CHEM 341 Problem Set 25 Key Acyl-Transfer Reactions: Back to the Basics The acyl transfer reaction is a very common reaction pathway for carboxylic acid derivatives. It is the reason aspirin works. It is how proteins are made. It is how nylon and Kevlar are synthesized. To understand how it works, we need to look at the reaction itself. acylating agent O nucleophile O Y X R X R Y Acyl group being transferred The reaction consists of two reactants: an acylating agent and a nucleophile. The rate of the reaction (and its mechanism) is dependent on the acylating agent and the nucleophile. For the most part, the reactivity of the acylating agent can be predicted by the stability of the leaving group X:-. The more stable the X:- the more reactive the acylating agent. Think basicity. 1.) Rank the following in terms of reactivity with 1 being the most reactive: O O O O O O Ph O Cl N O H O 4 1 5 3 2 amide anhydride ester acid chloride phenyl ester The more basic the nucleophile, the more reactive it is in acyl transfer chemistry. 2.) Rank the following nucleophiles with 1 being the most reactive: NH OH O 2 Cl 3 1 2 4 3.) O R" cat. O O O + OH H3O O O HO OH R OH R' OH "R OH H2O O R' glycerol fatty acids R O (glycerine) O 4.) O R" O O O OH O 3 NaOH O HO OH R ONa R' ONa "R ONa O R' glycerol surfactants R O (glycerine) O Chem 341 Reaction Sheets: Transesterification O O NaOEt OMe O EtOH Mechanism: O NaOEt OMe EtOH Summary (Key words): The entire reaction is reversible. Base can be catalytic. Works best if the base matches the solvent ie: NaOEt/EtOH or NaOMe/MeOH. Base cannot be hydroxide. Hydroxide leads to saponification. Chem 341 Reaction Sheets: Formation of a 2-aminonitrile O NH NH4Cl 2 KCN CN racemic Mechanism: O NH4Cl KCN Summary (Key words): All arrows reversible. Form the imine first, otherwise you cannot get rid of the OH. Chem 341 Reaction Sheets: Cleavage of a tertiary ester O O HCl O Cl OH Mechanism: O HCl O Summary (Key words): This is just an SN1 reaction. All steps reversible. If sulfuric acid is used, the mechanism switches to an E1 reaction. Chem 341 Reaction Sheets: Reaction of a Grignard with an Ester O OH O 1.) MeMgBr, Et2O + 2.) H3O Mechanism: O O 1.) MeMgBr, Et2O + 2.) H3O How do you make a Grignard? Grignards are made by adding Mg and ether to an organohalide. Summary (Key words): The carbon-carbon bond formation step is irreversible. Grignards and organolithiums react multiple times with an ester to form an alchol. You cannot stop at the ketone. It does not matter if you use an excess of the ester, the ketone will not be the major product, because ketones are much more reactive than esters. Chem 341 Reaction Sheets: Reaction of a Grignard with Carbon Dioxide O 1.) MeMgBr, Et2O CO 2.) H O+ 2 3 OH Mechanism: 1.) MeMgBr, Et2O + CO2 2.) H3O Summary (Key words): The carbon-carbon bond formation step is irreversible. Grignards are not reactive enough to react with a carboxylate regardless of how much Grignard reagent is used. Chem 341 Reaction Sheets: Reaction of an organolithium with carbon dioxide O 1.) 1.0 eq. MeLi 1.) excess MeLi O O O CO2 OH 2.) H O+ + 3 2.) H3O Mechanisms: 1.) 1.0 eq. MeLi O CO2 + 2.) H3O 1.) excess MeLi O CO2 + 2.) H3O Two ways to make an organolithium: Organolithiums are made by adding Li and ether to an organohalide or by adding BuLi and ether to an organohalide. Summary (Key words): Organolithiums are more reactive than Grignard reagents. They are capable of reacting with carboxylates while Grignards cannot. Other than that, organolithiums typically do everything Grignards do. The carbon-carbon bond formation step is irreversible. Chem 341 Reaction Sheets: Reaction of an organolithium with a carboxylic acid O O 1.) excess MeLi OH O + 2.) H3O Mechanism: O 1.) excess MeLi OH O + 2.) H3O Summary (Key words): Organolithiums are more reactive than Grignard reagents. They are capable of reacting with carboxylates while Grignards cannot. Other than that, organolithiums typically do everything Grignards do. If one equivalent of organolithium is used, then the reaction stops at the carboxylate. The carbon-carbon bond formation step is irreversible. Chem 341 Reaction Sheets: Reaction of a nitrile with a Grignard CN O 1.) MeMgBr, Et2O + 2.) H3O Mechanism: CN 1.) MeMgBr, Et2O + 2.) H3O Summary (Key words): Grignards and organolithiums add once to nitriles. Neither is strong enough to react with a deprotonated imine to form a nitrogen with a -2 charge. The carbon-carbon bond formation step is irreversible. .