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“Acyl-Transfer Reactions” I. Introduction Resonance Chem 215 F12 Notes – Dr. Masato Koreeda - Page 1 of 17. Date: October 5, 2012 Chapter 15: Carboxylic Acids and Their Derivatives and 21.3 B, C/21.5 A “Acyl-Transfer Reactions” I. Introduction Examples: note: R could be "H" R Z R O H R O R' ester O carboxylic acid O O an acyl group bonded to R X R S acid halide* R' an electronegative atom (Z) thioester O X = halogen O R' R, R', R": alkyl, alkenyl, alkynyl, R O R' R N or aryl group R" amide O O O acid anhydride one of or both of R' and R" * acid halides could be "H" R F R Cl R Br R I O O O O acid fluoride acid chloride acid bromide acid iodide R Z sp2 hybridized; trigonal planar making it relatively "uncrowded" O The electronegative O atom polarizes the C=O group, making the C=O carbon "electrophilic." Resonance contribution by Z δ * R Z R Z R Z R Z C C C C O O O δ O hybrid structure The basicity and size of Z determine how much this resonance structure contributes to the hybrid. * The more basic Z is, the more it donates its electron pair, and the more resonance structure * contributes to the hybrid. similar basicity O R' Cl OH OR' NR'R" Trends in basicity: O weakest increasing basiciy strongest base base Check the pKa values of the conjugate acids of these bases. Chem 215 F12 Notes –Dr. Masato Koreeda - Page 2 of 17. Date: October 5, 2012 Chem 215 F12 Notes – Dr. Masato Koreeda - Page 3 of 17. Date: October 5, 2012 II. Acyl-transfer Reactions – Acylation Reactions Chem 215 F12 Notes – Dr. Masato Koreeda - Page 4 of 17. Date: October 5, 2012 III. Synthesis of Carboxylic Acids (1) With the same number of carbon atoms as the starting material: (2) Fewer carbon atoms than the starting material: (3) One more carbon atom than the starting material: Chem 215 F12 Notes – Dr. Masato Koreeda - Page 5 of 17. Date: October 5, 2012 III Synthesis of carboxylic acid (continued) Note: Nitriles can be hydrolyzed to the corresponding carboxylates under strongly basic conditions (e.g., NaOH, - H2O, Δ). Mechanism? Avoid the formation of a RR’N species. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 6 of 17. Date: October 5, 2012 III Synthesis of Carboxylic Acids (cont’d) Hydrolysis of nitriles under basic conditions: Under milder basic conditions, an amide is obtained. IV. Synthesis of Acid Chlorides and Acid Anhydrides (1) Acid Chlorides: highly electrophilic C=O carbons; react with even weak nucleophiles such as ROH; need to be prepared under anhydrous conditions. Prepared from carboxylic acids. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 7 of 17. Date: October 5, 2012 V. Esterification (1) Esterification reactions The experimental equilibrium constant for the reaction above is: As in any equilibrium processes, the reaction may be driven in one direction by adjusting the concentration of one of the either the reactants or products (Le Châtelier’s principle). Equilibrium compositions ____________________________________________________________________________________________________________________ i) at start: 1.0 1.0 0 0 at equilibrium 0.35 0.35 0.65 0.65_ ii) at start 1.0 10.0 0 0 at equilibrium 0.03 9.03 0.97 0.97_ iii) at start 1.0 100.0 0 0 at equilibrium 0.007 99.007 0.993 0.993 _____________________________________________________________________________ Taken from “ Introduction to Organic Chemistry”; 4th Ed.; Streitweiser, A. et al.; Macmillan Publ.: New York, 1992. (2) The mechanism for the acid-catalyzed esterification [Commonly referred to as the Fischer esterification: see pp 623-624 of the textbook]. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 8 of 17. Date: October 5, 2012 V. Esterification (cont’d) Mechanism for the acid-catalyzed esterification ---------------------------------------------------------------------------------------------------------------------------- Notes: i) The acid-catalyzed esterification reaction is reversible. The reverse reaction from an ester with an acid and water is the acid-catalyzed hydrolsis of an ester to form the corresponding acid and alcohol. ii) The C=O lone pairs are more “basic” than those of the ether oxygen of an ester (i.e., -OR). Chem 215 F12 Notes – Dr. Masato Koreeda - Page 9 of 17. Date: October 5, 2012 VI. Ester Hydrolysis As is mentioned on page 7 of this handout, the ester formation from carboxylic acid is reversible. As such, treatment of an ester with water and a catalytic amount of an (strong) acid leads to the formation of the corresponding acid and alcohol. This process is called hydrolysis. 1) Acid-catalyzed Hydrolysis of an Ester: usually requires stronger conditions (i.e., high temp.) Mechanism for the hydrolysis of an ester under acidic conditions is virtually identical with that for the esterification from an acid, but to the reverse direction. 