Acyl-Transfer Reactions

Transcription

1 hem W13 otes Dr. Masato Koreeda - Page 1 of 17. Date: March 18, 2013 hapter 15: arboxylic Acids and Their Derivatives and 21.3, /21.5 A Acyl-Transfer eactions I. Introduction Examples: note: could be "" carboxylic acid ' ester an acyl group bonded to an electronegative atom () X acid halide* X = halogen S ' thioester * acid halides, ', ": alkyl, alkenyl, alkynyl, or aryl group ' acid anhydride ' " amide one of or both of ' and " could be "" F r I acid fluoride acid chloride acid bromide acid iodide sp 2 hybridized; trigonal planar making it relatively "uncrowded" The electronegative atom polarizes the = group, making the = carbon "electrophilic." esonance contribution by * hybrid structure * The more basic is, the more it donates its electron pair, and the more resonance structure * contributes to the hybrid. The basicity and size of determine how much this resonance structure contributes to the hybrid. Trends in basicity: weakest base ' increasing basiciy similar basicity ' '" strongest base heck the pka values of the conjugate acids of these bases.

2 hem W13 otes Dr. Masato Koreeda - Page 2 of 17. Date: March 18, 2013 elative stabilities of carboxylic acid derivatives against nucleophiles As the basicity of increases, the stability of increases because of added resonance stabilization. less stable (i.e., more reactive) toward nucleophiles acid halide acid anhydride ' ' ester carboxylic acid '" amide carboxylate elative stabilities of A few naming issues 's against nucleophiles most stable (i.e., least reactive) toward nucleophiles The group obtained from a carboxylic acid by the removal of the is called an acyl group, i.e., e.g., 3 acetyl group; often abbreviated as Ac 6 5 benzoyl group; often abbreviated as z ames of the 2 = derivatives [IUPA names in parentheses] 3 acetic acid (ethanoic acid) 3 a sodium acetate (sodium ethanoate) ethyl acetate (ethyl ethanoate) 3 2 acetamide (ethanamide) 3 acetyl chloride (ethanoyl chloride) 3 3 acetic anhydride (ethanoic anhydride) [abbreviated as Ac 2 ] cyano group: considered to be an acid derivative as it can be hydrolyzed to form an amide and carboxylic acid 3 acetonitrile [IUPA 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 group. For example, pentanenitrile [IUPA name] benzonitrile [IUPA name]

3 hem W13 otes Dr. Masato Koreeda - Page 3 of 17. Date: March 18, 2013 II. Acyl-transfer eactions Acylation eactions u "acylating" agent ucleophilic attack u For this reaction to occur, must be a better leaving group than u. Two possible leaving groups u verall, "The acyl group, -(=)-, has been transferred from to u." Leaving group ability and pka values of the conjugate acids of leaving groups The better the leaving group, the more reactive is in nucleophilic acyl substitution. > ' >>, >> 2 better leaving group ompare pka values of the conjugate acids of these leaving groups: - (pka -6); -(=)-' (pka ~ 4.7); - (pka 15.7)- (pka 16-19); - 2 (pka 35) Acyl-transfer reactions of carboxylic acid derivatives S 2 3 epresents an acylation reaction of 2. Most reactive! S as 2 3 or S /base or 3 2 a 3 2 (1 mol. equiv.) or a 3 2 (2 or more mol. equiv.*) *2nd mol equiv needed to do 3 [can be prepated from any of the above by treatment with ] 3

4 hem W13 otes Dr. Masato Koreeda - Page 4 of 17. Date: March 18, 2013 III. Synthesis of arboxylic Acids (1) With the same number of carbon atoms as the starting material: a. 1 -alcohol oxidation e.g., pyridinium chlorochromate (P) or Swern method aldehyde oxidation carboxylic acid e.g., Jones' reagent [r 3, 2 S 4, 2, acetone] *A potential byproduct in the Jones oxidation of a primary alcohol: 2 - (ester) b. aldehyde Ag 2, a, 2 (Tollens reagent) Selective for aldehyde! a sodium carboxylate 3 (to p ~2) carboxylic acid Ag 0 (silver mirror) Ag Ag Ag An example of the selective oxidation of an aldehyde group: Ag 2, a, 2 (Tollens reagent) 3 (to p ~2) (2) Fewer carbon atoms than the starting material: oxidative work-up (e.g., Ag 2, - then 3 ) (3) ne more carbon atom than the starting material: a. Use of organometallic reagents r Mg Mgr Mgr 3 (to p ~2) -

