyclotriphosphazatrienes 2a-d. As expected, only one set of (31)P NMR signals was observed for the achiral compounds 2a-d, even on addition of CSA. Two sets of (31)P NMR ABX multiplets corresponding to meso and racemic diastereoisomers were observed for compounds 1a-c; on addition of CSA, the signals of at least one of the multiplets for each compound separated into more than the expected groups of three lines with an intensity distribution of 2:1:1. To understand this phenomenon, the meso and racemic forms of 1a and 1b and the meso form of 1c have been separated and characterized by X-ray crystallography. On addition of CSA to the racemic forms of 1a and 1b, the (31)P NMR spectrum shows the expected doubling of signals, but, unexpectedly, the same is observed for each of the meso forms of 1a-c. Analogous results using both CSA and CSR have been obtained for the meso and racemic forms of the diastereoisomeric piperazine-bridged macrocyclic-phosphazene compound, 3, whereas no effect was observed for the two meso forms of the doubly bridged macrocyclic-phosphazene compound 4. The phenomenon of doubling of the (31)P NMR signals of the meso form of singly bridged cyclotriphosphazatrienes, 1a-c and 3, is explained by consideration of the equilibrium in solution of independent complexation of a chiral ligand with molecules that have two chiral cyclophosphazene moieties separated by an achiral spacer group. The results show that the stereogenicity of such diastereoisomeric molecules in solution cannot be characterized unequivocally by NMR measurements on addition of either CSR or CSA.

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Nucleophilic substitution reactions of N(3)P(3)Cl(4)[NH(CH(2))(3)NMe] (1) and N(3)P(3)Cl(4)[NH(CH(2))(3)O] (2) with mono-functional alcohols (methanol, 2,2,2-trifluoroethanol, phenol) and a secondary amine (pyrrolidine) were used to investigate the relationship between the incoming nucleophile and the proportions of products with substituents that are cis or trans to the spiro NH moiety. The reaction products were characterized by elemental analysis, mass spectrometry, (1)H and (31)P NMR spectroscopy and the configurational isomers by X-ray crystallography. Six products have been characterised with the substituent cis to the spiro NH group for the alcohol (methanol, phenol) and pyrrolidine derivatives of both compounds 1 and 2, compared to just one derivative with the substituent trans to the spiro NH group, that for the pyrrolidine derivative of compound 2. For each reaction the relative proportions of cis and trans isomers were determined by (31)P NMR measurements of the reaction mixtures. It was found that the reactions of compound 1 with all three alcohols and of compound 2 with methanol lead to exclusive formation of isomers with the substituent cis to the NH moiety, whereas all other reactions lead to mixtures of cis and trans isomers in different ratios under standard reaction conditions. However, when crown ether is included in the reaction medium for the reactions of compound 2 with both 2,2,2-trifluoroethanol and phenol, it is found that only cis isomers are formed. All these results are rationalised in terms of the competition between at least two effects; the cis-directing effect by hydrogen bonding of the incoming nucleophile to the spiro N-H group already present on the cyclophophazene ring and the cis-directing effect of the sodium cation coordinating to the oxygen lone pairs of the P-O moiety of the spiro ring.