Halides, displacement reactions

The Williamson ether synthesis (Sec tion 16 6) An alkoxide ion displaces a halide or similar leaving group in an Sn2 reaction The alkyl halide cannot be one that is prone to elimination and so this reaction is limited to methyl and primary alkyl halides There is no limitation on the alkoxide ion that can be used... 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively." ... 

Various sources of fluoride ion have been investigated, of which highly nucleophilic tetraalkylammonium fluorides ate the most effective Thuf, fluoro alkyl halides and N (fluoroalkyl)amines are efficiently synthesized by treatment of the corresponding trifluoromethanesulfonic esters with tetrabutylammonium fluoride trihydrate in aprotic solvents [5fl] (equation 34) The displacement reactions proceed quantitatively at room temperature within seconds, but tail with hydrogen fluoride-pyridine and give reasonable yields only with hydrogen fluo ride-alkylamine reagents... 

Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) The a-halo acids obtained by halogenation of carboxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reactive substrates in nucleophilic substitution processes. A standard method for the preparation of a-amino acids is displacement of halide from a-halo acids by nucleophilic substitution using excess aqueous ammonia. 

In a similar vein, the amino group in sulfide 14 (obtained presumably by an aromatic displacement reaction) is first converted to the bromide by Sandmeyer reaction to give 25. Reduction of the nitro group (16) followed by cyclization gives the substituted phenothiazine. Alkylation with the familiar halide (3) affords dimethothiazine (18). ... 

Substitution of an additional nitrogen atom onto the three-carbon side chain also serves to suppress tranquilizing activity at the expense of antispasmodic activity. Reaction of phenothia zine with epichlorohydrin by means of sodium hydride gives the epoxide 121. It should be noted that, even if initial attack in this reaction is on the epoxide, the alkoxide ion that would result from this nucleophilic addition can readily displace the adjacent chlorine to give the observed product. Opening of the oxirane with dimethylamine proceeds at the terminal position to afford the amino alcohol, 122. The amino alcohol is then converted to the halide (123). A displacement reaction with dimethylamine gives aminopromazine (124). ... 

Another entry into the anti ulcer sweepstakes is etinfidine (50). It is synthesized by displacement of halide from 4-chloromethyl-5-methylimidazole (4 ) with substituted thiol The latter is itself made from thiourea analogue by an addition-elimination reaction with cysteamine 52. °... 

Nucleophilic displacement reactions One of the most common reactions in organic synthesis is the nucleophilic displacement reaction. The first attempt at a nucleophilic substitution reaction in a molten salt was carried out by Ford and co-workers [47, 48, 49]. FFere, the rates of reaction between halide ion (in the form of its tri-ethylammonium salt) and methyl tosylate in the molten salt triethylhexylammoni-um triethylhexylborate were studied (Scheme 5.1-20) and compared with similar reactions in dimethylformamide (DMF) and methanol. The reaction rates in the molten salt appeared to be intermediate in rate between methanol and DMF (a dipolar aprotic solvent loiown to accelerate Sn2 substitution reactions). 

An extensive study (6) of Sn displacement reactions of allyl halides using silyl anions/anionoids has provided the following regioselective alternatives ... 

Pyridones can also be converted to 2-chloropyridines by exchanging the carbonyl functionality using phosphoroxychloride (POCI3) [72]. A combination of N-halosuccinimides and triphenylphosphine has also been applied to introduce halogens in this position [73]. The carbonyl functionality in 2-pyridones makes these systems reactive towards nucleophiles as well, which add in 1,4-reactions with displacement of halides [74]. The use of transition metal mediated couplings like Heck, and Suzuki have also been successfully applied on halogenated 2-pyridones (d. Scheme 10) [36,75]. 

Sulphoxides can be used as phase transfer catalysts, for example, a-phosphoryl sulphoxides (Scheme 24) have been used as phase transfer catalysts in the two-phase alkylation of phenylacetonitrile or phenylacetone with alkyl halides and aqueous sodium hydroxide. However, they are considered to be inefficient catalysts for simple displacement reactions. ... 

Extractive alkylation is used to derivatize acids, phenols, alcohols or amides in aqueous solution [435,441,448,502]. The pH of the aqueous phase is adjusted to ensure complete ionization of the acidic substance which is then extracted as an ion pair with a tetraalkylammonium hydroxide into a suitable immiscible organic solvent. In the poorly solvating organic medium, the substrate anion possesses high reactivity and the nucleophilic displacement reaction with an alkyl halide occurs under favorable conditions. 

Sn2 and SN2 Reactions with Halides and Sulfonates. Corey and Posner discovered that lithium dimethylcuprate can replace iodine or bromine by methyl in a wide variety of compounds, including aryl, alkenyl, and alkyl derivatives. This halogen displacement reaction is more general and gives higher yields than displacements with... 

Direct nucleophilic displacement of halide and sulfonate groups from aromatic rings is difficult, although the reaction can be useful in specific cases. These reactions can occur by either addition-elimination (Section 11.2.2) or elimination-addition (Section 11.2.3). Recently, there has been rapid development of metal ion catalysis, and old methods involving copper salts have been greatly improved. Palladium catalysts for nucleophilic substitutions have been developed and have led to better procedures. These reactions are discussed in Section 11.3. 

Besides addition reactions, azides or hydrazoic acid can also yield tetrazoles through displacement reactions. Thus, halide displacement in imide chloride (78) yields 1,5-disubstituted tetrazoles (79), and in 2-chloro-pyridine (80), yields tetrazolopyridine (81) (Eq. 16a,b).141 143 Vinylogous... 

Route A 1- is very convenient for the substitution of OH groups by bromide or iodide. The reaction conditions are relatively mild (acetonitrile, room temperature, and reflux for 1—3 h, neutral medium). The activating halide (methyl iodide, ally or benzyl bromide) is added in excess (5 equivalents) or in large excess (10 equivalents) when the resultant halide is nearly as reactive as the activating halide. The imidazolium-iV-carboxylates are the important intermediates, which undergo a displacement reaction to give the halides,... 

A type of reaction that has probably received more detailed study than any other—largely due to the monumental work of Ingold and his school—is nucleophilic substitution at a saturated carbon atom the classical displacement reaction exemplified by the conversion of an alkyl halide into an alcohol by the action of aqueous base ... 

Reference has already been made in the last chapter to the generation of carbocations, in ion pairs, as intermediates in some displacement reactions at a saturated carbon atom, e.g. the solvolysis of an alkyl halide via the SN1 mechanism. Carbocations are, however, fairly widespread in occurrence and, although their existence is often only transient, they are of considerable importance in a wide variety of chemical reactions. 

Probably the most common aromatic nucleophilic displacement reactions involve the displacement of Hal from a halide activated by electron-withdrawing groups, e.g. (80) ... 

Construction of isolated or benzannulated five-membered rings of NHPs can be accomplished by means of various condensation or cycloaddition reactions all of which involve interaction of an electrophilic Pj and a nucleophilic C2N2 building block. Salts containing 1,3,2-diazaphospholide anions or 1,3,2-diazaphospholenium cations can be directly accessed by some of these reactions but the products are in most cases neutral 1,3,2-diazaphospholes or NHP. A particularly concerted effort has been directed toward the synthesis of P-halogen-substituted NHP which are capable of undergoing further reactions via halide displacement or halide abstraction and serve thus as entry points for the preparation of a wide variety of neutral and cationic NHP derivatives. 1,3,2-Diazaphospholide anions are normally accessed by deprotonation of suitable iV-H-substituted precursors. 

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