5 hem W13 otes Dr. Masato Koreeda - Page 5 of 17. Date: March 18, 2013 III Synthesis of carboxylic acid (continued) (3) b. y an S 2 reaction with, followed by hydrolysis a ethanol benzyl chloride 2 phenylacetamide 2, 2, 2 S 4, 100 phenylacetonitrile or directly with 2, 2 S 4, 100 phenylacetic acid ( 4 ) 2 S 4 Mechanism for the acid-catalyzed hydrolysis of nitriles: nitrile pka ~ amide From an amide: 2 3 amide carboxylic acid ote: itriles can be hydrolyzed to the corresponding carboxylates under strongly basic conditions (e.g., a, 2, Δ). Mechanism? Avoid the formation of a - species.

6 hem W13 otes Dr. Masato Koreeda - Page 6 of 17. Date: March 18, 2013 III Synthesis of arboxylic Acids (cont d) ydrolysis of nitriles under basic conditions: Under milder basic conditions, an amide is obtained. Mechanism for the base-catalyzed hydrolysis of nitriles: nitrile ternatively, * * ** 2 amide carboxylate * This is to avoid the generation of highly unfavorable - species. The pka of - 2 is at ~35. ** This is stabilized by resonance with =, thus allowable! The pka of an amide is at ~12. IV. Synthesis of Acid hlorides and Acid Anhydrides (1) Acid hlorides: highly electrophilic = carbons; react with even weak nucleophiles such as ; need to be prepared under anhydrous conditions. Prepared from carboxylic acids. a.with S 2 : (more common) mechanism: 3 Δ S 2 3 S S S S b. With P 3 : Δ 3 P P S 2 (gas) (gas) -S (2) Acid Anhydrides Δ 2 removed by 3 high 2 heating at ~100 temperatures 3 3 (800 ) bp higher than 2 Δ 3 ( 2 ) ( 2 ) ( 2 ) 10 3 An "acyl transfer reaction" at = carbons via intermediate mp 42 bp 118 (decanoic anhydride) (can be selectively distilled off from the mixture) 3 - becomes highly acidic upon heating at hight emperatures, thus 3 ( 2 ) 10 (mixed anhydride) catalyzes anhydride formation by protonating the =s.

7 hem W13 otes Dr. Masato Koreeda - Page 7 of 17. Date: March 18, 2013 V. Esterification (1) Esterification reactions 3 acetic acid ethanol Δ ethyl acetate The experimental equilibrium constant for the reaction above is: 2 [ethyl acetate] x [ 2 ] K eq = = 3.38 [acetic acid] x [ethanol] 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 hâtelier s principle). Equilibrium compositions acetic acid ethanol ethyl acetate i) at start: at equilibrium _ ii) at start at equilibrium _ iii) at start at equilibrium Taken from Introduction to rganic hemistry ; 4 th Ed.; Streitweiser, A. et al.; Macmillan Publ.: ew York, Δ (2) The mechanism for the acid-catalyzed esterification [ommonly referred to as the Fischer esterification: see pp of the textbook] Δ Suggesting not cleaved in this reaction. so, 3 this bond not cleaved 3 optically active Δ 3 3 optically active this bond not cleaved 2 i) verall, the Fischer esterification consitutes an acyl transfer from an to an ' group. 3 - ii) Esterification of a carboxylic acid can't take place in the presence of base. ase deprotonates the carboxylic acid, forming a carboxylate anion, thus preventing a nucleophile (i.e., ) from attacking the carbonyl carbon. 3

8 hem W13 otes Dr. Masato Koreeda - Page 8 of 17. Date: March 18, 2013 V. Esterification (cont d) Mechanism for the acid-catalyzed esterification Δ acetic acid ethanol ethyl acetate 3 acid [acetic acid] alcohol S 4 (acid catalyst) 3 resonance stabilized 3 Use - for the rφnsted acid. note: S pk a ester [ethyl acetate] ester hydrate tetrahedral, sp 3 intermediate pk a -6 pk a lone pairassisted ionization! otes: i) The acid-catalyzed esterification reaction is reversible. The reverse reaction from an ester with an acid and water is the acid-catalyzed hydrolysis of an ester to form the corresponding acid and alcohol. ii) The = lone pairs are more basic than those of the ether oxygen of an ester (i.e., -). 3 3 "more basic" 3 3 X The charge stabilized by the two identical resonance contributors. iii) Direct S 2-like substitution not possible at an sp 2 center no resonance stabilization of the charge ot feasible

