Question

At some point during the synthesis of a target molecule, it may be necessary to protect an -OH group (i.e., to prevent its reacting). In addition to the trimethylsilyl, tert-butyldimethylsilyl, and other trialkylsilyl groups described in Section 11.6, and the tetrahydropyranyl group described in Section 16.7D, the ethoxyethyl group may also be used as a protecting group. (a) Propose a mechanism for the acid-catalyzed formation of the ethoxyethyl protecting group. (b) Suggest an experimental procedure whereby this protecting group can be removed to regenerate the unprotected alcohol.

Short answer

Question: Propose a mechanism for the acid-catalyzed formation of the ethoxyethyl protecting group and suggest an experimental procedure to remove this protecting group and regenerate the unprotected alcohol. Answer: (a) The mechanism for the acid-catalyzed formation of the ethoxyethyl protecting group involves protonation of the alcohol, nucleophilic attack by ethylene glycol diethyl ether (EGDE), and deprotonation to form the final ethoxyethyl-protected alcohol compound. (b) To remove the ethoxyethyl protecting group and regenerate the unprotected alcohol, hydrolyze the protected alcohol using an acid catalyst in the presence of water, extract the regenerated alcohol, neutralize the aqueous layer, and isolate the alcohol using a suitable purification technique.

Step-by-step solution

(a) Mechanism for the acid-catalyzed formation of the ethoxyethyl protecting group

The acid-catalyzed formation of the ethoxyethyl protecting group can be achieved by reacting the alcohol with ethylene glycol diethyl ether (EGDE) in the presence of an acid catalyst. The mechanism involves the following steps: 1. Protonation of the alcohol: The acid catalyst (usually a strong acid, like H2SO4 or HCl) protonates the -OH group of the alcohol, forming a good leaving group. OH + H+ -> OH2+ 2. Nucleophilic attack: Ethylene glycol diethyl ether (EGDE), acting as a nucleophile, attacks the positively charged oxygen atom of the protonated alcohol, leading to formation of a new C-O bond. OH2+ + (EtO)2CH2CH2 -> (EtO)2CH2CH2-OH 3. Deprotonation: The ethoxyethyl-attached alcohol now deprotonates, forming the final ethoxyethyl-protected alcohol compound. (EtO)2CH2CH2OH -> (EtO)2CH2CH2O- -> (EtO)2CH2CH2O-R

(b) Experimental procedure to remove the ethoxyethyl protecting group

The removal of the ethoxyethyl protecting group can be achieved by hydrolysis using an acid catalyst in the presence of water. The procedure can be as follows: 1. Dissolve the ethoxyethyl-protected alcohol in a solvent, such as dichloromethane (DCM) or ethyl acetate (EtOAc). 2. Add an aqueous solution of a strong acid, such as HCl or H2SO4, to the reaction mixture. This acid will catalyze the hydrolysis of the ethoxyethyl group. 3. Stir the reaction mixture at room temperature for a few hours, allowing the hydrolysis reaction to proceed. 4. Separate the organic and aqueous layers by extraction, and collect the aqueous layer containing the regenerated alcohol. 5. Neutralize the aqueous layer by adding a weak base, such as sodium bicarbonate (NaHCO3) or sodium hydroxide (NaOH). This will form water-soluble salts, which can be removed by washing the aqueous layer with water. 6. Isolate the alcohol by evaporating the solvent from the aqueous layer, or by using a suitable purification technique, such as distillation or crystallization.