With nucleophilic substitution

A mechanism that accounts for both the inversion of configuration and the second-order kinetics that are observed with nucleophilic substitution reactions was suggested in 1937 by E. D. Hughes and Christopher Ingold, who formulated what they called the SN2 reaction—short for substitution, nucleophilic, birnolecu-lar. (Birnolecular means that two molecules, nucleophile and alkyl halide, take part in the step whose kinetics are measured.)... 

Ejfect ofSolvent. In addition to the solvent effects on certain SeI reactions, mentioned earlier (p. 764), solvents can influence the mechanism that is preferred. As with nucleophilic substitution (p. 448), an increase in solvent polarity increases the possibility of an ionizing mechanism, in this case SeI, in comparison with the second-order mechanisms, which do not involve ions. As previously mentioned (p. 763), the solvent can also exert an influence between the Se2 (front or back) and SeI mechanisms in that the rates of Se2 mechanisms should be increased by an increase in solvent polarity, while Sni mechanisms are much less affected. 

Although diselenonium-, ditelluronium- and mixed sulfonium-selenonium dications can exhibit either oxidative or electrophilic properties in reactions with nucleophiles, substitution at the onium chalcogen atom is more typical.96 Owing to the increased stability of heavier dichalcogenium-dications, they react only with highly activated substrates such as aniline and tV,A-dimethylaniline, while no reaction is observed with phenol and diphenylamine.113 Reactions of ditelluronium dications with activated aromatics are also not known (Scheme 44).114... 

The mechanism of hydrolysis of cysteine peptidases, in particular cysteine endopeptidases (EC 3.4.22), shows similarities and differences with that of serine peptidases [2] [3a] [55 - 59]. Cysteine peptidases also form a covalent, ac-ylated intermediate, but here the attacking nucleophile is the SH group of a cysteine residue, or, rather, the deprotonated thiolate group. Like in serine hydrolases, the imidazole ring of a histidine residue activates the nucleophile, but there is a major difference, since here proton abstraction does not appear to be concerted with nucleophilic substitution but with formation of the stable thiolate-imidazolium ion pair. Presumably as a result of this specific activation of the nucleophile, a H-bond acceptor group like Glu or Asp as found in serine hydrolases is seldom present to complete a catalytic triad. For this reason, cysteine endopeptidases are considered to possess a catalytic dyad (i.e., Cys-S plus H-His+). The active site also contains an oxyanion hole where the terminal NH2 group of a glutamine residue plays a major role. 

In another report of Singh and Han [61], Ir-catalyzed decarboxylative amidations of benzyl allyl imidodicarboxylates derived from enantiomerically enriched branched allylic alcohols are described. This reaction proceeded with complete stereospecificity-that is, with complete conservation of enantiomeric purity and retention of configuration. This result underlines once again (cf. Section 9.2.2) that the isomerization of intermediary (allyl) Ir complexes is a slow process in comparison with nucleophilic substitution. 

Synthesizing amines with nucleophilic substitution reactions is normally an Sp 2 process. This means that methyl amines react more readily than primary cimines, and secondary and tertiary amines show very little reactivity. 

In conjunction with this, Jeong reported the cycloadditions of bis(allyl) and bis(homoallyl) acetals of alkynals leading to bicyclic lactols. Smaltz extended its utility to the synthesis of carbocyclic nucleoside by coupling with nucleophilic substitution of a 7r-allylic palladium complex (Equation (46)). ... 

As well as increasing anion nucleophilicity, crown or cryptand complexation can enhance the basicity of the anion. Table 3 exemplifies this effect with 1-bromooctane where base-promoted elimination to 1-octene competes with nucleophilic substitution. Being small and poorly solvated, naked fluoride is a strong and hard base which causes, in the case of certain substrates (e.g. Scheme 6), the elimination product to predominate. As the naked anions increase in size they display less basic characteristics but retain high nucleophilic reactivity (74JA2250). 

It is, in fact, true that the temperature dependence studies provide the only substantial evidence suggestive of an additional mode of interaction between the alkyl halide and the complex. The magnitudes of the observed activation energies are much smaller than those usually associated with nucleophilic substitution at the saturated carbon atom (15 to 30 kcal. per mole) (13, 22). This might arise from some sort of pre-equilibrium. 

With our first example of chemical reactions, we want to get acquainted with a very important type of reaction in organic chemistry, that is, with nucleophilic substitution at a saturated carbon atom. Since halogens are very common constituents of man-made organic chemicals, we consider their displacement by environmentally relevant nucleophiles. In these cases the halogen plays the role of the leaving group. 

An elimination reaction is a reaction in which a functional group is split (eliminated) from adjacent carbons. This is a reaction that can often compete with nucleophilic substitution and is highly dependant on the leaving group present in the molecule. Elimination reactions are favored by the presence of strong bases. 

