2.7. Reaction: Alpha- (α-) Halogenation
It is possible to add a halogen (X; X = Cl, Br, I) adjacent to a carbonyl using an enol nucleophile (Scheme 2.13). There are multiple ways of doing this, though the classical method is to use a dihalide and a strong acid as a catalyst. This is sometimes referred to as α-halogenation (alpha-halogenation).
Scheme 2.13 – Generalized Reaction Equation for Acid-Catalyzed Alpha-Halogenation.
This approach will not work with fluorine (F2). Other methods exist to add fluorine adjacent to a carbonyl but are generally more complicated and/or rely on special reagents.
The mechanism for this reaction follows the standard sequence for acid-catalyzed enol reactions (Scheme 2.14). The strong acid reacts with water to form hydronium (not shown). This is the active catalyst. First, the acid catalyzes the formation of the enol. Second, the electrophile (Br2) gets activated by the catalyst. This greatly increases its electrophilicity. Then the enol (nucleophile) attacks the halogen (electrophile). This creates a new C-Br bond and a strong acid (H-Br). Finally, water removes a proton, generating the final product and regenerating the catalyst.
Scheme 2.14 – Reaction Mechanism for Acid-Catalyzed Alpha-Halogenation of Acetone with Bromine.
If the two sides of the carbonyl are not identical (and both have a hydrogen adjacent to the carbonyl) regioselectivity is theoretically possible. In general, this reaction affords poor regioselectivity. A mixture of all possible regioisomers is typically obtained.
The carbons in alkenes are sp2 hybridized and trigonal planar. The p orbitals which make up the nucleophilic π bond are located both above and below the alkene. Assuming there are no pre-existing stereocentres in the starting material, the nucleophilic attack (enol attacks halogen) will not be stereoselective as attacking from the top of the alkene is sterically and electronically equivalent to attacking from the bottom of the alkene (Figure 2.11). If a new stereocentre is formed during this step, it will be formed as an equal mixture of both (R) and (S). This step is not stereoselective. This is true regardless of the E/Z configuration of the alkene.
Figure 2.11 – Comparison of Products from Nucleophilic Attacks from the Top and Bottom Sides of But-2-en-2-ol.
If another stereocentre (or multiple stereocentres) exists then the resulting products will be diastereomers. Because there is a steric and/or electronic difference between attacking the top or bottom in these cases, the two stereoisomers are NOT formed equally and the product is a non-one-to-one mixture of diastereomers. In these cases, it is important only to recognize that the product will be formed as a mixture of diastereomers. Predicting which diastereomer should be favoured is not required.
The same reaction can technically be performed using a strong base as a catalyst. However, this approach has a problem: after halogenation the alpha hydrogen(s) in the product are more acidic than those of the starting material (Figure 2.12).
Figure 2.12 – Comparison of Acidity of Alpha-Hydrogen of Reactant and Product from Alpha-Halogenation.
If a base catalyst is used the added acidity means that the product will also undergo alpha-halogenation. The reaction will occur repeatedly and replace all of the carbonyl-adjacent hydrogens with halogens (Scheme 2.15). This leads to other reactions also occurring, such as elimination, which severely lowers the yield of the desired product. As such base catalysis is not practical for alpha-halogenation.
Scheme 2.15 – Overhalogenation from Base-Catalyzed Alpha-Halogenation of Pentan-3-one.
