Introduction to Nucleophilic Substitution Reactions

Introduction to Nucleophilic Substitution Reactions—common reaction involving sfp hybridized carbon atoms is a nucleophilic substitution reaction, in which a nucleophile attacks the electrophilic... 

The Peterson reaction has two more advantages over the Wittig reaction 1. it is sometimes less vulnerable to sterical hindrance, and 2. groups, which are susceptible to nucleophilic substitution, are not attacked by silylated carbanions. The introduction of a methylene group into a sterically hindered ketone (R.K. Boeckman, Jr., 1973) and the syntheses of olefins with sulfur, selenium, silicon, or tin substituents (D. Seebach, 1973 B.T. Grdbel, 1974, 1977) illustrate useful applications. The reaction is, however, more limited and time consuming than the Wittig reaction, since metallated silicon derivatives are difficult to synthesize and their reactions are rarely stereoselective (T.H. Chan, 1974 ... 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Charge diagrams suggest that the 2-amino-5-halothiazoles are less sensitive to nucleophilic attack on 5-position than their thiazole counterpart. Recent kinetic data on this reactivity however, show, that this expectation is not fulfilled (67) the ratio fc.. bron.c.-2-am.noih.azoie/ -biomoth.azoie O"" (reaction with sodium methoxide) emphasizes the very unusual amino activation to nucleophilic substitution. The reason of this activation could lie in the protomeric equilibrium, the reactive species being either under protomeric form 2 or 3 (General Introduction to Protomeric Thiazoles). The reactivity of halothiazoles should, however, be reinvestigated under the point of view of the mechanism (1690). 

Nucleophilic substitution reactions, to which the aromatic rings are activated by the presence of the carbonyl groups, are commonly used in the elaboration of the anthraquinone nucleus, particularly for the introduction of hydroxy and amino groups. Commonly these substitution reactions are catalysed by either boric acid or by transition metal ions. As an example, amino and hydroxy groups may be introduced into the anthraquinone system by nucleophilic displacement of sulfonic acid groups. Another example of an industrially useful nucleophilic substitution is the reaction of l-amino-4-bromoanthraquinone-2-sulfonic acid (bromamine acid) (76) with aromatic amines, as shown in Scheme 4.5, to give a series of useful water-soluble blue dyes. The displacement of bromine in these reactions is catalysed markedly by the presence of copper(n) ions. 

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

The introduction of substituents into position 7 of a 2,4-disubstituted pteridine can be effected very cleanly by the use of acyl radicals typically and has been known for many years. Treatment of aldehydes with /-butyl hydroperoxide and iron(ll) generates acyl radicals which add selectively to the 7-position. A recent exploitation of this chemistry has provided a large number of new examples including both aryl and alkyl acyl radicals as reagents <2004PTR129> pA , data have been compiled (Section 10.18.4) and many nucleophilic substitution reactions of the 7-acylated pteridines and functional group modifications have been described (Section 10.18.7.2). 

Substitution of the central carbon of RX may induce significant mechanistic variations within the range of nucleophilic substitution reactions. For example, introduction of electron-releasing substituents on R will lead to a stabilization of the carbocation configuration [22]. An excellent illustration of this type of process is the reaction of methoxymethyl derivatives (83) taken from Jencks work (Knier and Jencks, 1980). The carbocation within [22] is stabilized by the resonance interaction (84). Thus the configuration diagram... 

HO-OH2+.14 This reaction forms two water molecules and a carbenium ion, which is then hydrated to form the protonated alcohol. The degenerate gas-phase reactions between HF and protonated alkyl fluorides RFH+ (R = Me, Et, i-Pr, r-Bu) were investigated by ab initio methods.15 With the exception of MeFFi+, the protonated alkyl fluorides can be viewed as weak complexes of the carbocation R+ and FiF. Both frontside and backside substitutions occur, supporting the proposal (see Introduction)8 that nucleophilic substitution reactions are better understood through such a competition as opposed to the traditional S /S 2 competition. 

Substituted bicycloalkyl halides are very unreactive toward nucleophilic substitution reactions. The low reactivity in S l reactions has been attributed to the fact that a planar configuration at the bridgehead carbon cannot be obtained without the introduction of considerable strain119. On the other hand, the S 2 reaction is precluded because a backside approach of the nucleophile cannot occur at a bridgehead position for a steric reason. The lack of reactivity of 1 -halobicycloalkanes toward nucleophiles by polar mechanisms makes them attractive substrates for the S l mechanism. 

Mild N-arylations of indoles can be achieved in good yields by nucleophilic substitution reactions of the sodium salt of indole on various haloarenetricarbonylchromium complexes. Thus, o-fluoroanisole-Cr(CO)3 33a reacts with the indole N anion within 0.75 h at 0 °C to give complex 3m (Nu = indolyl) in 83 % yield. The chloro derivatives require longer reaction times and higher temperatures (Scheme 18) [37]. The authors were able to extend this procedure to the introduction of two indole rings on the same aromatic nucleus. 

The direct nucleophilic substitution reactions (Scheme 2) [16-22], restricted mainly to n-activated alcohols such as secondary arylmethanols, allylic and propargylic alcohols, and tertiary alcohols that can readily form stable carbocationic intermediates, are mechanistically different to hydrogen autotransfer reactions. Although these reactions are not the focus of this chapter, since they are also very relevant research areas, this brief introduction is anticipated to provide potentially helpful references to assist interested researchers in their studies, especially in boardline research where elucidation of reaction mechanisms is difficult. 

PROBLEM 1.69 Choose the Introduction on the bottom left of the Table of Contents page. Read this short document. Under the Technical Issues heading there is a discussion of solvent effects. After reading this section, how do you think using a polar solvent in the Unimolecular nucleophilic substitution reaction might affect the answer to the previous question That is, would a polar solvent have more impact on a homolytic or a heterolytic cleavage ... 

In SPOS, the choice of the linker that serves to attach the library scaffold to the polymer support is critical. As a result, a variety of elegant linking methods have been developed that enable the introduction of additional diversity into the products during the cleavage reactions. The sulfone linker is an example of a safety-catch linker that can be cleaved from resins by using nucleophilic substitution reactions with amines. 

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