Lone-pair, basicity of the nitrogen

Monomeric structures are also observed in sterically crowded borylamides such as [(Et2O)2LLN(R)BMes2] (R = Ph " or Mes b or [(tmeda)LiN(Bu )BBu 2 where B-N n bonding may lower the basicity of the nitrogen lone pair and disfavour aggregation. 

The formation of five-membered y-lactam 64 in high yield was also reported [22] subsequently by the photolysis of N,N-dibenzyl-2-benzoylacetamide (63) in benzene. The presence of acyl moiety in 63 suppressed the basicity of the nitrogen lone pair and prevented its involvement in the quenching of the carbonyl excited state by an electron-transfer processes (Scheme 8.19). 

As mentioned above, N-acylation of amino ketones suppresses the basicity of the nitrogen lone pair and thus its electron-donor potential. That being the case, P-amido ketones operate much Hke P-alkoxy... 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

In contrast with amines, amides (RCONH ) are nonbasic. Amides don t undergo substantial protonation by aqueous acids, and they are poor nucleophiles. The main reason for this difference in basicity between amines and amides is that an amide is stabilized by delocalization of the nitrogen lone-pair electrons through orbital overlap with the carbonyl group. In resonance terms, amides are more stable and less reactive than amines because they are hybrids of two resonance forms. This amide resonance stabilization is lost when the nitrogen atom is protonated, so protonation is disfavored. Electrostatic potential maps show clearly the decreased electron density on the amide nitrogen. 

The relatively high aromaticity of the parent 1,2,5-thiadiazole renders it good thermal stability (stable up to 220 °C) despite this, 3,4-diphenyl-l,2,5-thiadiazole 8 suffers slow photochemical degradation to give benzonitrile and sulfur. The low basicity of 1,2,5-thiadiazole indicates a relatively high electron density in the Jt-orbital and corresponding low electron density of the nitrogen lone pairs. Addition reactions such as Walkylation do not occur readily. A-Oxidation is... 

In the two systems so far discussed it is impossible to obtain a quantitative idea of the relative importance of the inductive and resonance effects because it is impossible to achieve the operation of one of the effects without the other. When nitrogen is the basic centre, this becomes possible by steric fixation of the nitrogen lone pair orbital in the plane of the benzene ring, which virtually eliminates its overlap with the 7r-electron orbital of the ring carbon and hence also the mesomerism. So the enhanced acidity of the anilinium ion (pAT = 4-62) as compared with methylammonium (pAfg = 10-67) has been shown (Wepster, 1952) to be half inductive and half mesomeric in origin by a consideration of the following systems ([10]-[12]) ... 

Note that the side-chains of glutamine and asparagine are not basic these side-chains contain amide functions, which do not have basic properties (see Section 4.5.4). The heterocyclic ring in tryptophan can also be considered as non-basic, since the nitrogen lone pair electrons form part of the aromatic jt electrons and are unavailable for bonding to a proton (see Section 11.8.2). 

Hydrogen bond basicity is of much relevance to the problem of drug design. Hydrogen bond basicity was shown to correlate with the location of the electrostatic potential local minimum along the axis of the nitrogen lone pair in a series of heterocycles (94JCS(P2)199). The experimental and calculated basicities for oxazole, 2,4,5-trimethyloxazole, and pyridine are shown in Table 2. 

Belleau and collaborators (30-32) have recently pointed out that one aspect of conformation-activity relationships which has escaped attention concerns the importance of stereoelectronic effects. More specifically, they have proposed that stereoelectronic effects about the basic nitrogen of morphin-ans as opposed to stereoisomerism about chiral carbons play an important role at the analgesic receptor level. They have presented concrete evidence that the relative spatial orientation of the nitrogen lone pair in morphin-ans is of critical importance for productive interaction with the opiate receptors. 

The involvement of the nitrogen lone pair in the aromatic sextet means that the nitrogen of pyrrole is non-basic. When the pyrrole ring system is protonated. addition takes place at C-2 (Scheme 4.30a). Electrophilic attack on pyrrole is rapid and also takes place at C-2. Reaction at C-3 is less favoured (Scheme 4.30b). 

Solvent effects are found to operate in a similar way with regard to the basicity of azoles, benzazoles, and benzazoles carrying a methyl group a to the basic center (84JHC269). Again, three families of compounds, whose pK, values correlate with the ionization energy of the nitrogen lone pair (the basic... 

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