2 -Methylpiperidine, conformational

Piperidine derivatives. Again, both MM2 and MM3 do a good job in reproducing the experimental axial-equatorial energy differences of piperidine derivatives. All other force fields rather seriously overestimate the stability of axial conformations and consequently underestimate the energy difference. The only exception is UFF, which overestimates the aforementioned energy difference for /V-rncthy I piperidine and 2-methylpiperidine. 

Booth and Little40 observed a chemical shift difference (Aae) of about 0.4 ppm for the C-2 and C-6 methylene protons in 4-methylpiperidine, which was assumed to exist as an equilibrium containing 95% of the C-methyl equatorial conformation. N-Methylation of 4-methylpiperidine caused an upfield shift of 0.22 ppm for the C-2 equatorial proton and of 0.68 ppm for the C-2 axial proton. Comparison of these values with those observed for the proton adjacent to methyl groups in cyclohexane led these authors to the... 

The Kerr constant is related to the difference between the refractive indices of the medium parallel and perpendicular to an applied field, and these may be calculated for the assumed conformations. On this basis a 50 50 A-Meax lV-Meeq equilibrium was estimated for iV-methylpiperidine and an 80% N-Hai preference for piperidine in benzene solution.116 Some theoretical support117 was produced for this latter preference in terms of a more effective overall electron bonding in the iV-Hax conformer. These results are very much out of line with those estimates based on other methods and the Kerr-constant work has been criticized3 on the grounds of insufficient accuracy in the bond polarizabilities used in the calculations.118... 

Photoelectron spectra and STO-3G calculations on methylpiperidines show that equatorial methyl substituents at the 2-, 3-, and 4-positions lower the ionization potential of the nitrogen lone pair by <0.1 eV. An axial methyl at C-2, however, lowers the ionization potential by 0.26 eV. These influences on ionization potentials are nearly identical in both piperidines and A-methylpiperidines, indicating that the lone-pair orientations in both systems are similar. The STO-3G calculations indicate a favoring of the equatorial A-H conformation of the piperidines by 1.0—1.9 kcal mol-1.174... 

Summary of Published Work on the Position of Conformational Equilibrium in N-Methylpiperidine... 

Thus the conformational free energy of the N-methyl group may be accepted as 2.7kcal mol-1 and the difference from that (1.7 kcal mol 1) in methylcyclohexane is primarily due to the changes in bond lengths, causing an increase in the syn-axial interactions in axial N-methylpiperidine. 

The conformational free energies of C-methyl groups in piperidine and yV-methylpiperidine have been estimated183 by low temperature ( — 80 to... 

The AG° value for 3-Me appears to be somewhat smaller than that for the 4-Me as expected for nonbonded interaction in the axial form with the nitrogen atom rather than with a CH bond. Most striking is the variation in conformational free energy of the 2-Me substituent in piperidine and its N-methyl derivative. The lower value in the N-methylpiperidine must be a result of an interaction between 2-Meeq and N-Me, caused by puckering at the nitrogen end of the chair. 

Comparison of the conformational free energies for the (V-methyl group in Af-methylpiperidine (2.7 kcal mol- ) and in Af-methyltetrahydro-1,3-oxazine (AG° 0 kcal mol1) with the value of 1.0 kcal mol-1 for the 1,4,2-dioxazine just mentioned, suggests that the corresponding free energy of the methyl group in lV-methyltetrahydro-l,2-oxazine may be nearer 2.7 + 1.0 = 3.7 kcal mol-1. 

The successive change in position of the N-Mem N-Meeq equilibrium from that in 5-methyldihydro-l,3,5-dioxazine (AG° > 1 kcal mol-1) to 3-methyltetrahydro-l,3-oxazine (AG° 0.10 + 0.05 at — 120°C) to that (AG° —2.7 kcal mol-1) in 1-methylpiperidine results from successive differences of syn-axial interactions involving the axial methyl group and a favoring of the axial methyl conformer by the generalized anomeric effect. 

The difference in conformational free energy of the N-Me group in N-methylpiperidine (2.7 kcal mol-1, favoring N-Meeq) and in N-methyltetra-hydro-l,3-thiazine (0.7 kcal mol-1, favoring lV-Meax at -120°C) suggests the predominance of the lV-Meax conformer 463 of 5-methyldihydro-1,3,5-dithiazine (462 R = Me). Indeed, H-NMR spectra and dipole-moment data show that NR axial is the predominant conformer for a series of AT-alkyl-dihydro-l,3,5-dithiazines (462 R = Me, Et, iPr, -Bu).356 This even applies to the Af-tert-butyl compound, which possesses an unconstrained axial tert-butyl group.357... 

The conformational equilibrium of A-methylpiperidine-m-2,6-fif2 favors conformer 40 with both deuteriums equatorial, with an equilibrium constant of 1.23.110 To the extent that the conformational preference in the protonated amine is much smaller and can be neglected, this IE also corresponds to a greater basicity of the conformer 41 with the deuteriums axial. Similarly the preferences of 3-azabicyclo[3.2.2]nonanes and (PhCHD)3N for conformers with H anti to the nitrogen lone pair implies a lower basicity for those conformers.111,112... 

Crowley, P. J. Robinson, M. J. T. Ward, M. G. Conformational effects in compounds with 6-membered rings XII. The conformational equilibrium in N-methylpiperidine. Tetrahedron 1977, 33, 915-925. 

Otherwise, the piperidine ring system was considered to be in the stable chair conformation. The two different experimental barriers to ring inversion and N-inversion of N-methylpiperidine were reconsidered. An accurate line shape analysis of the dynamic NMR spectra in the gas phase... 

The X-ray structure of l-piperidino-2,4-dinitrobenzene was published (95MI801). The piperidine ring exhibits a slightly distorted chair conformation the N-atom is almost in a plane due to the partial C,N double bond, and the aromatic ring shows a slight boat deformation with the o/p-nitro groups twisted out of plane. UV and NMR data indicate that the molecule in solution presents a conformation similar to that in the solid state. In the crystalline anhydrous N-methylpiperidine betaine 86 (cf. Scheme 33) the piperidine ring adopts the usual chair conformation... 

Isoprodines (28), related to /3-pethidine, are inactive in mice in doses up to 100 mg/kg(76) the bicyclic analog 29 with the piperidine ring constrained to a boat conformation is about half as active as a-prodine in rats while its diastereoisomer is inactive/77 Results on /3-pethidine and isoprodine should be compared with data on 3-aryl-3-methylpiperidines that lack an oxygen substitutent in the piperidine ring but possess one in the aromatic moiety (p. 279). 

Abbreviations conform to Tarr s nomenclature F, formic acid A, acetic acid fA, trifluoroacetic acid KNm, dimethylformamide mSO, methylsulfoxide MOH, methanol EOH, ethanol MCN, acetonitrile M5KN, N-methyl-pyrrolidone 6N, pyridine N, ammonia ENm, dimethylethylamine M6N, N-methylpiperidine M6NO, N-methylmorpholine E6NO, N-ethylmorpholine ENip, diisopropylethylamine eN, triethylamine fmK, hexafluoroacetone (hydrate) cit, citric acid W, water NaA, sodium acetate eN+, tetraethylammonium MNT, methylthiocarbamyl NT, phenylthiocarbamyl MNGS, methylisothiocyanate ONCS, phenylisothiocyanate NPN-TNdab, N-aminopropyl-N -p-dimethylaminoazobenzene thiourea. 

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