The addition-elimination mechanism

But in the aromatic compound, the C-Br bond is in the plane of the ring as the carbon atom is trigonal. To attack from the back, the nucleophile would have to appear inside the benzene ring and invert the carbon atom in an absurd way. This reaction is of course not possible. This is another example of the general rule  

If Sn2 is impossible, what about SnI This is possible but very unfavourable unless the leaving group is an exceptionally good one (see below for an example). It would involve the unaided loss of the leaving group and the formation of an aryl cation. All the cations we saw as intermediates in the S l reaction (Chapter IS) were planar with an empty p orbital. This cation is planar but the p orbital is full—it is part of the aromatic ring—and the empty orbital is an sp2 orbital outside the ring. 

Imagine a cyclic 3-fluoro-enone reacting with a secondary amine in a conjugate substitution reaction. The normal addition to form the enolate followed by return of the negative charge to expel the fluoride ion gives the product. 

Now imagine just the same reaction with two extra double bonds in the ring. These play no part in our mechanism they just make what was an aliphatic ring into an aromatic one. Conjugate substitution has become nucleophilic aromatic substitution. 

CHAPTER 22 CONJUGATE ADDITION AND NUCLEOPHILIC AROMATIC SUBSTITUTION 

The most important mechanism for aromatic nucleophilic substitution follows directly from conjugate substitution and we shall introduce it that way. It is called the addition-elimination mechanism . 

Since the nitro group is usually introduced by electrophilic aromatic substitution (Chapter 22) and halides direct ortho/para in nitration reactions, a common sequence is nitration followed by nucleophilic substitution. 

This sequence is useful because the nitro group could not be added directly to give the final product as nitration would go in the wrong position. The cyanide is mcfa-directing, while the alkyl group (R) is orthoy para-directing. 

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The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution... 

THE ADDITION-ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION... 

Write equations describing the addition-elimination mechanism for the reaction of hexafluorobenzene with sodium methoxide clearly showing the structure of the rate determining intermediate j... 

Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

The product of this reaction as its sodium salt is called a Meisenheimer complex after the Ger man chemist Jacob Meisenheimer who reported on their formation and reactions in 1902 A Meisenheimer complex corresponds to the product of the nucleophilic addition stage in the addition-elimination mechanism for nucleophilic aromatic substitution... 

The reaction of benzenesulfomc acid with sodium hydroxide (first entry m Table 24 3) proceeds by the addition-elimination mechanism of nucleophilic aromatic substi... 

Cycloalkene (Section 5 1) A cyclic hydrocarbon characterized by a double bond between two of the nng carbons Cycloalkyne (Section 9 4) A cyclic hydrocarbon characterized by a tnple bond between two of the nng carbons Cyclohexadienyl anion (Section 23 6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism It is represented by the general structure shown where Y is the nucleophile and X is the leaving group... 

Both ( )- and (Z)-l-halo-l-alkenes can be prepared by hydroboration of 1-alkynes or 1-halo-l-alkynes followed by halogenation of the intermediate boronic esters (244,245). Differences in the addition—elimination mechanisms operating in these reactions lead to the opposite configurations of iodides as compared to bromides and chlorides. 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

SECTION 10.5. NUCLEOPHILIC AROMAHC SUBSTITUTION BY THE ADDITION-ELIMINATION MECHANISM... 

Nucleophilic Aromatic Substitution by the Addition-Elimination Mechanism... 

There are several mechanisms by which net nucleophilic aromatic substitution can occur. In this section we will discuss the addition-elimination mechanism and the elimination-addition mechanism. Substitutions via organometallic intermediates and via aryl diazo-nium ions will be considered in Chapter 11 of Part B. 

The addition-elimination mechanism uses one of the vacant n orbitals for bonding interaction with the nucleophile. This permits addition of the nucleophile to the aromatic ring without displacement of any of the existing substituents. If attack occurs at a position occupied by a potential leaving group, net substitution can occur by a second step in which the leaving group is expelled. 

Kinetics of the reaction of p-nitrochlorobenzene with the sodium enolate of ethyl cyanoacetate are consistent with this mechanism. Also, radical scavengers have no effect on the reaction, contrary to what would be expected for a chain mechanism in which aryl radicals would need to encounter the enolate in a propagation step. The reactant, /i-nitrophenyl chloride, however, is one which might also react by the addition-elimination mechanism, and the postulated mechanism is essentially the stepwise electron-transfer version of this mechanism. The issue then becomes the question of whether the postulated radical pair is a distinct intermediate. 

A fluormated enol ether formed by the reaction of sodium ethoxide with chlorotnfluoroethylene is much less reactive than the starting fluoroolefin To replace the second fluorine atom, it is necessary to reflux the reaction mixture. The nucleophilic substitution proceeds by the addition-elimination mechanism [30] (equation 26). 

