Aryl halides electrophilic substitution

The two mam methods for the preparation of aryl halides halogenation of arenes by electrophilic aromatic substitution and preparation by way of aryl diazomum salts were described earlier and are reviewed m Table 23 2 A number of aryl halides occur natu rally some of which are shown m Figure 23 1... 

As we ve seen, aromatic substitution reactions usually occur by an electrophilic mechanism. Aryl halides that have electron-withdrawing substituents, however, can also undergo nucleophilic aromatic substitution. For example. 2,4,6-trinitrochlorobenzene reacts with aqueous NaOH at room temperature to give 2,4,6-trinitrophenol. The nucleophile OH- has substituted for Cl-. 

A second group of aromatic substitution reactions involves aryl diazonium ions. As for electrophilic aromatic substitution, many of the reactions of aromatic diazonium ions date to the nineteenth century. There have continued to be methodological developments for substitution reactions of diazonium intermediates. These reactions provide routes to aryl halides, cyanides, and azides, phenols, and in some cases to alkenyl derivatives. 

The rhodium-catalyzed arylation of phenols with aryl halides occurs in the presence of phosphinites [PR2(OAr)] as a co-catalyst (Equation (59)).66 The phosphorus atom coordinates to the rhodium atom to facilitate the electrophilic substitution with the rhodium(m) species at the ortho-pos i on. 

Like simple aryl halides, furyl halides take part in Suzuki couplings as electrophiles [41, 42]. Young and Martin coupled 2-bromofuran with 5-indolylboronic acid to prepare 5-substituted indole 37 [43]. Terashima s group cross-coupled 3-bromofuran with diethyl-(4-isoquinolyl)borane 38 to make 4-substituted isoquinoline 39 [44]. Similarly, 2- and 3-substituted isoquinolines were also synthesized in the same fashion [45]. 

To be really satisfactory, a Friedel-Crafts alkylation requires one relatively stable secondary or tertiary carbocation to be formed from the alkyl halide by interaction with the Lewis acid, i.e. cases where there is not going to be any chance of rearrangement. Note also that we are unable to generate carboca-tions from an aryl halide - aryl cations (also vinyl cations, see Section 8.1.3) are unfavourable - so that we cannot nse the Friedel-Crafts reaction to join aromatic gronps. There is also one further difficulty, as we shall see below. This is the fact that introduction of an alkyl substitnent on to an aromatic ring activates the ring towards fnrther electrophilic substitution. The result is that the initial product from Friedel-Crafts alkylations is more reactive than the... 

Reissert compounds (cf Section 3.2.1.6.8.iv) can be deprotonated (NaH/HCONMe2) to give anions (e.g. 507) which react with electrophiles to give intermediates (508) which can be hydrolyzed to substituted heterocycles (509). Electrophiles utilized include alkyl and reactive aryl halides and carbonyl compounds. 

Secondary and tertiary dialkylcuprates, lithium dialkenyl-, and even diphenyl-cuprates, add in very good yields to the reactive propionaldehyde diethyl acetal. The syn addition products may be trapped with a variety of electrophiles such as alkyl, alkenyl, alkynyl and aryl halides. The method has been used for the synthesis of several natural products. Substituted alkynic acetals also react with lithium dialkylcuprates in ether to furnish stable dialkenylcuprates of type (128) which do not eliminate to the corresponding alkoxy allenes (129) if the temperature is maintained below -20 C.164-179... 

Primary alkyl, secondary alkyl, and aryl groups all migrate readily, and migration occurs with retention of configuration. The reaction is thus more versatile than the deprotonation/alkylation approach to substituted alkynes, which is generally only efficient for primary electrophiles and does not proceed at all for aryl halides. For example, triphenylborane may be used to incorporate a phenyl group into an alkyne (Equation B4.6). 

In 2001, Oi et al. [54] reported on the ruthenium(II) phosphine catalyzed re-gioselective arylation of 2-arylpyridines using aryl halides (Eq. 29). C-C bond formation occurs predominantly at the position ortho to the pyridyl group. The same catalyst system is also effective for the arylation of aromatic imines (Eq. 30) [55]. Although the reaction mechanism has not been elucidated, it was proposed that a tetravalent arylruthenium complex,for example,Ru(Ph)(Br)(Cl)2(I) ,reacts electrophilically with the arylimines. Therefore, C-H bond cleavage is believed to proceed via an electrophilic substitution pathway. 

Electrophilic Substitution Reactions in Aryl Grignard and Aryllithium Compounds That Are Accessible from Aryl Halides... 

Nucleophilic aromatic substitution is much more restrictive in its applications than electrophilic aromatic substitution. In nucleophilic aromatic substitution, a strong nucleophile replaces a leaving group such as a halide. The mechanism cannot be the Sn2 mechanism because aryl halides cannot achieve the correct geometry for backside displacement. The aromatic ring blocks approach of the nucleophile to the back of the carbon bearing the halogen. 

The facility of arene reductive elimination underpins numerous C-C, C-O and C-N bond-forming reactions, which may be catalysed by late transition metals, in particular palladium (Figure 4.10). Although there are many variants, the general reaction scheme involves introduction of the aryl in electrophilic form via oxidative addition of an aryl halide (or sulfonate), substitution of the palladium halide by a nucleophile (which may also be carbon based) followed by reductive elimination. It is noteworthy that nucleophilic aromatic substitution in the absence of such catalysts can be difficult. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

---