Alkyl halides with acetylide anions

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. 

Finally, acetylide anions have been alkylated with propargyl halides to give excellent yields of dialkynes643,644. Similar reactions have been used in the synthesis of a wide variety of natural products including lactones and macrolides645,646 and leukotrienes647-651. With many halides, reaction with acetylide anions is not useful however, due to elimination side-reactions caused by the significant basicity of the carbanion. 

Although nucleophilic substitution with acetylide anions is a very valuable carbon-carbon bondforming reaction, it has the same limitations as any Sn2 reaction. Steric hindrance around the leaving group causes 2° and 3° alkyl halides to undergo elimination by an E2 mechanism, as shown with 2-bromo-2-methylpropane. Thus, nucleophilic substitution with acetylide anions forms new carbon-carbon bonds in high yield only with unhindered CH3X and 1 ° alkyl halides. 

Step [3] B is prepared from acetylene and two 1 alkyl halides (C and D) by using Sn2 reactions with acetylide anions. 

A Sn2 reaction of an alkyl halide with an acetylide anion, C=CR 11.11B Opening of an epoxide ring with an acetylide anion, C=CR... 

Because an alkyl group is added to the original alkyne molecule, this type of reaction is called an alkylation reaction. We limit our discussion in this chapter to reactions of acetylide anions with methyl and primary haloalkanes. We will discuss the scope and limitation of this type of nucleophilic substitution in more detail in Chapter 7. For reasons we will discuss there, alkylation of nucleophilic acetylide anions is practical only for methyl and primary halides. While this alkylation reaction can be used with limited success with secondary haloalkanes, it fails altogether for tertiary haloalkanes. 

Sn2 reaction of an alkyl halide with an acetylide anion, X=CR... 

The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes. 

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... 

The negative charge and unshared electron pair on carbon make an acetylide anion strongly nucleophilic. As a result, an acetylide anion can react with an alkyl halide such as bromomethane to substitute for the halogen and yield a new alkyne product. 

The alkylation reaction is limited to the use of primary alkyl bromides and alkyl iodides because acetylide ions are sufficiently strong bases to cause dehydrohalogenation instead of substitution when they react with secondary and tertiary alkyl halides. For example, reaction of bromocyclohexane with propyne anion yields the elimination product cyclohexene rather than the substitution product 1-propynylcyclohexane. 

A wide array of substances can be prepared using nucleophilic substitution reactions. In fact, we ve already seen examples in previous chapters. The reaction of an acetylide anion with an alkyl halide (Section 8.8), for instance, is an Sn2 reaction in which the acetylide nucleophile replaces halide. 

Here too, a second alkylation can be made to take place yielding RC=CR or R C=CR. It should, however, be remembered that the above carbanions—particularly the acetylide anion (57)—are the anions of very weak acids, and are thus themselves strong bases, as well as powerful nucleophiles. They can thus induce elimination (p. 260) as well as displacement, and reaction with tertiary halides is often found to result in alkene formation to the exclusion of alkylation. 

Under the same conditions simple etiolates react vigorously with alkyl halides (which must be primary) to give mono- and polyalkylated products. The reactivity of the simple enolate is greater and cannot be controlled at room temperature. However, if the alkylation is carried out at low temperature, the reaction can be controlled and smooth monoalkylation of simple enolates can be achieved. The same is true for the alkylation of acetylide anions, which must be carried out at low temperature for successful alkylation. 

Terminal alkynes are weakly acidic. The alkyne hydrogen can he removed by s strong base 9uch ae Na NH.. to yield nn a<%tylide anipn An acetylide anion ads as a nucleophile and can displace a halide ion from a primary alkyl halide in a n alkylation reaction. Acetylide anions are more stable iJian either alkyl anions or vinylic anions because their m ative charge is in a hybrid orbital with 50% s character, allowing the charge to be doser to the nucleus. 

Terminal alkynes are readily converted to acetylide anions with strong base. These anions are strong nucleophiles, capable of reacting with electrophiles such as alkyl halides and epoxides. 

A Reaction of Acetylide Anions with Alkyl Halides... 

Acetylide anions react with unhindered alkyl halides to yield products of nucleophilic substitution. 

Because acetylide anions are strong nucleophiles, the mechanism of nucleophilic substitution is S 2, and thus the reaction is fastest with CH3X and 1° alkyl halides. Terminal alkynes (Reaction [1]) or internal alkynes (Reaction [2]) can be prepared depending on the identity of the acetylide anion. 

In each step, the base NHg removes an sp hybridized proton, and the resulting acetylide anion reacts as a nucleophile with an alkyl halide to yield an Sn2 product. The first two-step reaction sequence forms the terminal alkyne A by nucleophilic attack of the acetylide anion on CHaBr. 

Three steps are needed to complete the synthesis. Treatment of HC CH with NaH forms the acetylide anion, which undergoes an Sn2 reaction with an alkyl halide to form a four-carbon terminal alkyne. Hydration of the alkyne with HgO, H2SO4, and HgS04 yields the target compound. 

---