Protective group chemistry

The need of protective groups arises from the low chemoselectivity of many reagents used in synthetic organic chemistry The main problem is that the use of protective groups usually adds two (or more) steps to the reaction sequence This generates additional waste  It also decreases atom economy (=atoms used that are part of the final product versus atoms used in the reaction sequence)  Therefore the need for new reagent arises that only target one specific functional group

When performing Grignard reactions, many functional groups react with the Grignard reagent due to various reasons: Some functional groups protonate the Grignard reagent because they possess hydrogen atoms that are acidic: -OH (pK a ~16-18 (alcohol), pK a ~8-12 (phenols)), -NH x (pK a ~35), -C≡CH (pK a ~25), -SH (pK a ~9-12), -COOH (pK a ~3-5) Some functional groups react with the reagent because they contain electrophilic atoms: -CHO, -COR, -CONR 2, -COOR, -C≡N, -NO 2, -SO 2 R, epoxides (ring opening) If more than one of these functional groups is present in the molecule, the groups that are not suppose to react will have to be protected temporarily because some of these reactions are irreversible (i.e., C-C bond formation)

Example 1: Reaction of a ketone in the presence of a phenol group Pathway 1 Step 1: Acid-base reaction Step 2: Nucleophilic attack Step 3: Acidic workup Pathway 2 Step 1: Protection of OH-group Step 2: Nucleophilic attack Step 3: Acidic workup In both reactions, the same final product is obtained but the first pathway requires two equivalents of the Grignard reagent due to the initial acid-base reaction -PhH

Example 2: Reaction of a ketone in the presence of an aldehyde function The problem in this reaction is that aldehydes are generally more reactive than ketones which means that both groups would react with the Grignard reagent, albeit with different rates The higher reactivity of the aldehyde is exploited in the formation of the cyclic acetal using 1,3-propanediol The acetal does not react with the Grignard reagent After the Grignard reaction is performed, the protective group is removed during the acidic workup which restores the aldehyde function

Sodium borohydride (NaBH 4 ) is less reactive and more chemoselective than lithium aluminum hydride (LiAlH 4 ) NaBH 4 will only reduce ketones and aldehydes and tolerates the presence of esters, amides, C≡C, nitro, sulfone, R-X, etc. LiAlH 4 will reduce all carbonyl functions and a broad variety of other functional groups as well 

Example 3: Reduction of an ester in the presence of a ketone/aldehyde The ketone function has to be protected using ethylene glycol to form a cyclic ketal before the reduction of the ester function is performed The protective group is removed during the acidic workup, which restores the ketone function

If the two amino acids, glycine (Gly) and alanine (Ala), were reacted, four dipeptides (aside of polypetides) would be possible: Gly-Gly, Gly-Ala, Ala-Gly and Ala-Ala  In order to obtain one specific dipeptide i.e., Gly-Ala only, several protective groups have to be used during the dipeptide formation The amino group in glycine is protected using the Boc-group The carboxylic acid group of alanine is protected by a benzyl group (benzyl ester)

The protected forms of the amino acids are then reacted to form one specific dipeptide DCC is used to activate the carboxylic acid The treatment of the initial product with Acid removes the BOC group (CO 2, tert.-BuOH) Pd-C/H 2 removes the benzyl group as toluene The resulting dipeptide is Gly-Ala only!