Primary alkyl halides synthesis

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... 

Preparation of ethers by the Williamson ether synthesis is most successful with methyl and 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... 

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... 

SOMMELET Aldehyde synthesis Aldehyde synthesis from primary alkyl halides with hexamethylene tetramine. 

An alkyne is a hydrocarbon that contains a carbon-carbon triple bond. Alkyne carbon atoms are sp-hybridized, and the triple bond consists of one sp-sp a bond and two p-p tt bonds. There are relatively few general methods of alkyne synthesis. Two good ones are the alkylation of an acetylide anion with a primary-alkyl halide and the twofold elimination of HX from a vicinal dihalide. 

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. 

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 ... 

Most often, the application of cyanohydrin acetonide couplings to a natural product synthesis calls for coupling with a primary alkyl halide. This has proven successful in every instance. However, on occasion, alkylations of more hindered epoxides or hindered alkyl halides are desirable. These reactions are less dependable. 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

Imidazolium salts that can be prepared by the first procedure, the alkylation of imidazole, are easy to obtain and often used for metal complex synthesis. Potassium imidazolide is reacted with the first equivalent of alkyl halide in toluene to give the 1-alkylimidazole. Subsequent alkylation in 3-position is achieved by addition of another equivalent of alkyl halide [Eq. (2)]. " A variant of this approach employs commercially available A-trimethylsilyl imidazole with 2 equiv of an alkyl chloride, under elimination of volatile MesSiCl. The drawback of these simple routes is the fact that only primary alkyl halides can be reacted in satisfactory yields because secondary and tertiary alkyl halides give substantial amounts of elimination by-products. 

A method by Gridnev and Mihaltseva allows the combination of both strategies (i) synthesis of the 1-alkylimidazole by a multicomponent reaction starting from glyoxal, formaldehyde, a primary amine and ammonium chloride, and (ii) subsequent alkylation by a primary alkyl halide to give the imidazolium salt [Eq. (4)]... 

Silver nitrite gives significantly higher yields of nitro compounds from primary alkyl halides, and consequently, the synthesis of Q, ty-dinitroalkanes from the reaction of o, )-dihaloalkanes with sodium nitrite is inferior to the same reaction with silver nitrite (Table 1.2). However, the use of a solvent system composed of DMSO and MEK is reported to considerably improve the yields of Q , y-dinitroalkane when using sodium nitrite. ... 

Cobalamin catalysed reduction of alkyl halides has found use in organic synthesis because, like square planar Ni(o), it allows formation of alkyl radicals in the bulk of the solution away from the electi ode surface. Alkyl radical addition to activated alkenes is achieved in high yields. In the cases of primary alkyl halides,... 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Primary nitro compounds RNO were oxidised to RCOOH (the Nef reaction, e.g. nitroethane to acetic acid, nitrohexane to hexanoic acid) by RuCl3/(Br03) /aq. M Naj(C03), activated primary alkyl halides RCl to RCOOH and secondary alkyl halides to ketones [213]. Corey used RuCl3/K3(S303)/aq. base pH 14 to oxidise a carbon-bearing nitro group to a carbonyl function as part of a total synthesis of antheridiogen (A, 2) [87]. 

Synthetic applications as well as mechanistic considerations were reviewed recently24. Extension of the methodology to the seven-membered ring resulted in the first asymmetric synthesis of chiral benzazepines by alkylation with primary alkyl halides (92-96% ee) in 57-82% yield25. 

Williamson ether synthesis preparation of ether The sodium or potassium alkoxides are strong bases and nucleophiles. Alkoxides (RO ) can react with primary alkyl halides to produce symmetrical or unsymmetrical ethers. This is known as Williamson ether synthesis. The reaction is limited to primary alkyl halides. Higher alkyl halides tend to react via elimination. For example, sodium ethoxide reacts with ethyl iodide to produce diethyl... 

In these alkylation reactions primary alkyl halides (the bromide for preference) should be used as the alkylating agents, since secondary and tertiary halides undergo extensive olefin-forming elimination reactions in the presence of the strongly basic acetylide ion. A typical synthesis is that of hex-l-yne (Expt 5.26). 

Ethers For the synthesis of ether, the Williamson ether synthesis is considered as the best method. It involves the SN2 reaction between a metal alkoxide and a primary alkyl halide or tosylate. The alkoxide needed for the reaction is obtained by treating an alcohol with a strong base like sodium hydride. An alternative procedure is to treat the alcohol directly with the alkyl halide in the presence of silver oxide, thus avoiding the need to prepare the alkoxide beforehand. 

For synthesis of an unsymmetrical ether, the most hindered alkoxide should be reacted with the simplest alkyl halide rather than the other way round (Following fig.). As this is an SN2 reaction, primary alkyl halides react better then secondary or tertiary alkyl halides. 

Nitriles can be prepared by the SN2 reaction of a cyanide ion with a primary alkyl halide. However, this limits the nitriles that can be synthesised to those having the following general formula RCH2CN. A more general synthesis of nitriles involves the dehydration of primary-amides with reagents such as thionyl chloride or phosphorus pentoxide ... 

The reaction of an acetylide ion with a primary alkyl halide allows the synthesis of di-substituted alkynes [Following fig.(a)]. 

When an alkoxide ion is used as the nucleophile, the reaction is called a Williamson ether synthesis. Because the basicity of an alkoxide ion is comparable to that of hydroxide ion, much of the discussion about the use of hydroxide as a nucleophile also applies here. Thus, alkoxide ions react by the SN2 mechanism and are subject to the usual Sn2 limitations. They give good yields with primary alkyl halides and sulfonate esters but are usually not used with secondary and tertiary substrates because elimination reactions predominate. 

Two different approaches are commonly used for the synthesis of alkynes. In the first, an appropriate electrophile undergoes nucleophilic attack by an acetylide ion. The electrophile may be an unhindered primary alkyl halide (undergoes Sn2), or it may be a carbonyl compound (undergoes addition to give an alcohol). Either reaction joins two fragments and gives a product with a lengthened carbon skeleton. This approach is used in many laboratory syntheses of alkynes. 

The alkoxide ion is a strong nucleophile as well as a powerful base. Unlike the alcohol itself, the alkoxide ion reacts with primary alkyl halides and tosylates to form ethers. This general reaction, called the Williamson ether synthesis, is an SN2 displacement. The alkyl halide (or tosylate) must be primary so that a back-side attack is not hindered. When the alkyl halide is not primary, elimination usually results. 

We have already seen most of the common methods for synthesizing ethers. We review them at this time, looking more closely at the mechanisms to see which methods are most suitable for preparing various kinds of ethers. The Williamson ether synthesis (Section 11-14) is the most reliable and versatile ether synthesis. This method involves the Sn2 attack of an alkoxide ion on an unhindered primary alkyl halide or tosylate. Secondary alkyl halides and tosylates are occasionally used in the Williamson synthesis, but elimination competes, and the yields are often poor. 

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