Reactions with Nucleophilic Reagents

In the reactions with amines or amino derivatives (Equations 3-5), either an excess of the amino compound is employed or the reaction is carried out in the presence of a tertiary base, e.g. pyridine or triethylamine. It is preferable for the reaction to be performed in non-aqueous media, e.g. acetone or acetonitrile to avoid competing base-catalysed hydrolysis. 

The mechanism of the reaction of arylsulfonyl halides with nucleophilic reagents has been widely studied and reviewed. The majority of kinetic and other evidence indicates that the reactions of an arylsulfonyl chloride 1 with a nucleophile (Nu ) generally follow the concerted bimolecular SN2-type mechanism as depicted in Equation 7 with a linear bipyramidal transition state which is similar to the Sn2 (acyl) pathway established for acyl halides.  

The main evidence in support of this mechanism derives from studies of stereochemical inversions as in the reaction of a chiral sulfonate with a Grignard Reagent isotopic experiments on the hydrolysis of arylsulfonates and the rates of hydrolysis of alkyl and arylsulfonyl halides.  

Various other workers have proposed alternative reaction mechanisms, namely the unimolecular (SnI) and the stepwise addition-elimination pathway (SaN) (Equations 8 and 9 respectively). 

By analogy with acyl halides, the SnI mechanism (Equation 8) should be possible for arylsulfonyl halides, provided they contain sufficiently electron-donating substitutents as in the hydrolysis of 2,4,6-trimethylbenzenesulfonyl chloride. However, this evidence has been disputed by the work of Rogne in Norway in a series of papers thus in the reaction of imidazole with substituted 

Just as electrophilic substitution is the characteristic reaction of benzene and electron-rich heteroaromatic compounds (pyrrole, furan etc.), so substitution reactions with nucleophiles can be looked on as characteristic of pyridines. 

Reaction with alkyl- or aryl-lithiums proceeds in two discrete steps addition to give a dihydro-pyridine iV-lithio-salt which can then be converted into the substituted aromatic pyridine by oxidation (e.g. by air), disproportionation or elimination of lithium hydride. The N-lithio-salts can be observed spectroscopically and in some cases isolated as solids. Attack is nearly always at an a-position reaction with 3-substituted-pyridines usually takes place at both available a-positions, but predominantly at C-2 this regioselectivity may be associated with relief of strain when C-2 rehybridises to sp during addition. 

It is possible to trap the 2-substituted lithium derivatives produced by organometalUc addition with electrophiles for example the use of di-f-butyl azodicarboxylate leads, after a simple aerial oxidative re-aromatisation, to 2,5-disubstituted pyridines.  

From the preparative viewpoint, nucleophilic alkylations can be greatly facilitated by the device of prior quatemisation of the pyridine in such a way that the iV-substituent can be subsequently removed - these processes are dealt with in 8.12.2. 

More vigorous conditions are required for the amination of 2- or 4-alkyl-pyridines, since proton abstraction from the side-chain (cf. 8.10) by the amide occurs first, and ring attack must therefore involve a dianionic intermediate. Amination of 3-alkyl-pyridines is regioselective for the 2-position.  

Vicarious nucleophilic substitution (section 2.3.3) permits the introduction of amino groups ortfto to nitro groups by reaction with methoxyamine as illustrated below. 

Hydroxide ion, being a much weaker nucleophile than amide, attacks pyridine only at very high temperatures to produce a low yield of 2-pyridone, which can be usefully contrasted with the much more efficient reaction of hydroxide with quinoline and isoquinoline (section 6.3.1.3) and with pyridinium salts (section 5.13.4). 

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Halogenomethyl, hydroxymethyl and aminomethyl groups readily undergo displacement reactions with nucleophilic reagents. Both side-chain and nuclear substitution products have been obtained (Scheme 57). These two possibilities are exemplified by the reaction of furfuryl chloride with sodium cyanide (Scheme 58). 

Methyl-3,4-dinitropyrrole (170) undergoes some interesting reactions with nucleophilic reagents. With methanolic sodium methoxide it yields a product (171) which on treatment with trifluoroacetic acid gives the 2-methoxypyrrole (172) 78CC564). 

