Methylpiperidine axial-equatorial

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. 

Figure 6 Calculated conformational energy differences (axial-equatorial) in kcal/mol for N-methylpiperidine. The dashed line shows the experimental value.

In piperidine the electron lone-pair can occupy either an axial or an equatorial position in 1-methylpiperidine the axial orientation (lb) is favoured by 99 1 over the equatorial (la). PE spectra and ab initio calculations on methylpiperidines indicate that axial 2-methyl substituents lower the amine lone-pair ionization potential by about 0.26 eV, while equatorial 2-methyl substituents as well as methyl groups on carbon atoms 3 and 4 lower the lone-pair IP by less than 0.1 eV63. This establishes the mechanism of stabilization of the amine radical cation as hyperconjugative electron release, which is larger for CC bonds than for CH bonds. The anti-periplanar orientation of the nitrogen lone-pair and the vicinal C—Me bond (lc) is much more favourable for this type of interaction than the synclinal orientation (Id). 

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 existence of a linear correlation between 15N shifts of piperidine derivatives with predominantly axial N-H bonds and those with predominantly equatorial N-U bonds and the 13C shifts of hydrocarbon analogs showed that, whereas 15N chemical shifts of N-methylpiperidines depend on the configuration of the V-substituent, those of W-H-substituted piperidines... 

The dipole moments of N-axial and N-equatorial methylpiperidine may not be equal because of differing hybridization changes at nitrogen. 

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... 

This NMR titration method was subsequently applied to equilibrium IEs on acidity.30 33 Like the previous methods, it too benefits from the high sensitivity of 13C and 19F chemical shifts, and even 111 chemical shifts, to both isotopic substitution and state of protonation. Figure 1 shows the NMR titration of a mixture of tri(methyl-d)amine and tri(methyl-t/2)amine in D20, plotted according to Equation (19). The slope is 1.1618 0.0004. The intercept is -0.0061 0.0046, properly zero. The correlation coefficient is an impressive 0.999999, which is an indication of the accuracy achievable. Another remarkable result was the measurement of the relative basicity of the two exceedingly similar isotopomers of 1 -benzyl-4-methylpiperidine-2,2,6-t/3 (6). These are truly isotopomers (here stereoisomers), which bear the same number of isotopic substitutions and differ only in the position of the isotope, which is either axial or equatorial. 

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... 

Another common fragment in medicinal chemistry is V-methylpiperidine [43]. Fig. 6 shows the calculated energy difference between the axial and equatorial con-formers for the different force fields. All force fields correctly predict the equatorial... 

In 1-methylpiperidine, the chair conformation with an equatorial N-CH group is more stable by 11.3 kJ mol" than with an axial group. 

Such an intermediate could arise in a rate-determining internal proton transfer. The greater rate of apparent j>> -c7ina/-elimination could be explained in terms of easier proton abstraction from an equatorial than an axial conformation. A similar cyclic transition state is not possible with N-methylpiperidine as the base and this suggests an obvious experiment. 

Tabled Free-energy difference (kj moC ) between Equatorial and Axial Methyl Groups at Position Indicated for C-methyloxanes (X = O), C-methylpiperidine.s (X = NH), and C-methylthianes (X = S) (cf. Figure 10)...

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