As we saw in Chapter 8, elimination reactions often compete with nucleophilic substitution reactions. Both reactions can be useful in synthesis if this competition can be controlled. This chapter discusses the two common mechanisms by which elimination reactions occur, the stereochemistry of the reactions, the direction of the elimination, and the factors that control the competition between elimination and substitution. Based on these factors, procedures are presented that can be used to minimize elimination if the substitution product is the desired one or to maximize elimination if the alkene is the desired product. 

As was the case with nucleophilic substitution reactions, there are two mechanisms for these elimination reactions. One mechanism is concerted and parallels the SN2 reaction, whereas the other involves the formation of a carbocation intermediate and parallels the SN1 reaction. The concerted mechanism is discussed first. 

In this chapter we deal with nucleophilic substitution reactions at the saturated, that is, the sp3-hybridized C atom (abbreviated SN reactions ). In these reactions, alkyl groups are transferred to the nucleophiles. Organic electrophiles of this type are referred to as alkylating agents. They have the structure (R3 H ) Csp>—X. The group X is displaced by the nucleophile according to the equation... 

Under the section dealing with nucleophilic substitution it has been pointed out that the extremely labile 7-methoxy group in the pyrimidine (671) is rapidly substituted by amines. In aqueous acid, however, hydrolytic cleavage of the pyrimidine ring occurs (64JOC2121). 

Other examples of the cyanide as a leaving group are shown in Table 3 (entries 1-3). The chemistry shown in Table 3, entry 3, indicates that not only does nucleophilic substitution of a thiocyanate group displace the cyanide to form a thioether, but an extra equivalent of CH3MgI results in addition to the aldehyde and subsequent dehydrolysis to yield the final product. Typically addition to the cyanide group is competitive, with nucleophilic substitution resulting in a mixture of reaction products. 

Similar reactivity studies have been conducted with nucleophilic substitution reactions both at the furan nucleus and at side-chain groupings,374" 375,419,422 t e on y additional feature being the formation of Meisenheimer complexes in reactions with nitrofurans.456,4563... 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

As generally observed with nucleophilic substitutions in the pyrido[2,3-J]pyrimidine system, exchange occurs most readily at the 4-position.77,79 Thus, under mild conditions, 2,4-dichloropyrido[2,3-rf]pyrimidine (21) with dilute aqueous sodium hydroxide gives 2-chloropy-rido[2,3-c ]pyrimidin-4(3// )-one (24).7-79... 

The reactions in this group probably mainly involve nucleophilic additions, compared with nucleophilic substitutions in compounds of the ether series, since the phenoxide involved under basic conditions can be concluded to be reacting as a carbanion. It seems most likely that from an initially formed methylol, a quinone methide results to which the carbanion, from a phenoxide, then adds to afford first the dihydroxymethane shown which then reacts again to continue the sequence (R CgHig, CgHiy). In the reaction of formaldehyde with alkylphenols as well as nucleophilic addition in alkaline media, electrophilic substitution under acidic conditions can take place leading to the same product. 

The main effect of the oxygen atom next to a reaction centre in chemical terms is to stabilise the buildup of positive charge on the central atoms the lone pairs of electrons on the oxygen atom release electrons into the vacant p orbital of an adjacent carbonium ion centre. This means that, compared with nucleophilic substitutions at purely carbon centres, the C—X bond can break to a much greater extent before there is much C—Y bond formation. Indeed, in the limit, for most processes in water the C—X bond completely breaks first and the oxocarbonium ion is a discrete intermediate. 

Alkyl halides undergo photoreduction on irradiation in methanol or diethyl ether (in competition with nucleophilic substitution), but the mechanism of reduction is not simple homolytic fission of the carbon-halogen bond, followed by hydrogen abstraction.85 Thus, irradiation of (41a) or (41b) in MeOD gives... 

As with nucleophilic substitution reactions, rates of dehydrohalogenation reactions will be dependent on the strength of the C-X bond being broken in the elimination process. Accordingly, it is expected that the ease of elimination of X will follow the series Br>Cl>F. The relative reactivities of Br and Cl toward elimination is evident from the hydrolysis product studies of 1,2-dibromo-3-chloropropane (DBCP Burlinson et al., 1982). DBCP has been used widely in this country as a soil fumigant for nematode control and has been detected in groundwaters (Mason et al., 1981) and subsoils (Nelson, et al., 1981). Hydrolysis kinetic studies demonstrated that the hydrolysis of DBCP is first order both in DBCP and hydroxide ion concentration above pH 7. Below pH 7, hydrolysis occurs via neutral hydrolysis however, the base-catalyzed reaction will contribute to the overall rate of hydrolysis as low as pH 5. Product studies performed at pH 9 indicate that transformation of DBCP occurs initially by E2 elimination of HBr and HCl (Figure 2.4). 

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