Electrophilic reactions addition-elimination

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Electrophilic metals or metal complexes, when incorporated into either the acyl or alcohol functions of the ester, might be expected to increase the rate of addition of amine. This might occur through direct carbonyl-0 or alcohol-0 coordination (21 or 22, Scheme 21) or by being positioned at a discrete distance from these (cf. 23 and 24). When the metal is attached to the alcohol function loss of this group might also be accelerated (in a stepwise addition-elimination reaction), but with acyl activation loss of alcohol might be expected to be retarded. 

As we have seen (Section 4, p. 191) the range of effective molarities associated with ring-closure reactions is very much greater than that characteristic of intramolecular general acid-base catalysis the main classification is therefore in terms of mechanism. By far the largest section (I, Tables A-D) gives EM s for intramolecular nucleophilic reactions. These can be concerted displacements (mostly at tetrahedral carbon), stepwise displacements (mostly addition-elimination reactions at trigonal carbon), or additions, and they have been classified in terms of the nucleophilic and electrophilic centres. 

Two substitutions are occurring here H to Br, and Br to MeO. Looking at the order of reagents, the first substitution is H to Br. Br2 is electrophilic, so the a-C of the acyl bromide must be made nucleophilic. This is done by enolization. The substitution of Br with MeO occurs by a conventional addition-elimination reaction under acidic conditions. 

The 7r-electron excessive character of pyrrole and indole renders both systems extremely susceptible to electrophilic attack and the fused benzene rings of carbazole also undergo electrophilic substitution more readily than does an unsubstituted benzene ring. In contrast, the 2/7-isoindole system only survives intact during electrophilic substitution reactions under the mildest of conditions and the system is more susceptible to [ 4 + 2] cycloaddition reactions than is pyrrole. 1,1-Disubstituted IH-isoindoles generally undergo nucleophilic addition-elimination reactions across the 2,3-bond or yield products derived from an initial electrophilic attack at the 2-position. 

The addition-elimination reaction between 2-chlorocarbonyI-lfl-pyr-rolizin-l-one and chlorine has been described (see Section III,B,2,c). The 2,5-dichloro derivative 21b isolated in the same reaction must presumably be derived from an electrophilic substitution on the initially formed 2-chloro-pyrrolizinone.26 The iminopyrrolizine 270 can be methylated, first with Meerwein s reagent and then by methyl iodide to give the quaternary salt 271, which reacts readily with nucleophiles (see Section III,B,5). 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

Previous reactions in this chapter have involved only addition of the nucleophile and a hydrogen to the carbonyl group. In this reaction, addition is followed by elimination of the oxygen to form a double bond between the carbonyl carbon and the nucleophile. Such an addition-elimination reaction occurs when the nucleophile has or can generate (by the loss of a proton or a phosphorus group) a second pair of electrons that can be used to form a second bond to the electrophilic carbon. In the case of the Wittig reaction, the phosphorus and the oxygen are eliminated to form the alkene. The forma-... 

The reaction presented in this problem is known as a Friedel-Crafts acylation. Technically, this example belongs to a class of reactions referred to as electrophilic aromatic substitutions. Furthermore, the actual mechanism associated with this reaction, utilizing Lewis acid reagents as catalysts, proceeds through initial formation of an electrophilic acyl cation followed by reaction with an aromatic ring acting as a nucleophile. This mechanism, shown below, reflects distinct parallels to standard addition-elimination reaction mechanisms warranting introduction at this time. 

Please note that while the Friedel-Crafts acylation reaction is presented in discussions of addition-elimination reaction mechanisms, this reaction is actually an electrophilic aromatic substitution reaction. The correct mechanisms for a Freidel-Crafts acylation was presented in the solution for Problem 6 (h) from Chapter 7. 

The formation of acetoxy compounds VII which was originally thought to be a result of electrophilic substitution [36] has been shown to occur as an addition -elimination reaction through the ipjo-attack [37). The formation of cyclohexadienyl derivatives of type VI provide a rational explanation of some non-conventional aromatic substitutions [38]. 

Stereochemistry chi 4 Elimination reactions Electrophilic additions to alkenes... 

The alkene bond of 3-sulfolene (and some derivatives) is quite reactive to electrophiles and this allows access to 3-substituted sulfolenes through addition-elimination reactions. 

Thionyl chloride Is electrophilic, and susceptible to attack by the carboxylic acid a sequence of addition-elimination reactions gives the corresponding acid chloride. 

These electrophilic substances can react with nucleophilic compounds, for example, of the microbial cell, by way of an elimination reaction in the case of micro-bicides with an activated halogen in the a-position to an electronegative group, whereas microbicides with vinyl-activated halogen combine with nucleophiles by way of an addition-elimination reaction (Fig. 3). 

When DMF is treated with POCI3, a more complex equilibrium mixture of iminium salts of varying electrophilicities is produced. A similar sequence of addition-elimination reactions initially takes place to yield iminium salts 1 and 2, which can react further with DMF to produce 3 and 4. Although each salt below is capable of undergoing a subsequent acylation reaction, salt 2 is generally considered to be the active Vilsmeier reagent. 

In the first reaction of the citric acid cycle, acetyl-CoA reacts with oxaloacetate to form citrate. The mechanism for the reaction shows that an aspartate side chain of the enzyme removes a proton from the a-carbon of acetyl-CoA, creating an enolate ion. This enolate ion adds to the keto carbonyl carbon of oxaloacetate and the carbonyl oxygen picks up a proton from a histidine side chain. This is similar to an aldol addition where the a-carbanion (enolate ion) of one molecule is the nucleophile and the carbonyl carbon of another is the electrophile (Section 18.10). The intermediate (a thioester) that results is hydrolyzed to citrate in a nucleophilic addition-elimination reaction (Section 16.9). 

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