The proton magnetic resonance spectra of hexahydropyrrolizine, its salts, its 3-methyl derivatives, and its methiodide

Abstract

The spectra are discussed and many assignments made from considerations of the bond anisotropies. Double resonance provided some checks and gave IJgeml for the a-methylene protons of hexahydropyrrolizine.Over the range -70 to +190" hexahydropyrrolizine exists mainly, if not entirely, in the cis-fused form. The 3-endo-methyl derivative, however, shows rapid nitrogen inversion at room temperature, and only below -60" does it exist predominantly in the cis-fused form. Incidentally, the configurations of the two stereoisomers of 3-methylhexa hydropyrrolizine were confirmed.The shielding of the methyl group in hexahydropyrrolizine methiodide is compared with that in the methiodides of cisand trans-octahydroindolizine and of trans-octahydroquinolizine.MOLECULAR models (of various types) suggest that in simple hexahydropyrrolizines (I) the rings are cis-fused. This configuration is free of strain and rather flexible, allowing interconversion between ' unfolded ' (Ia) and ' folded ' (Ib) conformations, through a ' half-folded ' conformation (not shown). A Courtauld model of (Ia) is sufficiently flexible to suggest that pseudo-rotation occurs in each ring. In contrast, the trans-fused system (Ic) is rigid and perhaps strained. Nevertheless tram-9 R (I) [exo-bonds (x), solid; (IV) R = H (or D) endo (n), dotted] (V) R = Me, X = I (11) 3x-Me (111) 3n-Me (3,5,8 = a-positions; 1,2,6,7 = /3-positions) 1 (Ia) ( I d (Ia) cis-I-Iexahydropyrrolizine system, unfolded ' conform-(Ib) cis-Hexahydropyrrolizine system, ' folded ' conformation * (Ic) trans-Hexahydropyrrolizine * ation * * The dotted line represents the lone electron pair orbital or h-H(9) or h-C(9) bondring juncture is possible, as has been demonstrated in some annelated quaternary derivatives ,l and the models of simple hexahydropyrrolizine do indicate that cis-trans interconversion should be possible through nitrogen inversion. of simple hexahydropyrrolizines has not been verified by any physical method and so we have studied the system by lH n.m.r. over a temperature range.

Cis-trans-conversion of the bicycle in pyrrolizidines: The effect of the preferred conformations on the properties of the bases and the thermodynamics of conformational transformation of the ring fusion type. (Review)

“…On the contrary, a clear temperature dependence was observed for the 1 H NMR spectrum of cis-3,8-H-3-methylpyrrolizidine 9 in a close temperature range (between -85 and +171°C) [16].…”

“…From analysis of the temperature variations in the chemical shift of the H-8 proton of the isomer 9 (the upfield shift of the signal of this proton with increase in temperature) and the effects of its screening in conformations 9A and 9B it was concluded that the conformational equilibrium is shifted toward form 9B and that the fraction of the conformer 9A increases in the transition from low to higher temperatures [16]. The validity of this suggestion was later confirmed by data from the 1 H NMR spectra of the highly strained predominantly trans-fused cis-3,8-H-3-tert-butylpyrrolizidine (10) and cis-3,8-H-cis-5,8-H-3,5-dimethylpyrrolizidine (11) [17].…”

“…The first attempt at the experimental detection of conformational heterogeneity in pyrrolizidines involved observation of the temperature dependence of the 1 H NMR spectra of unsubstituted pyrrolizidine 1 and also of 3-methylpyrrolizidines 8 and 9 [16]. The spectra of compound 1 and of trans-3,8-H-3-methylpyrrolizidine 8 hardly changed at all with variation of the temperature in the ranges between -70 and +190 and between -80 and +100°C respectively.…”

“…In comparison with compound 3 the base 1 in conformation B is destabilized on account of the stronger nonbonding interactions of the endo-oriented hydrogen atoms at C (3) and C (5) [16,17], since the C-N bonds are shorter than the C-C bonds. On the other hand, in the trans-fused conformation A it experiences further stabilization in connection with the delocalization of the unshared electron pair of the nitrogen atom according to the above-mentioned mechanism [47][48][49][50].…”

“…This increases their strain and reduces the absolute value of the difference in free energies between forms 5B and 5A. Experiment shows that it becomes possible to observe a change in the conformational equilibrium 5A 5B with variation of temperature [16] and to determine the content of the individual conformers [17,18] even in the case of the smallest substituent Me.…”