Nucleophilic addition – charged nucleophiles

NUCLEOPHILIC ADDITION – CHARGED NUCLEOPHILES

Key Notes

Carbanion addition

Grignard reagents (RMgX) and organolithium reagents (RLi) are used as the source of carbanions. The reaction mechanism involves nucleophilic addi- tion of the carbanion to the aldehyde or ketone to form a negatively charged intermediate. Addition of acid completes the reaction. Both reactions are important because they involve C–C bond formation allowing the synthesis of complex molecules from simple starting materials. Primary alcohols are obtained  from  formaldehyde,  secondary  alcohols  from  aldehydes  and tertiary alcohols from ketones.

Hydride addition

Lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4) are reducing agents and the overall reaction corresponds to the nucleophilic addition of a hydride ion (H: –). The reaction is a functional group transfor- mation where primary alcohols are obtained from aldehydes and secondary alcohols are obtained from ketones.

Cyanide addition

Reaction of aldehydes and ketones with HCN and KCN produce cyano- hydrins. The cyanide ion is the nucleophile and adds to the electrophilic carbonyl carbon.

Bisulfite addition

The bisulfite ion is a weakly nucleophilic anion which will only react with aldehydes and methyl ketones. The product is a water-soluble salt and so the reaction can be used to separate aldehydes and methyl ketones from larger ketones or from other water-insoluble compounds. The aldehyde and methyl ketone can be recovered by treating the salt with acid or base.

Aldol reaction

The Aldol reaction involves the nucleophilic addition of enolate ions to aldehydes and ketones to form β-hydroxycarbonyl compounds.

Carbanion addition

Carbanions are extremely reactive species and do not occur in isolation. However, there are two reagents which can supply the equivalent of a carbanion. These are Grignard reagents and organolithium reagents. We shall look first of all at the reaction of a Grignard reagent with aldehydes and ketones (Fig. 1).

The  Grignard  reagent  in  this  reaction  is  called  methyl  magnesium  iodide (CH3MgI) and is the source of a methyl carbanion. 

In reality, the methyl carbanion is never present as a separate ion, but the reaction proceeds as if it were. The methyl carbanion is the nucleophile in this reaction and the nucleophilic center is the negatively charged carbon atom. The aldehyde is the electrophile. Its electrophilic center is the carbonyl carbon atom since it is electron deficient.

The carbanion uses its lone pair of electrons to form a bond to the electrophilic carbonyl carbon (Fig. 3). At the same time, the relatively weak π bond of the car-bonyl group breaks and both electrons move to the oxygen to give it a third lone pair of electrons and a negative charge (Step 1). The reaction stops at this stage, since the negatively charged oxygen is complexed with magnesium which acts as a counterion (not shown). Aqueous acid is now added to provide an electrophile in the shape of a proton. The intermediate is negatively charged and can act as a nucleophile/base. A lone pair of electrons on the negatively charged oxygen is used to form a bond to the proton and the final product is obtained (Step 2).

The reaction of aldehydes and ketones with Grignard reagents is a useful method of synthesizing primary, secondary, and tertiary alcohols (Fig. 4). Primary alcohols can be obtained from formaldehyde, secondary alcohols can be obtained from aldehydes, and tertiary alcohols can be obtained from ketones. The reaction involves the formation of a carbon–carbon bond and so this is an important way of building up complex organic structures from simple starting materials.

The Grignard reagent itself is synthesized from an alkyl halide and a large variety of reagents are possible.

Organolithium reagents such as CH₃Li can also be used to provide the nucleophilic carbanion and the reaction mechanism is exactly the same as that described for the Grignard reaction (Fig. 5).

Hydride addition

Reducing agents such as sodium borohydride (NaBH₄) and lithium aluminum hydride (LiAlH₄) react with aldehydes and ketones as if they are providing a hydride ion (:H^–; Fig. 6). This species is not present as such and the reaction mechanism is more complex. However, we can explain the reaction by viewing these reagents as hydride equivalents (:H^–). The overall reaction is an example of a functional group transformation since the carbon skeleton is unaffected. Aldehydes are converted to primary alcohols and ketones are converted to secondary alcohols.

The mechanism of the reaction is the same as that described above for the Grignard reaction (Fig. 7). The hydride ion equivalent adds to the carbonyl group and a negatively charged intermediate is obtained which is complexed as a lithium salt (Step 1). Subsequent treatment with acid gives the final product (Step 2). It should be emphasized again that the mechanism is actually more complex than this because the hydride ion is too reactive to exist in isolation.

Cyanide addition

Nucleophilic addition of a cyanide ion to an aldehyde or ketone gives a cyanohydrin (Fig. 8). In the reaction, there is a catalytic amount of potassiumcyanide present and this supplies the attacking nucleophile in the form of the cyanide ion (CN^–). The nucleophilic center of the nitrile group is the carbon atom since this is the atom with the negative charge. The carbon atom uses its lone pair of electrons to form a new bond to the electrophilic carbon of the carbonyl group (Fig. 9). As this new bond forms, the relatively weak Ï€ bond of the carbonyl group breaks and the two electrons making up that bond move onto the oxygen to give it a third lone pair of electrons and a negative charge (Step 1). The intermediate formed can now act as a nucleophile/base since it is negatively charged and it reacts with the acidic hydrogen of HCN. A lone pair of electrons from oxygen is used to form a bond to the acidic proton and the H–CN σ bond is broken at the same time such that these electrons move onto the neighboring carbon to give it a lone pair of electrons and a negative charge (Step 2). The products are the cyanohydrin and the cyanide ion. Note that a cyanide ion started the reaction and a cyanide ion is regenerated. Therefore, only a catalytic amount of cyanide ion is required to start the reaction and once the reaction has taken place, a cyanide ion is regenerated to continue the reaction with another molecule of ketone.

Cyanohydrins are useful in synthesis because the cyanide group can be converted to an amine or to a carboxylic acid.

Bisulfite addition

The reaction of an aldehyde or a methyl ketone with sodium bisulfite (NaHSO₃) involves nucleophilic addition of a bisulfite ion (^–:SO₃H) to the carbonyl group to give a water soluble salt (Fig. 11). The bisulfite ion is a relatively weak nucleophile compared to other charged nucleophiles and so only the most reactive carbonyl compounds will react. Larger ketones do not react since larger alkyl groups hinder attack. The reaction is also reversible and so it is a useful method of separating aldehydes and methyl ketones from other ketones or from other organic molecules. This is usually done during an experimental work up where the products of the reaction are dissolved in a water immiscible organic solvent. Aqueous sodium bisulfite is then added and the mixture is shaken thoroughly in a separating funnel. Once the layers have separated, any aldehydes and methyl ketones will have undergone nucleophilic addition with the bisulfite solution and will be dissolved in the aqueous layer as the water soluble salt. The layers can now be separated. If the aldehyde or methyl ketone is desired, it can be recovered by adding acid or base to the aqueous layer which reverses the reaction and regenerates the carbonyl compound.

Aldol reaction

Another nucleophilic addition involving a charged nucleophile is the Aldol reaction. This involves the nucleophilic addition of enolate ions to aldehydes and ketones to form β-hydroxycarbonyl compounds (Fig. 12).