Reactivity of the Nitrogen Atom

In order to study the reactivity of the nitrogen atom in saccharidic OZT moieties Rollin and co-workers13,55 explored some standard reactions IV-acylation, IV-sulfonylation, IV-vinylsulfonylation by Michael addition, reductive elimination, conjugated addition and cycloaddition. 

The influence of substituents, including aza, on reactivity of the nitrogen atom in such systems have been considered in detail1 6,7,47 102,188 189 and may be correlated with Dewar—Grisdale calculations [Eq. (2)],6 33-190-192 or dual-substituent parameter [Eqs. (3) and (4)].6,7,47,188-190 Thus, analysis6 of pXa s (HzO, 25°) of substituted quinolinium and isoquinolinium cations according to Eq. (20) gave the results shown in Table V, where they are compared with those for substituted naphthoic acids (aq. EtOH, 25°). 

It should be clear that the reactivity of amines normally involves some process in which a bond is made to the unshared electron pair on nitrogen. Therefore any reaction of an amine that reduces the reactivity of this electron pair should reduce the reactivity of the nitrogen atom. The simplest way to do this would be to convert the amine to an ammonium salt with an acid. Protonation amounts to protection of the amine function ... 

An interesting observation was reported by Deady who advocated a lone-pair cooperativity in the N-alkylation of some N,N -bridged 2,2 -bii-midazoles. The second order rate constants of alkylation are in the order 525 > 524 > 523. Bridging has a considerable effect on the reactivity of the nitrogen atom (81AJC2569). Such a quantitative study would be interesting on other ortho-orthc/-Mnked azaheterocycles. 

The diazonium ions formed from aminoazoles are relatively strong acids. The pa s values of five di-, tri- and tetrazolediazonium ions are reported to be between 3 and 4, i.e. about 10 units lower (more acidic) than those of the respective unsubstituted heterocycles (Vilarrasa and coworkers ). Therefore, deprotonation of the diazonium ion is easy and, depending on reaction conditions, yields either the diazonium salt or its conjugate base, i.e. the diazo compound. The electrophilic reactivity of the nitrogen atom in the diazo group of the base is lower than the reactivity of the diazonio group of the cation. ... 

The nucleophilic reactivity of the nitrogen atoms in thioureas towards carbonyl compounds has been further exemplified by some recently described addition and addition-elimination reactions of thioureas with aldehydes. The same reactivity also played an important part in recent syntheses of heterocyclic compounds containing the thioureido-grouping. ... 

It is well known that the attempts to transform laudanosoline (199, 200) or iV-norlaudanosoline (201) into aporphine bases by oxidation have failed instead compounds with a dibenzopyrrocoline structure (CXXXIX) were obtained. Franck and Schlingloff (202) found that if the reactivity of the nitrogen atom is eliminated by quaternization, then the mild oxidation of laudanosoline methiodide (CXL) with ferric chloride in aqueous solution affords in 60% yield the aporphine base... 

The protonation of the nitrogen atom of thiazole induces a large increase in reactivity of the 2-position (193, 194). This is in contrast to the pyridine series, where the reactivity of both positions adjacent to the nitrogen atom are enhanced (194). The phenylation of conjugate acid of 5-alkylthiazoles may then be considered as a preparative route to alkyl-thiazoles. The results (isomer percent and overall reactivity) are indicated in Tables III-31 (196) and 01-32 (196). 

In the case of alkyl radicals [e.g., methyl radical (197, 198) and cyclohexyl radical (198)], their nucleophilic behaviour enhances the reactivity of the 2-position. Here it is necessary to have full protonation of the nitrogen atom and to use specific solvents and radical sources. 

The quatemization of the nitrogen atom of the thiazole ring (the Menschutkin s reaction) by alkyl halide or methyl tosylate can be used to measure the reactivity of this atom and thus to evaluate steric and electronic effects of ring substituents. 

Each of these intermediates can be hthiated in the 2-position in good yield. The reactivity toward hthiation is due to the inductive effect of the nitrogen atom and coordination by oxygen from the N-substituent. A wide variety of electrophiles can then carry out substitution at the 2-position. Lithiation at other positions on the ring can be achieved by halogen—metal exchange 3-hthio and 5-hthioindoles have also been used as reactive intermediates. 

Mesomerism involving polarized and nonpolarized contributing enamine forms influences the enamine s spectral properties and chemical reactivity. For mesomerism to be present, a planar arrangement is required for the three atoms of enamine grouping and the five atoms immediately bound to this system. If this condition is not fulfilled, full interaction of the tt electrons of the double bond with the free electron pair on the nitrogen atom is impossible. Enamines in which mesomerism is inhibited do not show the properties characteristic of enamines, and only the mutual electrostatic interaction of the double bond and lone electron pair of the nitrogen atom can be observed. Such steric hindrance of mesomerism occurs mainly in polycyclic systems. 

The presently known electrophilic substitution reactions all occur at the 4-position of the isoxazole nucleus, corresponding to the j3-position in pyridine. Thus the influence of the nitrogen atom is predominant. The introduction of alkyl and, particularly, aryl substituents into the isoxazole nucleus markedly increases its reactivity (on the other hand, during nitration and sulfonation the isoxazole nucleus also activates the phenyl nucleus). 

On the other hand, an electronically stabilized heavy ketone by the coordination of the nitrogen atom shows extremely low reactivity. It does not react with phosphanes, phosphates, ketones, epoxides, Mel, HC1, etc., although it undergoes methanolysis and hydrolysis (Scheme 21).168... 

In order to evaluate the influence of the nitrogen atom on reactivity, computations on BhQ and BfQ derivatives were compared with the data obtained for the corresponding carbon analogue (Phe) (26). Both bay-region structures... 

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