Primary alkyl halides reactions

Hydroalumination of alkenes. Hydroalumination of alkynes is a well-known reaction, but hydroalumination of alkenes has been achieved only recently under catalysis by TiCU or ZrCU, (8, 288). As expected hydroalumination affords a convenient, high-yield route to primary alkanes (by hydrolysis), terminal primary alcohols (by oxygenation), and primary alkyl halides (reaction with halogens, N-halosuccinimides, or CuXa). ... 

Anions of acetylene and terminal alkynes are nucleophilic and react with methyl and primary alkyl halides to form carbon-carbon bonds by nucleophilic substitution Some useful applications of this reaction will be discussed m the following section... 

The major limitation to this reaction is that synthetically acceptable yields are obtained only with methyl halides and primary alkyl halides Acetylide anions are very basic much more basic than hydroxide for example and react with secondary and ter tiary alkyl halides by elimination... 

These compounds are sources of the nucleophilic anion RC=C and their reaction with primary alkyl halides provides an effective synthesis of alkynes (Section 9 6) The nucleophilicity of acetylide anions is also evident m their reactions with aldehydes and ketones which are entirely analogous to those of Grignard and organolithium reagents... 

Lithium diarylcuprates are prepared m the same way as lithium dialkylcuprates and undergo comparable reactions with primary alkyl halides... 

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... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Because fhe new carbon-carbon bond is formed by an 8 2 lype reaction fhe alkyl halide musl nol be slerically hindered Melhyl and primary alkyl halides work besl secondary alkyl halides give lower yields Tertiary alkyl halides fail reacting only by elimination nol subslilulion... 

Weak acid (Section 1 16) An acid that is weaker than 1130" Weak base (Section 1 16) A base that is weaker than HO Williamson ether synthesis (Section 16 6) Method for the preparation of ethers involving an Sfj2 reaction between an alkoxide ion and a primary alkyl halide... 

Table 7. Reactions of Primary Alkyl Halides with Potassium Fluoride and Hexadecyltributylphosphom um Bromide [6S]...

As a practical matter, elimination can always be made to occur quantitatively. Strong bases, especially bulky ones such as terr-butoxide ion, react even with primary alkyl halides by an E2 process at elevated temperatures. The more difficult task is to find conditions that promote substitution. In general, the best approach is to choose conditions that favor the Sn2 mechanism—an unhindered substrate, a good nucleophile that is not strongly basic, and the lowest practical temperature consistent with reasonable reaction rates. 

The alkyl halide must be one that reacts readily by an Sn2 mechanism. Thus, methyl and primary alkyl halides are the most effective alkylating agents. Elimination competes with substitution when secondary alkyl halides are used and is the only reaction observed with tertiary alkyl halides. 

It is a reaction of wide scope both the phosphite 1 and the alkyl halide 2 can be varied. Most often used are primary alkyl halides iodides react better than chlorides or bromides. With secondary alkyl halides side reactions such as elimination of HX can be observed. Aryl halides are unreactive. 

With primary alkyl halides 1 the Finkelstein reaction proceeds by a Sn2-mechanism. An alkali halide is used to deliver the nucleophilic halide anion ... 

The reaction works well with primary alkyl halides, especially with allylic and benzylic halides, as well as other alkyl derivatives with good leaving groups. Secondary alkyl halides give poor yields. Tertiary alkyl halides react under the usual reaction conditions by elimination of HX only. Nitriles from tertiary alkyl halides can however be obtained by reaction with trimethylsilyl cyanide 4 ... 

This variant gives good to very good yields, and it is chemoselective the primary alkyl halide function in 3 is left unaffected under these reaction conditions. 

Yet a final limitation to the Friedel-Crafts reaction is that a skeletal rearrangement of the alkyl carbocation electrophile sometimes occurs during reaction, particularly when a primary alkyl halide is used. Treatment of benzene with 1-chlorobutane at 0 °C, for instance, gives an approximately 2 1 ratio of rearranged (sec-butyl) to unrearranged (butyl) products. 

Ethers can be prepared by reaction of an alkoxide or phenoxide ion with a primary alkyl halide. Anisole, for instance, results from reaction of sodium phenoxide with iodomethane. What kind of reaction is occurring Show the mechanism. 

The most generally useful method of preparing ethers is by the Williamson ether synthesis, in which analkoxido ion reacts with a primary alkyl halide or tosylate in an S 2 reaction. As we saw earlier in Section 17.2, thealkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH. 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

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 ... 

An aldehyde or ketone reacts with a phosphorus ylide to yield an alkene in which the oxygen atom of the carbonyl reactant is replaced by the =0 2 of the ylide. Preparation of the phosphorus ylide itself usually involves reaction of a primary alkyl halide with triphenylphosphine, so the ylide is typically primary, RCH = P Ph)3-This means that the disubstituted alkene carbon in the product comes from the carbonyl reactant, while the monosubstituted alkene carbon comes from the ylicle. 

Perhaps the most useful reaction of carboxylic acids is their conversion into esters. There are many methods for accomplishing the transformation, including the S -2 reaction of a carboxylate anion with a primary alkyl halide that we saw in Section 11.3. 

Esters are usually prepared from carboxylic acids by the methods already discussed. Thus, carboxylic acids are converted directly into esters by SK2 reaction of a carboxyfate ion with a primary alkyl halide or by Fischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters by treatment with an alcohol in the presence of base (Section 21.4). 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

The procedure described here illustrates the preparation of mixed lithium arylhetero(alkyl)cuprate reagents and their reactions with carboxylic acid chlorides,4 These mixed cuprate reagents also react with a,a -dibromoketones,12 primary alkyl halides,4 and a,/3-unsaturated ketones,4 with selective transfer of only the alkyl group. 

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- ... 

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (10-43), but the cyanate ion practically always gives exclusive N-alkylation. ° Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide (NaNCNN02) and m-chloroperoxybenzoic acid, followed by heating of the initially produced RN(N02)CN. ° When alkyl halides are treated with NCO in the presence of ethanol, carbamates can be prepared directly (see 16-7). ° Acyl halides give the corresponding acyl isocyanates and isothiocyanates. For the formation of isocyanides, see 10-111. 

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