Ring structures nucleophilic substitution

Quinoline forms part of quinine (structure at the head of this chapter) and isoquinoline forms the central skeleton of the isoquinoline alkaloids, which we will discuss at some length in Chapter 51. In this chapter we need not say much about quinoline because it behaves rather as you would expect—its chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring. So nitration of quinoline gives two products—the 5-nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinoline. 

In his review on pentavalent phosphorus. Holmes states that the influence of a six-membered ring on nucleophilic substitution will be minimal reactivity will mirror that of corresponding acyclic compounds. He predicts that the inversion mechanism should dominate and that in analogy with acyclic compounds. . the presence of steric effects in six-membered structures may cause some reactions to lack stereospecificity (Holmes, 1980b, p, 149). 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

One of the most important reactions of purines is the bromination of guanine or adenine at the C-8 position. It is this site that is the most common point of modification for bioconjugate techniques using purine bases (Figure 1.53). Either an aqueous solution of bromine or the compound N-bromosuccinimide can be used for this reaction. The brominated derivatives then can be used to couple amine-containing compounds to the pyrimidine ring structure by nucleophilic substitution (Chapter 27, Section 2.1). 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

The next step is not immediately obvious. The generation of an ethyl ester from a lactone can be accommodated by transesterification (we might alternatively consider esterification of the free hydroxyacid). The incorporation of chlorine where we effectively had the alcohol part of the lactone leads us to nucleophilic substitution. That it can be SnI is a consequence of the tertiary site. Cyclopropane ring formation from an Sn2 reaction in which an enolate anion displaces a halide should be deducible from the structural relationships and basic conditions. 

The 3-0-benzyl derivative underwent a rapid reaction with TASF at reflux temperature to give methyl 3-0-benzyl-A,6-0-benzylidene-2-deoxy-2-fluoro-p- -glucopyranoside (J ) in A5% yield, and a minor product (19% yield) tentatively assigned the structure of methyl 3-0-benzvl-A.6-0-benzvlldene-2-deoxv-B-D-ervthro-hex-2-enopyranoslde. Base-catalyzed elimination reactions with trlflyl derivatives are uncommon (, ), but have been observed In certain furanoid (A0,A2) and, recently, in pyranoid (33,35) ring systems (see also Table I). Eliminations in glycopyranosldes occurred (33,35) under conditions which decreased the ease of nucleophilic substitution (33,A3,AA). 

A more detailed evaluation of the diverse structures proposed for the secondary species goes beyond the scope of this review. We mwely emphasize that the ESR results provide detailed evidence for the nature of the radical center, but fail to elucidate the cationic site. The identity of this center is left to secondary considerations or speculation. We also note that any alternative structure has the virtue of not contradicting the ab irutio calculations the potential c ture of chloride ion has precedent in the nucleophilic substitution at a cyclopropane carbon (see Section 7). Another type of ring-opened structure has been postulated as an intermediate in the aminium radical cation catalyzed rearrangement of l-aryl-2-vinylcyclopropanes (see Section 5). 

This chapter is concerned with reactions that introduce or replace substituent groups on aromatic rings. The most important group of reactions is electrophilic aromatic substitution. The mechanism of electrophile aromatic substitution has been studied in great detail, and much information is available about structure-reactivity relationships. There are also important reactions which occur by nucleophilic substitution, including reactions of diazonium ion intermediates and metal-catalyzed substitution. The mechanistic aspects of these reactions were discussed in Chapter 10 of Part A. In this chapter, the synthetic aspects of aromatic substitution will be emphasized. 

For conjugated structures thermolytic reactions with loss of sulfur have been studied since 1980 and afford various types of cyclic and acyclic products (Section 4.11.5.1). Nucleophilic attack at ring carbon is very characteristic of 1,2,3-dithiazoles (Section 4.11.5.4). This type of reaction was especially prolific with Appel s salt, studied mostly by Appel, Rees and their co-workers. The preferential site of attack is C(5) but nucleophilic substitution may occur at C(4) when the C(5) site is blocked by poorly leaving substituents, see the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) for examples of 1,2,3-dithiazoles <84CHEC-I(6)924> and 1,2,3-oxathiazoles <84CHEC-l(6)930>. Nucleophilic attack at ring sulfur in 1,2,3-dithiazoles occurs on S(2) (Section 4.11.5.5), see... 

Only a few exchange reactions of substituents directly bound to the heterocyclic ring have been reported. Gompper has studied the nucleophilic substitution of bromo- and chloro-l,2,3-triazines and observed replacement of bromine or chlorine with sodium ethoxide, sodium ethanethiolate and amines. In most cases yields are quantitative. With the trihalo compound, first the 4-mono- then the 4,6-di-substituted derivative is obtained (79CB1529). Reaction of 5-chloro-2-methyl-4,6-bis(dimethylamino)-l,2,3-triazinium iodide (61) with malononitrile affords compound (62). Compounds of the general structure (63) are hydrolyzed to l,2,3-triazin-5(2//)-ones (64) (79CB1535). 

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