SN2 alkylating agents

CN is considered less than lethal or nonlethal because it has a large safety ratio. That is, its effective dose or concentration ECtfo is low compared to its lethal dose or concentration (LCtfo). In the body, CN is converted to an electrophilic metabolite. It is an SN2 alkylating agent that reacts with SH groups and other nucleophilic sites of biomolecules. Alkylation of SH-containing enzymes leads to enzyme inhibition with disruption of cellular processes. CN was found to inhibit human plasma cholinesterase via a non-SH interaction, and some of the toxic effects may be due to alkylation of SH-containing enzymes. 

CS and CN are SN2-alkylating agents with activated halogen groups that react readily at nucleophilic sites. The prime targets include... 

Next, an alkyl halide (the alkylating agent) is added to the solution of sodium acetylide. Acetylide ion acts as a nucleophile, displacing halide from carbon and forming a new carbon-carbon bond. Substitution occurs by an Sn2 mechanism. 

The alkyl halide must be one that reacts readily by an Sn2 mechanism. Thus, methyl and primary alkyl halides are the most effective alkylating agents. Elimination competes with substitution when secondary alkyl halides are used and is the only reaction observed with tertiary alkyl halides. 

Alkylation reactions are subject to the same constraints that affect all Sn2 reactions (Section 11.3). Thus, the leaving group X in the alkylating agent R—X can be chloride, bromide, iodide, or tosylate. The alkyl group R should be primary or methyl, and preferably should be allylic or benzylic. Secondary halides react poorly, and tertiary halides don t react at all because a competing E2 elimination of HX occurs instead. Vinylic and aryl halides are also unreactive because backside approach is sterically prevented. 

Asymmetric allylic substitution reactions have been studied for many years because they provide valuable chiral compounds. Regardless of the alkylating agent used, there are two major goals in these reactions (i) to minimize the amount of Sn2 products, and (ii) to maximize the enantiomeric purity of the Sn2 products. Various approaches have been investigated to achieve these goals. Recently, the efforts of several research groups have been focused on the... 

Simple alkylations of carboxylate anions, by such alkylating agents as alkyl halides, dialkyl sulphates, and quaternary ammonium compounds, are generally straightforward SN2 reactions, and will not be discussed here. 

The transient nature of carbocations arises from their extreme reactivity with nucleophiles. The use of low-nucleophilicity counterions, particularly tetrafluorobo-rates (B I, ), enabled Meerwein in the 1940s to prepare a series of oxonium and carboxonium ion salts, such as R30+BF4 and HC(OR)2+BF4, respectively.13 These Meerwein salts are effective alkylating agents, and they transfer alkyl cations in SN2-type reactions. However, simple alkyl cation salts (R 1 BF4 ) were not obtained in Meerwein s studies. The first acetyl tetrafluoroborate—that is, acetylium tetrafluor-oborate—was obtained by Seel14 in 1943 by reacting acetyl fluoride with boron trifluoride at low temperature [Eq. (3.1)]. 

How substituents in the alkylating agent influence the rate constants of SN2 reactions can be explained by means of the transition state model developed in Section 2.4.3. This model makes it possible to understand both the steric and the electronic substituent effects. 

First, the SN2 reactivity of an alkylating agent decreases with an increasing number of the alkyl substituents at the electrophilic C atom. In other words, a-branching at the C atom of the alkylating agent reduces its SN2 reactivity. This reduces the reactivity so much that tertiary C atoms don t react via the SN2 mechanism in intermolecular processes ... 

Because of the substituent effect just described, allyl and benzyl halides generally react with nucleophiles according to an SN2 mechanism. This occurs even though the SN1 reactivity of allyl and benzyl halides is higher than that of nonconjugated alkylating agents (see Section 2.5.4). 

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