The reaction of benzenesulfonic acid with sodium hydroxide (first entry in Table 24.3) proceeds by the addition-elimination mechanism of nucleophilic aromatic substitution (Section 23.6). Hydroxide replaces sulfite ion (S03 ) at the carbon atom that bear s the leaving group. Thus, p-toluenesulfonic acid is converted exclusively to p-cresol by an analogous reaction ... 

Cyclohexadienyl anion (Section 23.6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism. It is represented by the general structure shown, where Y is the nucleophile and X is the leaving group. 

The addition-elimination mechanism involves two intermediates, a chlorophenyl anion and benzyne. A simple displacement mechanism can be ruled out because reaetion of ort/io-chlorotoluene gives not only ort/io-methylphenol but also meto-methylphenol. 

Heterocyclic compounds may show a higher tendency than carbocycles to react with nucleophiles according to the addition-elimination mechanism than via arynes. 

Further, if the addition-elimination mechanism is correct, then one should observe acetoxylation by nitric acid in acetic acid none has been reported. 

Nucleophilic substitution at a vinylic carbon is difficult (see p. 433), but many examples are known. The most common mechanisms are the tetrahedral mechanism and the closely related addition-elimination mechanism. Both of these mechanisms are impossible at a saturated substrate. The addition-elimination mechanism has... 

The steps are the same as in the addition-elimination mechanism, but in reverse order. Evidence for this sequence is as follows (1) The reaction does not proceed without ethoxide ion, and the rate is dependent on the concentration of this ion and not on that of ArS. (2) Under the same reaction conditions, chloroacetylene gave 83 and 80. (3) Compound 83, treated with ArS, gave no reaction but, when EtO was added, 80 was obtained. It is interesting that the elimination-addition mechanism has even been shown to occur in five- and six-membered cyclic systems, where triple bonds are greatly strained. Note that both the addition-elimination and elimination-addition sequences, as shown above, lead to overall retention of configuration, since in each case both addition and elimination are anti. 

Smith, M.B. Hrubiec, R.T. Tetrahedron, 1984, 40, 1457 Hrubiec, R.T. Smith, M.B. J. Org. Chem., 1984,49, 385 Hrubiec, R.T. Smith, M.B. Tetrahedron Lett., 1983,24, 5031. This mechanism has also been called the addition-elimination mechanism, but in this book we limit this term to the type of mechanism shown on page 428. 

The reaction has been applied to nonheterocyclic aromatic compounds Benzene, naphthalene, and phenanthrene have been alkylated with alkyllithium reagents, though the usual reaction with these reagents is 12-20, and Grignard reagents have been used to alkylate naphthalene. The addition-elimination mechanism apparently applies in these cases too. A protected form of benzaldehyde (protected as the benzyl imine) has been similarly alkylated at the ortho position with butyl-lithium. ... 

The addition-elimination mechanism has been used primarily for arylation of oxygen and nitrogen nucleophiles. There are not many successful examples of arylation of carbanions by this mechanism. A major limitation is the fact that aromatic nitro... 

For neutral nucleophiles (e.g. amines, alcohols, water) there is much evidence that the addition-elimination mechanism depicted in equation 1 fits very well most of the intermolecular and intramolecular nucleophilic displacements involving nitro-activated aromatic substrates1. 

The addition-elimination mechanism also provides a reasonable explanation for nucleophilic substitution reactions at sulfur that occur with retention of configuration. It is assumed that nucleophilic attack occurs at sulfur in an apical position opposite a substituent... 

The first mechanism appears to be the better basis for describing most of the results referred to by Cramer (56). It will, however, be noted that the addition-elimination mechanism requires that the metal catalyst be supplied as a metal hydride. Where the catalyst has not been supplied in this form, the reaction has usually been carried out in the presence of reagents known to convert transition metal compounds to hydrides (e.g. protonic acids, alcohols or hydrogen). These substances are known as co-catalysts and, where they have been used, induction periods have been encountered which are consistent with hydride formation as required in mechanism (a), but which would not be expected for (b). 

As well as the Bingel reaction and its modifications some more reactions that involve the addition-elimination mechanism have been discovered. 1,2-Methano-[60]fullerenes are obtainable in good yields by reaction with phosphorus- [44] or sulfur-ylides [45,46] or by fluorine-ion-mediated reaction with silylated nucleophiles [47]. The reaction with ylides requires stabilized sulfur or phosphorus ylides (Scheme 3.9). As well as representing a new route to l,2-methano[60]fullerenes, the synthesis of methanofullerenes with a formyl group at the bridgehead-carbon is possible. This formyl-group can be easily transformed into imines with various aromatic amines. 

With the above-mentioned variety of addition reactions based on the addition-elimination mechanism almost any functional group or molecule can be attached to CgQ. Some examples are acetylenes [43, 52], peptides [53], DNA-fragments [53], polymers [54], macrocycles [55, 56], porphyrins [56, 57], dendrimers [58-60] or ligands for complex formation [56], Cjq can be turned into hybrids that are biologically active, water soluble, amphiphilic or mixable with polymers [53-55, 58, 61-69],... 

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