Lecture Notes hemistry 342-2008 Mukund P. Sibi eactions at the Alpha-arbon of arbonyl ompounds Enolates are nucleophilic and undergo reaction with electrophiles. For example, one can do halogenation under basic conditions. Even a weak base is sufficient for the reaction. As soon as the enolate is formed, it reacts immediately with the electrophile forming the product. It is not necessary to form the enolate completely. Na 2 2 + - carbon nucleophile It is difficult to control halogenation of ketones under basic conditions. The product halo compound is more reactive than the starting material. Thus one obtains products with multiple halogen atoms. The final product in this reaction is a carboxylic acid and a trihalomethane. The reaction is called the haloform reaction. ne can use chlorine, bromine and iodine as the halogen. The aloform eaction Na 2 2 + + omoform Enolate Alkylation: Formation of - bonds ne of the important modes of reactivity for the enolate is the formation of - bonds by alkylation. The enolate nucleophile can react with alkyl halides in an S N 2 reaction. ere the alkyl halides function as electrophiles. Enolate Alkylation + S N 2 + - Enolate Ion Alkylating Agent Since this is an S N 2 reaction, there are only a few alkylating agents that can be used. They need to be primary, allylic or benzylic. eactions with secondary halides are not
Lecture Notes hemistry 342-2008 Mukund P. Sibi efficient and tertiary halides do not undergo S N 2 substitution. Tosylates, iodides, bromides, and chlorides can be used as a leaving group. elative reactivity of alkylating agents Tosylate > I > > l allylic ~ benzylic > 3 > 2 - Malonic Ester Synthesis The hydrogens on alpha carbon of carbonyl compounds are only modestly acidic and require a strong base for complete deprotonation. n the other hand, the methylene groups of 1,3-dicarbonyl compounds have pka from 9-13 and they can be deprotonated readily using simple inorganic bases. Note from our previous discussion, methylenes flanked by two carbonyl groups are quite acidic because the negative charge is highly delocalized. Malonic esters, acetoacetic esters, and malononitriles can be used as the nucleophile. Malonic esters (pka = 13) can be alkylated readily using sodium alkoxide as a base. The monoalkylated malonic ester can be further alkylated with a second electrophile to provide dialkylated products. Monoalkylation of malonic esters 3 3 Dimethylmalonate Na 3 3 3 Na + 3 Sodio malonic ester 3 3 Alkylated malonic ester Dialkylation of malonic esters 3 3 Na 3 3 3 Na + 3 Sodio malonic ester 1 3 3 1 Dialkylated malonic ester The malonic esters can be hydrolyzed readily under aqueous acidic conditions. The esters are hydrolyzed to the corresponding acids. After this, the diacid undergoes decarboxylation to furnish a monoacid. 3 3 3 + + 2 + 2 3 3 1 3 3 + 1 1 + 2 + 2 3
Lecture Notes hemistry 342-2008 Mukund P. Sibi The decarboxylation occurs only with malonic and acetoacetic acids. These compounds are β-keto acids. The decarboxylation occurs through a cyclic mechanism. For decarboxylation to occur it is essential that there be a carbonyl group beta to the carboxylic acid. "! "! malonic acid!-keto acid 1 Decarboxylation of malonic esters 3 3 3 + Decarboxylation of!-keto esters 3 1 3 + 1-2 - 2 1 arboxylic acid 1 Ketone By applying the malonic ester reaction, one can convert an alkyl halide to a carboxylic acid. verall the process adds two extra carbon atoms to the alkyl halides. This reaction provides a convenient method for the preparation of carboxylic acids from alkyl halides. 2 3 2 3 + Na 3 3 1 carbon halide 2 3 3 2 3 3 + 3 2 3 carbon acid 2 3 3 2 3 + Na 3 2 3 3 2 3 3 + 3 2 2 3 2 3 + Na 3 2 3 2 3 3 + 2
Lecture Notes hemistry 342-2008 Mukund P. Sibi Acetoacetic Ester Synthesis Acetoacetic ester (a β-keto ester) undergoes alkylation similar to malonates. The alkylated product can be hydrolyzed to furnish a methyl ketone. Alkylation of Acetoacetic ester 3 3 Na 3-3 3 3 + 3!-Keto ester Methyl Ketone Similar to malonic esters, acetoacetic esters can also be dialkylated. The product β-keto esters can also be hydrolyzed under acidic conditions to produce methyl ketones. As noted before, alkylation of ketones requires a strong base and anhydrous conditions. In contrast, the acetoacetic ester method allows for a clever way of enhancing the acidity of alpha - bonds in ketones and the ability to alkylate under simple conditions. nce, the product is formed, simple hydrolysis gives the alkylated ketones. ne important characteristic of β-ketoester synthesis is its generality. Any β-keto ester with an alpha - bond can be used. ver all it is a three step process involving (1) enolate formation (2) alkylation and (3) hydrolysis and decarboxylation. Alkylation of Acetoacetic ester 3 3 Na 3 3 2 3 3 2 3 3 + 3 2 3 Na 3 3 + 3 3 Direct Alkylation of Ketones, Esters, and Nitriles As illustrated earlier, one can generate an enolate completely by the use of a strong nonnucleophilic base. For example, will deprotonate cyclohexanone readily. is a strong enough base that it can deprotonate the alpha - bonds of esters, lactones, and nitriles. The resulting enolates can be alkylated with alkylating agents. Aldehydes are too reactive and the enolate will react with the starting aldehyde very rapidly. The direct alkylation has some advantage over the acetoacetic ester reaction in that it takes only one
Lecture Notes hemistry 342-2008 Mukund P. Sibi step. ontrolling regiochemistry is an issue with ketones. In the cyclohexanone example the major product is the 2,6-disubstituted cyclohexanone. Ketone 3 I 3 TF 3 3 3 TF 3 3 Ester 3 TF 3 I 3 Lactone TF Nitrile N TF N I N