N-Methyl substituents

In the 6-31G basis the pyramidalization from type 116 to 117 leads to a shortening of the C=C bond and a lengthening of both C—N distances by about 0.01 A in all three molecules, which is again an indication of diminished conjugation. The energy 

TABLE 13. Basis set dependence of calculated heavy atom parameters of N-methylated vinylamines s-E-N-methylvinylamine (132a), s-Z-N-methylvinylamine (132b) and N,iV-dimethylvinyla-mine (133). Distances in A and angles in deg 

FIGURE 4. Schakal plot of calculated conformations (of types 118-121) of Af,Af-dimethylvinyl-amine (133) 

FIGURE 5. 6-31G total energies of AT,AT-dimethylvilynamine (133) with pyramidal sp3-nitrogen as dependent on rotational angle / around the C—N bond. Critical points belong to the types 117, 118, 120 and 121. Calculated and geometry optimized points are encircled 

For the other three critical points only positive force constants have been obtained, which is the criterion for energetical minima. Here we have to stress a warning Point 117 does not correspond to an energetical minimum, nevertheless only positive force constants are obtained. The reason is that this point was derived by the assumption of a fixed torsional angle ( / = 0.0°) and it is below the turning point of the energy curve and very close to the true minimum of the type 118. These three conditions explain that discrepancy. Between 118 and 121 we observe another saddle point. 

FIGURE 6. Pyramidalization and rotational distortion around the C N bond of enamines. (Reproduced with permission from Reference 234) 

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Glennon, R. A., Young, R., and Jacyno, J. M. (1983) Indolealkylamine and phenalkylamine hallucinogens Effect of a-methyl and N-methyl substituents on behavioral activity. Biochem. Pharmacol., 32 1267-1273. 

At all levels of theory, the N-acetyl group of N-acetyl-N-arylnitrenium ions is rotated out of the plane of the aromatic ring, although to different extents." The N-acetyl group destabilizes the ion by ca. 20 kcal/mol relative to an N-methyl substituent in comparison with the neutral amide and amine precursors. This destabilization was attributed by Ford and Herman to loss of resonance in the amide precursor on going to the nitrenium ion, not to inductive destabilization of the ion by the acyl group. 

Oettinger70 first reported the formation of 1,3,4,5-tetramethyIpyrazole from dry thermolysis of the iodide salt 61 subsequently, 1,2,3,4,5-penta-methylpyrazolium iodide was identified as a coproduct.47 The latter authors also observed that thermolysis of 62 gave 1,5-dimethyI-3,4-diphenyIpyrazole with none of the 1,3-dimethyl isomer, showing that no migration of the N-methyl substituent occurs.47... 

Let us now compare the pKa values (in AN) of the cation radicals derived from aniline, V-methylaniline, and. V-phenylaniline 5.5, 4.2, and 1.8, respectively (Jonsson et al. 1996). An additional N-methyl substituent produces only a marginal effect on the pKa of the aniline cation radical. At the same time, the effect of a single N-phenyl substituent in aniline is considerable. The phenyl-group effect on the aniline cation radical acidylation is predictable. 

The condensation of aminobenzotriazoles with DMAD gave (Z)-conjugate addition adducts which underwent ring closure in boiling Dowtherm to give triazolo[4,5-/]quinolinones (100) (Equation (57)) <93H(36)259>. The quinolinone form of the product (100) is supported by 13C NMR spectroscopic evidence. It was found that ring closure to the tricycle fails in the absence of an N-methyl substituent retro-Michael addition takes place instead. 

NEA is N-ethylamphetamine, NM-X is the exo- and NM-N the endo-isomer of 2-methyl-aminobenzobicyclo[2.2.2]octene, and 2M-X is the exo- and 2M-N the endo-isomer of 2-methylaminobenzobicyclo[2.2.1]heptene. The numbering for Ct through C9 and N10 is as shown in Figure 13. Ctl is the carbon attached to the nitrogen (the N-methyl substituent in the bicyclic compounds and the methylene group of the ethyl substituent in NEA), C1X is the bridgehead atom of the bicyclic system that is not a part of the amphetamine skeleton, and C1S and Cn are the bridge atoms (not part of the amphetamine skeleton) bonded to atoms C7 and C12. 

Spiro-annulated compounds 6a,b (Figure 16.14) exhibited much higher binding affinities. nor-Derivative (+)-6a bound at = 53.1 nM with a 10-fold higher affinity than its enantiomer (A" = 533 nM). Introduction of the N-methyl substituent resulted in a significant improvement. 

The components of the gentamicin complex contain C-methyl and N-methyl substituents, the source of which seems to be mainly due to methylation by L(—) methionine. The level of labelling does not completely support this argument. Reversible enzymatic reactions such as transmethylation, transamidation and deoxygenation are assumed ... 

S. aureus, but has little effect against the other two bacteria species tested. The two Gram-negative bacteria are sensitive to the presence of the pyrrolidinyl ring (RI2(7)) which reduces activity. For Ps. aeruginosa only, the 6-cyano group is a positive factor while the N-methyl substituent on the... 

Fig. 7.12 Two-dimensional structure and space-filUng models of morphine, codeine, and pholcodine showing the different substituents (R) at position 3. Note that any substituent at position 3 on all three compounds cannot restrict access of antibodies to the N-methyl substituent at position...

N-Substituted Polyhydrazides Several poly-hydrazides were prepared in which each hydrazide link had one N-methyl substituent (Table VIII). Only isotropic solutions were obtained in the aqueous organic bases. The nitrogen substituent presumably provides a more flexible type of amide link and changes the nature of the solvent association (see next section). 

This value is anomalous, perhaps because of differential Meje and Me2a interactions with the (equatorial) N-methyl substituent. 

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