Alkyl halides, nucleophilic displacement

The typical reaction of alkyl halides, we have seen (Sec. 14.5), is nucleophilic substitution. Halogen is displaced as halide ion by such bases as OH, OR, NH3, CN ", etc., to yield alcohols, ethers, amines, nitriles, etc. Even Friedel-Crafts alkylation is, from the standpoint of the alkyl halide, nucleophilic substitu tion by the basic aromatic ring. 

The situation is once more reversed on passing from an alkyl halide to an acyl halide. Nucleophilic displacements of halogen in the latter take... 

Phosphorus ylides are usually obtained from alkyl halides and triphenylphosphine in a two-step sequence. We recall that the nucleophilicity of third-row elements such as sulfur and phosphorus is greater than that of second-row elements because the atoms are more polarizable (Section 10.1). The phosphorus atom of triphenylphosphine is an effective nucleophile. Since it is also a weak base, a competing elimination does not occur, and bimolecular substitution of primary and secondary alkyl hahdes gives good yields. In the first step, the halide ion of the alkyl halide is displaced in an S 2 reaction to yield an alkyltriphenylphosphonium salt. 

As we have seen the nucleophile attacks the substrate m the rate determining step of the Sn2 mechanism it therefore follows that the rate of substitution may vary from nucleophile to nucleophile Just as some alkyl halides are more reactive than others some nucleophiles are more reactive than others Nucleophilic strength or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate By measuring the rate at which various Lewis bases react with methyl iodide m methanol a list of then nucleophihcities relative to methanol as the standard nucleophile has been compiled It is presented m Table 8 4... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Next an alkyl halide (the alkylating agent) is added to the solution of sodium acetylide Acetylide ion acts as a nucleophile displacing halide from carbon and forming a new carbon-carbon bond Substitution occurs by an 8 2 mechanism... 

Historically, simple Vz-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, and mild acid hydrolysis of acetal-type ethers) that seldom affect other functional groups in a molecule. 

The preparation of esters can be classified into two main categories (1) carboxy-late activation with a good leaving group and (2) nucleophilic displacement of a caiboxylate on an alkyl halide or sulfonate. The latter approach is generally not suitable for the preparation of esters if the halide or tosylate is sterically hindered, but there has been some success with simple secondaiy halides and tosylates (ROTs, DMF, K2CO3, 69-93% yield). ... 

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... 

FIGURE 8.11 When a Lewis base reacts with an alkyl halide, either substitution or elimination can occur. Substitution (Sn2) occurs when the Lewis base acts as a nucleophile and attacks carbon to displace bromide. Elimination (E2) occurs when the Lewis base abstracts a proton from the p carbon. The alkyl halide shown is isopropyl bromide, and elimination (E2) predominates over substitution with alkox-ide bases. 

Grignard reagents are rapidly hydrolysed by water or acid to give the parem hydrcxatbon, RH, but this reacdon is rarely of synthedc importance. Hydrocarbons can also be syndiesized by nucleophilic displacement of halide ion from a reacdve alkyl halide, e.g. 

Thiols are usually prepared from alkyl halides by Snj2 displacement with a sulfur nucleophile such as hydrosulfide anion, SH. 

The reaction often works poorly unless an excess of the nucleophile is used because the product thiol can undergo a second S 2 reaction with alkyl halide to give a sulfide as a by-product. To circumvent this problem, thiourea, (NH2J2C=S, is often used as the nucleophile in the preparation of a thiol from an alkyl halide. The reaction occurs by displacement of the halide ion to yield an intermediate alkyl isothiourea salt, which is hydrolyzed by subsequent reaction with aqueous base. 

Because they re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we ve already studied. For example, enolates react with primary alkyl halides in the SK2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C-C bond forms ... 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate, thereby forming a new C-C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack. 

A carboxylic acid (not the salt) can be the nucleophile if F is present. Mesylates are readily displaced, for example, by benzoic acid/CsF. Dihalides have been converted to diesters by this method. A COOH group can be conveniently protected by reaction of its ion with a phenacyl bromide (ArCOCH2Br). The resulting ester is easily cleaved when desired with zinc and acetic acid. Dialkyl carbonates can be prepared without phosgene (see 10-21) by phase-transfer catalyzed treatment of primary alkyl halides with dry KHCO3 and K2C03- ... 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

The usual sulfone synthesis by displacement of halide by sulfmate is assumed to have a nucleophilic 8 2 mechanism However, in special cases of alkyl halides with additional, electron-withdrawing substituents a radical substitution pathway has been observed (equation 32). Correspondingly, substitutions under formation of sulfones take... 

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. 

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