2) Base-catalyzed Hydrolysis of an Ester: under much milder conditions (i.e., usually at room temp). Requires acidification of the reaction mixture (pH ~1-2) in order to isolate free carboxylic acid. Namely, a step to protonate the carboxylate species is needed. Overall, the reaction is irreversible. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 10 of 17. Date: October 5, 2012 Chapter 15: Carboxylic Acids and Their Derivatives. VI. Ester Formation: Some of Other Commonly Used Methods (1) From carboxylic acids a. With diazomethane b. With base and reactive alkyl iodide [usually CH3I or CH3CH2I] or sulfate [usually (CH3)2SO4 (dimethyl sulfate) or CH3CH2SO4 (diethyl sulfate)] -------------------------------------------------------------------------------------------------- (2) With Acid Anhydrides and Acid Chlorides from Alcohols Chem 215 F12 Notes – Dr. Masato Koreeda - Page 11 of 17. Date: October 5, 2012 VII. Lactone Formation Lactone: A cyclic ester; usually formed from a carboxylic acid and hydroxyl groups in the same molecule, by an intramolecular reaction. Five- and six-membered lactones are often more stable than their corresponding open-chain hydroxy acids. Lactones that are not energetically favored may be synthesized from hydroxy acids by driving the equilibrium toward the products by continuous removal of the resulting water. The mechanism for the formation of lactones from their hydroxy acid precursors follows exactly the same pathway as in the (intermolecular) esterification reaction. VIII. Transesterification Transfer of an acyl group from one alcohol to another. A convenient method for the synthesis of complex esters starting from simple esters. acid-catalyzed: base-catalyzed: The mechanism for the transesterification process involves steps almost identical to those given acid- catalyzed and base-catalyzed ester hydrolysis. However, the major difference is not using water in the transesterification reaction. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 12 of 17. Date: October 5, 2012 VIII. Acylation of ammonia and Amines: Synthesis of Amides Amides: The planar nature of amide bonds is the basis of the conformational/helical structure of proteins (more on this later in the term). (1) Acylation of 1°- and 2°-amines a. With acid anhydride Mechanism: Chem 215 F12 Notes – Dr. Masato Koreeda - Page 13 of 17. Date: October 5, 2012 VIII. Acylation of ammonia and Amines: Synthesis of Amides Acylation of amines: a. With acid anhydrides (cont’d) • Selective reaction on an amino group over a hydroxyl group Note stoichiometry between an amine and acid anhydride (explanation on this in section VIII b below). Also, even if excess acetic anhydride is used, only the amide product can be obtained selectively. Acetylation of a hydroxyl group with an acid anhydride is quite slow at room temperature. However, when the reaction is carried out in the presence of pyridine, both NH2 and OH get acetylated. b. With acid chlorides: highly reactive with amines: Treatment of a 1°- or 2°-amine with an acid halide results in the rapid formation of its amide derivative. However, because of the extreme acidity of the N+-H in the initially produced amide-like product, at least two mol. equivalents of an amine are required (see the mechanism shown below). Alternatively, with the use of an appropriate base (usually a tertiary amine), an amide can be prepared in high yield with only one mol. equivalent of a 1°- or 2°-amine. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 14 of 17. Date: October 5, 2012 VIII. Acylation of ammonia and Amines: Synthesis of Amides (cont’d) c. With esters and lactones Esters and lactones easily react with 1° or 2°-amines to form amides and alcohols, often referred to as aminolysis; ammonolysis when ammonia (NH3) is used. Unlike the reaction of an acid chloride and an amine that requires two equivalents of amine, the aminolysis of an ester or lactone requires only one equivalent of amine. This is because the more basic alcoxide generated picks up the H+ generated in the reaction intermediate (see above). More examples: (1) In the example shown above, the low reaction temperature as well as short reaction time are necessary in order to avoid the SN2 reaction at the C-Cl site. (2) d. With carboxylic acids An amide can also be prepared directly from a carboxylic acid and a 1°- or 2°-amine. However, the reaction mixture needs to be heated at high temperatures in order to form an amide bond from the initially formed ammonium carboxylate salt. Chem 215 F12 Notes – Dr. Masato Koreeda - Page 15 of 17. Date: October 5, 2012 IX. Reactions of Carboxylic Acid Derivatives [Chapter 21.3 B, C and 21.5 A] (1) Reduction with hydride reagents NaBH4: typically in a protic solvent that serves as a proton source (e.g., CH3OH, and CH3CH2OH) reduces: aldehydes, ketones, imines, acid halides (to RCH2OH), - acid anhydrides [RC(=O)]2O [to RCH2OH and RC(=O)O ] But, does not reduce esters, acids, or amides.
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