Piperidine derivatives, conformational

Draw or build a molecular model of what you would expect to the most stable conformation of the piperidine derivative In which the hydro- gen bonded to nitrogen has been replaced by methyl. ... 

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. 

In principle, the estimation of conformational equilibrium in a piperidine derivative by protonation is very simple. If nitrogen inversion is slow compared to deuteronation, if H+/D+ exchange does not occur in the salts, and if H+/D+ exchange is unimportant in the mixing process, then the relative proportion of the salts corresponds to that of the conformers. Thus the spectrum of pure dry cis-3,5-dimethylpiperidine in deuterotrifluoroacetic acid (unchanged after 2 days) showed a septet at 8 2.70 for the 2,6-axial protons in 112 and 113. This was interpreted as a triplet for 112 and a quartet for 113 and analysis of the multiplets gave 54% 112 and 46% 113 (AG"... 

Table X. Conformational Equilibria (AG°/kcalmol 1) of 3- and 4-Substituted Piperidine Derivatives and the Intramolecular Hydrogen Bonding Energy (AGHB/kcal mol-1) of Nipecotic Acid and Derivatives at 22 °C...

A hypothesis has been advanced to explain the different pharmacological response to opioid agonists and antagonists in terms of conformational differences about the basic center, as discussed in Chapter 13. However, a study by 13C-nmr of two such pairs (morphine-nalorphine, oxymorphone-naloxone) revealed little difference between agonist and antagonist molecules in either piperidine ring conformation (chairs only) or ratio of N- R axial to equatorial forms (83 17 for morphine, virtually 100% eq JV-R for 14-OH derivatives).035 ... 

It was concluded that the nicotinic activity of choline phenyl ether and of choline o-tolyl ether is a reflection of the ability of the molecule to assume a "planar" conformation when interacting with the ganglionic nicotinic receptor. In contrast, the inactive 2,6-xylyl ether of choline cannot assume this planar disposition. Evaluation of additional conformation-ally restricted aiyl choline ethers (44-47) revealed that only the piperidine derivative (47) is a ganglionic stimulant (98). 

The following czs-2,6-disubstituted piperidine derivative is expected to exist largely in a single conformation. Please speculate on account of allylic strain and write the said conformer. 

Depending fully on the allylic strain, write the preferred conformation of the following , v-2,6-disubstituted piperidine derivative. 

The H-NMR spectra of salts of morphine and its congeners are complicated by the existence of protonated epimers, evident from signal duplication and first reported in a 600 MHz study carried out at low pH to slow the interconversion rate Figure 5.10 and [44]). The usual pronounced preference of N-methyl for the equatorial conformation in piperidine derivatives is reduced in the fused-ring system of morphine by non-bonded interactions with the fi-lO-... 

Analyses of various cyclohexane and piperidine derivatives have for the most part been imdertaken to determine the effects of different combinations of bulky substituents in distorting the molecular conformations from the stable or ideal forms of the unsubstituted molecules. Thus in epi-inositol (30), the two axial hydroxy-groups cause flattening of the chair conforma-... 

The importance of these piperidine derivatives hes in the clinical use of suitably substituted groups and the different ways available for making modifications in the anticipated structure of the pharmacologically active compoimd. Therefore, a series of piperidine derivatives with bulky aryl substitutions at the 2,6 positions and different substituents in different possible positions, especially the N-substitution, have been crystallized and their conformational features have been studied by crystallographic methods (Table 1) so as to correlate the biological activity with stereochemistry. 

With the above-mentioned nomenclature the 2,6-diaryl-substituted piperidine derivatives under study were characterized and are presented in Table 2. The analysis shows that the piperidine ring adopts a chair conformation if the hf-position is free or substituted by methyl groups irrespective of the substituents at the other positions. If the N-position contains a - X = Y group bearing tt electrons it invariably adopts either a boat or twist boat conformation. In the N-substituted group if relatively more electronegative atoms are present the piperidine ring prefers a twist-boat conformation. This is in line with the reported studies [62-66]. 

Table 2 Endocyclic torsion angles for piperidine derivatives with their conformer description...

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