At nitrogen

Chapter 9. Synthetic Modification of Indoles by Substitution at Nitrogen. 89... 

Trigonal pyramidal molecules are chiral if the central atom bears three different groups If one is to resolve substances of this type however the pyramidal inversion that mterconverts enantiomers must be slow at room temperature Pyramidal inversion at nitrogen is so fast that attempts to resolve chiral amines fail because of their rapid racemization... 

Unlike alcohols and alkyl halides which are classified as primary secondary or tertiary according to the degree of substitution at the carbon that bears the functional group amines are classified according to their degree of substitution at nitrogen An amine with... 

An orbital hybridization description of bonding m methylamme is shown m Figure 22 2 Nitrogen and carbon are both sp hybridized and are joined by a ct bond The unshared electron pair on nitrogen occupies an sp hybridized orbital This lone parr IS involved m reactions m which amines act as bases or nucleophiles The graphic that opened this chapter is an electrostatic potential map that clearly shows the concentration of electron density at nitrogen m methylamme... 

The geometry at nitrogen in amines is discussed in an arti cle entitled What Is the Geometry at Trigonal Nitro gen T in the January 1998 issue of the Journal of Chem ical Education pp 108-109... 

The orbital and resonance models for bonding in arylamines are simply alternative ways of describing the same phenomenon Delocalization of the nitrogen lone pair decreases the electron density at nitrogen while increasing it m the rr system of the aro matic ring We ve already seen one chemical consequence of this m the high level of reactivity of aniline m electrophilic aromatic substitution reactions (Section 12 12) Other ways m which electron delocalization affects the properties of arylamines are described m later sections of this chapter... 

Electrophilic Attack at Nitrogen. The lone pair on pyridiae (1) = 5.22) reacts with electrophiles under mild conditions, with protonic... 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

Michael-type addition, hydroxymethylation and Mannich reaction take place at nitrogen to give the corresponding 2-substituted 4-hydroxyphthalazin-l(2/f)-ones. 

The electron density at nitrogen in phenazine is intermediate between those of pyrazine and quinoxaline and the highest electron density on the carbon atoms of the benzene rings is at C-1 (with positions 4, 6 and 9 being equivalent). ... 

Chemical shifts of pyridine and the diazines have been measured as a function of pH in aqueous solution and generally protonation at nitrogen results in deshielding of the carbon resonances by up to 10 p.p.m. (73T1145). The pH dependence follows classic titration curves whose inflexions yield pK values in good agreement with those obtained by other methods. 

Electrophilic attack at oxygen is rare, alkylation normally occurring at nitrogen, but the 6-hydroxypyrido[2,3- f]pyrimidine (75) is methylated on oxygen in low yield (70CB1250), whilst the 6-cyano derivative (76) undergoes O-tosylation to (77) (75JHC311). 

Acylation of -ones and -diones appears to occur mainly at oxygen, but in the fused pyridazino[4,5-6]quinoline (312) the O-acyl derivative (313) was formed via an iV,0-diacyl derivative (72BSF1588). Reduced derivatives, however, are acylated at nitrogen. 

Complexation with metals has been observed with a variety of pyridopyridazinones, whilst electrophilic attack at nitrogen is involved in cyclizations to a variety of azolo and azino fused tricyclic systems, e.g. (65CPB586, 7UOC3812). 

The low basicity of pyrrole is a consequence of the loss of aromaticity which accompanies protonation on the ring nitrogen or on carbon 2 or carbon 3 of the ring. The thermodynamically most stable cation is the 2H-pyrrolium ion, and the p/sTa for protonation at C-2 has been recorded as -3.8 the corresponding pK values for protonation at C-3 and at nitrogen are -5.9 and ca. -10 (Scheme 7). 

Azolone anions are readily alkylated at nitrogen, e.g. 2-triazolone with methyl iodide gives the 1-methyl derivative. 

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