Anomalous NMR Behavior of Meso Compounds with Remote Stereogenic Centers on Addition of Chiral Shift Reagent or Chiral Solvating Agent

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 31P 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 31P NMR signals was observed for the achiral compounds
2a−d, even on addition of CSA. Two sets of 31P 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 31P 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 31P
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.