Abstract
^13^C NMR spin–lattice relaxation times (T~1~s) and nuclear Overhauser enhancements (NOE's) were measured for a series of clinically used tricyclic antidepressants (TCAs), imipramine (1), amitriptyline (2), doxepin (3) and dothiepin (4), at two magnetic field strengths (corresponding to ^13^C frequencies of 75 and 100 MHz). The measurements were carried out at a range of solution concentrations in CDCI~3~ and D~2~O in order to determine the factors that influence overall and internal molecular dynamics in these systems. Both the hydrochloride salts and free bases were examined. For solutions in CDCI3 over a range of concentrations, or for low‐concentration (0.03 M) solutions in D~2~O, T~1~ and NOE measurements were independent of magnetic field strength, indicating that motion of the TCAs was in the ‘extreme narrowing limit.’ In contrast, for 0.3 M solutions of the hydrochloride salts in D~2~O, T~1~ and NOE measurements were field dependent, indicating the presence of significantly slower molecular mobility. It is proposed that micelles are present at this concentration and are responsible for reduced overall tumbling of the TCAs. Several degrees of internal motion were detected by the relaxation and T~1~ measurements, viz. rapid flexing motion of the benzylic bridging carbons in the central seven‐membered ring and segmental motion of the side‐chain. From an examination of the effect of solvent, concentration and protonation state of the side‐chain on the latter motion, it was possible to derive information on side‐chain conformations and interactions.