Chem 215 F12 Notes 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 Notes –Dr. Masato Koreeda - Page 2 of 17. Date: October 5, 2012 Relative stabilities of carboxylic acid derivatives against nucleophiles R Z As the basicity of Z increases, the stability of increases because of added resonance stabilization. O less stable (i.e., more reactive) R Cl toward R O R' nucleophiles O O O R OH acid halide R OR' acid anhydride O O ester carboxylic R NR'R" R O acid O O amide carboxylate R Z Relative stabilities of 's against nucleophiles most stable O (i.e., least reactive) toward nucleophiles A few naming issues R • The group obtained from a carboxylic acid an acyl group, i.e., by the removal of the OH is called O e.g., H3C acetyl group; C6H5 benzoyl group; O often abbreviated as Ac O often abbreviated as Bz • Names of the C2 C=O derivatives [IUPAC names in parentheses] H C OH H C O Na H C O CH 3 3 3 C 3 O acetic acid O sodium acetate O H2 ethyl acetate (ethanoic acid) (sodium ethanoate) (ethyl ethanoate) H3C NH2 H3C Cl H3C O CH3 O acetamide O acetyl chloride O O acetic anhydride (ethanamide) (ethanoyl chloride) (ethanoic anhydride) [abbreviated as Ac2O] • C N cyano group: considered to be an acid derivative as it can be hydrolyzed to form an amide and carboxylic acid H3C C N acetonitrile [IUPAC name: ethanenitrile] The suffix -nitrile is added to the name of the hydrocarbon containing the same number of carbon atoms, including the carbon atom of the CN group. For example, 5 4 3 2 1 benzonitrile H3C-CH2-CH2-CH2-C N pentanenitrile C N [IUPAC name] [IUPAC name] Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 3 of 17. Date: October 5, 2012 II. Acyl-transfer Reactions – Acylation Reactions "acylating" agent O O For this reaction to occur, Z must O be a better leaving group than Nu. R C Z R C Z R C Nu Nucleophilic attack Nu Two possible leaving groups Nu Overall, "The acyl group, R-C(=O)-, has been transferred from Z to Nu." Leaving group ability and pKa values of the conjugate acids of leaving groups The better the leaving group, the more reactive R C Z is in nucleophilic acyl substitution. O O C R' Cl > >> OR, OH >> NH2 O better leaving group Compare pKa values of the conjugate acids of these leaving groups: H-Cl (pKa -6); H-O(O=C)-R' (pKa ~ 4.7); H-OH (pKa 15.7)H-OR (pKa 16-19); H-NH2 (pKa 35) Acyl-transfer reactions of carboxylic acid derivatives Most reactive! O O HO O Cl or O O O Na SOCl2 O O NaSCH2CH3 or HSCH2CH3 CH NH SCH2CH3 3 2 O (2 or more mol. O equiv.*) OH CH3CH2OH/base *2nd mol equiv needed to do OCH2CH3 or CH3CH2ONa O + CH3 H3O CH3NH2 N O (1 mol. equiv.) H Represents an acylation H H CH reaction of H2O. N 3 N H H3C H O [can be prepated from any of the above O by treatment with OH] Chem 215 F12 Notes 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: H H H OH a. oxidation oxidation R OH e.g., pyridinium chloro- R O R O chromate (PCC) 1°-alcohol or Swern method aldehyde carboxylic acid e.g., Jones' reagent [CrO3, H2SO4, H2O, acetone] *A potential byproduct in the Jones oxidation of a primary alcohol: O CH2-R (ester) R O H O+ H Ag2O, NaOH, H2O O Na 3 OH (Tollens reagent) (to pH ~2) b. R R O R O O aldehyde sodium carboxylic acid carboxylate Selective for aldehyde! Ag0 (silver mirror) OH H OH H H OH OH R R O O Ag O Ag R O Ag An example of the selective oxidation of an aldehyde group: O O H H + H H Ag2O, NaOH, H2O H3O H (Tollens reagent) (to pH ~2) O-H H H H-O H H-O H (2) Fewer carbon atoms than the starting material: OH OH 1. O3 O + 2. oxidative work-up O - (e.g., Ag2O, HO + then H3O ) (3) One more carbon atom than the starting material: a. Use of organometallic reagents MgBr O-H δ O H O+ Br MgBr C 3 C Mg O (to pH ~2) O δ O C O Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 5 of 17. Date: October 5, 2012 III Synthesis of carboxylic acid (continued) (3) b. By an SN2 reaction with C N , followed by hydrolysis Cl Na C N C phenylacetonitrile N ethanol or directly with benzyl chloride H2O, H2SO4, 100 °C H2O, HCl NH2 OH + (NH4)2SO4 O H2O, H2SO4, 100 °C O phenylacetamide phenylacetic acid Mechanism for the acid-catalyzed hydrolysis of nitriles: H H H O R N pKa ~ -10 C H δ δ O R C N H H O H H R C N H H H O nitrile H H H O H R N H R NH H H R N C 2 C H C H O R N O O O C H H H amide O H From an amide: H H H O H H O O H H H H H H O O H O R N C H R C NH2 R C N H R C NH3 O O O H O H H H H amide O H O H R C R C H carboxylic O O H O H acid 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 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. Mechanism for the base-catalyzed hydrolysis of nitriles: H O O H O O H H H H O * O O * O H H H H H H R C N C N R C N R C N R O R H H H C O O nitrile H H H O H O O H Alternatively, O H H H O H O R O O O O C C N ** C C N C N R NH2 R R O H H R H amide carboxylate * This is to avoid the generation of highly unfavorable R-NH species. The pKa of R-NH2 is at ~35. ** This N is stabilized by resonance with C=O, thus allowable! The pKa of an amide H is at ~12. 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. O a. O With SOCl2: + SOCl Δ + SO + HCl (more common) 2 2 H3C OH H3C Cl (gas) (gas) mechanism: O O O O S S S Cl O Cl -SO2 H -HCl O S O Cl O Cl O O Cl Cl R OH Cl R OH -Cl R R OH R OH R Cl Cl Cl Cl b. With PCl3: O Δ O 3 + PCl3 3 + H3PO3 H3C OH H3C Cl (2) Acid Anhydrides O Δ O O removed by 2 + H O high 2 heating at ~100 °C H3C OH H C O CH temperatures 3 3 (800 °C) bp higher than H2O O O O O Δ H3C (H2C)10 O 2 H3C (H2C)10 + O + 2 OH H C O CH 3 3 H3C (H2C)10 H3C OH An "acyl transfer reaction" at C=O carbons via intermediate mp 42 °C O bp 118 °C O (decanoic anhydride) (can be selectively distilled off from the mixture) H3C R-COOH becomes highly acidic upon O heating at hight emperatures, thus H3C (H2C)10 (mixed anhydride) catalyzes anhydride formation by O protonating the C=Os.