Excellent leaving groups

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

Consistent with this mechanism is the observation that trifluoroperoxyacetic acid is reported to be the most effective peracid in aromatic oxidation134 the great stability of the trifluoroacetate anion causes it to be an excellent leaving group so that heterolysis to give hydroxyl cations OH+ occurs most readily. 

Now that we have seen all four factors individually, we need to see how to put them all together. When analyzing a reaction, we need to look at all four factors and make a determination of which mechanism, SnI or Sn2, is predominating. It may not be just one mechanism in every case. Sometimes both mechanisms occur and it is difficult to predict which one predominates. Nevertheless, it is a lot more common to see situations that are obviously leaning toward one mechanism over the other. For example, it is clear that a reaction will be Sn2 if we have a primary substrate with a strong nucleophile in a polar aprotic solvent. On the flipside, a reaction will clearly be SnI if we have a tertiary substrate with a weak nucleophile and an excellent leaving group. 

Via an Si l process. With a tertiary alcohol, we can use an SnI process. We simply use an acid to protonate the OH group, converting it into an excellent leaving group. The first two steps of this reaction are identical to the El process that we just saw ... 

Similar nucleophilic addition of electrons can also occur to the carbonyl carbon atom of diesters such as (62), e.g. from sodium in solvents such as xylene, but the resultant dianion (63) differs from (59) in possessing excellent leaving groups, e.g. eOEt, and the overall result is the acyloin condensation ... 

The most significant term in the rate law for the aminolysis of organic esters RC(0)0R is that second-order in amine (k2, Eq. (6)). Only for reactive esters possessing excellent leaving groups (e.g., ni-trophenylacetates) does the ki pathway make a useful contribution (62-65). However, under most conditions, and especially in nonaque-ous solvents, the 3 term can also make a useful contribution. 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

The nitrolysis of tertiary amines in the form of fert-butylamines and methylenediamines has been used to synthesize numerous polynitramine-based energetic materials. In these reactions one of the N-C bonds is cleaved to generate a secondary nitramine and an alcohol the latter is usually 0-nitrated or oxidized under the reaction conditions (Equation 5.15). The ease in which nitrolysis occurs is related to the stability of the expelled alkyl cation. Consequently, the fert-butyl group and the iminium cation from methylenediamines are excellent leaving groups. 

Pyridine has another useful attribnte, in that it behaves as a nncleophilic catalyst, forming an intermediate acylpyridinium ion, which then reacts with the nucleophile. Pyridine is more nucleophilic than the carboxylate anion, and the acylpyridinium ion has an excellent leaving group (pATa pyridinium 5.2). The reaction thus becomes a double nucleophilic substitution. 

SAM, S-adenosylmethionine, has been encountered as a biological methylating agent, carrying out its function via a simple Sn2 reaction (see Box 6.5). This material is a nucleoside derivative formed by nucleophilic attack of the thiol group of methionine on to ATP (see Box 6.5). It provides in its structure an excellent leaving group, the neutral S-adenosylhomocysteine. 

Coenzyme A is another adenine nucleotide derivative, with its primary functional group, a thiol, some distance away from the nucleotide end of the molecule. This thiol plays an important role in biochemistry via its ability to form thioesters with suitable acyl compounds (see Box 7.18). We have seen how thioesters are considerably more reactive than oxygen esters, with particular attention being paid to their improved ability to form enolate anions, coupled with thiolates being excellent leaving groups (see Box 10.8). 

The l,2,4-oxadiazolidine-3,5-dione ring is an excellent leaving group. For example, compound... 

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