Quinoxalines undergo facile addition reactions with nucleophilic reagents. The reaction of quinoxaline with allylmagnesium bromide gives, after hydrolysis of the initial adduct, 86% of 2,3-diallyl-l,2,3,4-tetrahydroquinoxaline. Quinoxaline is more reactive to this nucleophile than related aza-heterocyclic compounds, and the observed order of reactivity is pyridine < quinoline isoquinoline < phenan-thridine acridine < quinoxaline. ... 

It has long been known that a, l -unsaturated sulfones resemble a, l -unsaturated ketones and aldehydes in undergoing addition reactions with nucleophilic reagents. These reactions are initiated by nucleophilic attack at the carbon jS to the sulfone group ... 

The following example is a good illustration of these two facts the spirophosphorane 70 (Scheme 9), with a TBP structure, is a racemate of the enantiomers x and x, which can both be in tautomeric equilibrium with 70a, a derivative of tricoordinated phosphorus. The pentacoordinated P is electrophilic and can therefore undergo a number of reactions with nucleophilic reagents, whereas the tricoordinated P atom of 70a is nucleophilic or even biphilic, and 70a itself, with its OH group, has a nucleophilic protic centre with all its specific chemical properties. 

There is a difference in the ease with which the two chlorine groups in 4,10-dichloro-l,7-phenanthroline are replaced by nucleophiles. For example, the 10-chloro substituent reacts with sodium ethoxide five hundred times faster than the 4-chloro substituent. Consequently, 4-chloro- 10-ethoxy, 4-chloro- 10-methoxy-, 4-chloro- 10-anilino, and 4-chloro-10-hydroxy-1,7-phenanthrolines can be prepared from 4,10-dichloro-l,7-phenanthroline.97, 171,172,336 The exceptional reactivity of the 10-chloro group is attributed to relief of strain in the transition state in its reaction with nucleophilic reagents.336 With excess of the nucleophilic reagents, both chlorines in 4,10-dichloro-l,7-phenanthroline are replaced.171, 172,336... 

The N-oxides of special position, although their reactions with nucleophilic reagents are similar to the reactions of other imines. These compounds have been studied particularly in connection with attempts to synthesize the cyclic skeleton corrin of vitamin B12. 

Several examples were discussed earlier of the use of substituent effects for the elucidation of the mechanisms of silene reactions with nucleophilic reagents. For example, the trends in the rate constants for reaction of the series of 1,1 -diarylsilenes 19a-e with alcohols, acetic acid, amines, methoxytrimethylsilane and acetone all indicate that inductive electron-withdrawing substituents at silicon enhance the reactivity of the Si=C bond, and are consistent with a common reaction mechanism in which reaction is initiated by the formation of an intermediate complex between the silene and the nucleophile. 

In the 2,3-dihydro-5-oxo-5Ff-oxazolo[3,2-c]pyrimidinium salt (207) there are three sites for reactions with nucleophilic reagents, viz. C-2, C-8a and C-7. Products resulting from attack at C-2 are observed with DMSO, water, alcohols, benzoate, chloride, diethylamine and pyridine. Products resulting from attack at C-8a are observed with water, hydroxide, alcohols, alkoxide and isopropylamine. Diethylamine also causes attack at C-7 of the cation, which results in cleavage of the pyrimidine ring (75JOC1713). 

C. The Quaternary Salts and Their Reactions with Nucleophilic Reagents ... 

Hydrogen atoms at the 3- and 5-positions of isoxazoles are readily removed as protons. Such reactions, with nucleophilic reagents acting as bases, usually result in ring opening. When the 3- and 5-positions are blocked, deprotonation at an unsubstituted 4-position can lead to metalla-tion by, for example, n-butyllithium, as in Eqs. (19)-(21).153-155... 

Reactions with Nucleophilic Reagents In close parallel with the oxidation of tropilidene derivatives by tropylium salts,81 for example, 1,2-dithiolium salts containing a single substituent in position 4 or 5, e.g. 70, can capture a hydride anion from the doubly substituted, highly strained leuco bases (71), thus oxidizing the latter to the more highly substituted and thermodynamically more stable salts (73).82... 

Mannich bases may afford polycondensation with concomitant amine elimination by reaction with nucleophilic reagents. In order to obtain polymeric products through a repetitive and cumulative reaction, both the Mannich base monomer (A-A) and the nucleophilic species (B-B) need to be at least bifunctional or both the aminomethyl- and nucleophilic groups must be present in the same molecule (A-B). Polymers 400 and 401 (Hg. 156) arc thus yielded, respectively. 

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