9 hem W13 otes Dr. Masato Koreeda - Page 9 of 17. Date: March 18, 2013 VI. Ester ydrolysis 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 ydrolysis of an Ester: usually requires stronger conditions (i.e., high temp.) 2 3 3, Δ 2 3 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 3 Use - for the rφnsted acid good old lone pair-assisted ionization! tetrahedral intermediate 2 3 2) ase-catalyzed ydrolysis of an Ester: under much milder conditions (i.e., usually at room temp). equires acidification of the reaction mixture (p ~1-2) in order to isolate free carboxylic acid. amely, a step to protonate the carboxylate species is needed. verall, the reaction is irreversible a, (p ~1-2) 2 3 Mechanism: 2 3 tetrahedral intermediate or acidification to p ~1-2

10 hem W13 otes Dr. Masato Koreeda - Page 10 of 17. Date: March 18, 2013 hapter 15: arboxylic Acids and Their Derivatives. VI. Ester Formation: Some of ther ommonly Used Methods (1) From carboxylic acids a. With diazomethane benzoic acid 2 (diazomethane) 2 3 (solvent) S 2! 3 (gas) 3 ester [methyl benzoate] b. With base and reactive alkyl iodide [usually 3 I or 3 2 I] or sulfate [usually ( 3 ) 2 S 4 (dimethyl sulfate) or 3 2 S 4 (diethyl sulfate)] 3 I 3 a I S 2! 3 a 3 (weak base) DMA* (solvent) 91% ai *,-dimethylacetamide: polar aprotic solvent that can dissolve a 3 ( 3 ) * S (diethyl sulfate) 2 3 a 2 3 (weak base) DMF* (solvent) 88%,-dimethylformamide: polar aprotic solvent that can dissolve a 2 3 ( 3 ) 2 (2) With Acid Anhydrides and Acid hlorides from cohols 3 The reaction mechanism involves the initial formation of [acetic anhydride] [Ac 3 2 ] 3 3 [pyridine: solvent] 99% 3 or 3 Ac=acetyl Ac 3 3

11 hem W13 otes Dr. Masato Koreeda - Page 11 of 17. Date: March 18, 2013 VII. Lactone Formation Lactone: A cyclic ester; usually formed from a carboxylic acid and hydroxyl groups in the same molecule, by an intramolecular reaction. 27% 73% 2 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. 9-hydroxynonanoic acid p-ts (catalytic) benzene (reflux) 95% 9-hydroxynonanoic acid lactone 2 (continuously removed by using a Dean Stark apparatus) 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 or base catalyst " ', acid or base catalyst acid-catalyzed: base-catalyzed: 3 p-ts (catalytic) Δ - 3 ( 2 ) 16 3 a 3 (catalytic)* ( 2 ) ( 2) (excess) ( 2 ) 16 3 tristearin (a fat) glycerol The mechanism for the transesterification process involves steps almost identical to those given acidcatalyzed and base-catalyzed ester hydrolysis. owever, the major difference is not using water in the transesterification reaction.

12 hem W13 otes Dr. Masato Koreeda - Page 12 of 17. Date: March 18, 2013 VIII. Acylation of ammonia and Amines: Synthesis of Amides Amides: ' " ' " An extremely significant resonance contributor to the structure of amides. 3 cf cm -1 I: ν= ~1670 cm l atoms except for the methyl hydrogens are on the same plane. 1 M: 2.98 ppm (singlet) ketone ppm (singlet) This - bond almost like a double bond. does not undergo free rotation at room temperature. 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: *These two steps could be reversed in order. 2 X tetrahedral intermediate 3 acyl group transferred from (=)3 to Ar * 3 3 * 3 or or ot an S 2!!

13 hem W13 otes Dr. Masato Koreeda - Page 13 of 17. Date: March 18, 2013 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 2 (acetic anhydride) ote stoichiometry between an amine and acid anhydride (explanation on this in section VIII b below). so, 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. owever, when the reaction is carried out in the presence of pyridine, both 2 and get acetylated. 2 (acetic anhydride) (pyridine) 2 3 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. owever, because of the extreme acidity of the - in the initially produced amide-like product, at least two mol. equivalents of an amine are required (see the mechanism shown below). 3 2 ( 3 ) ( 3 ) 2 Mechanism: ( 3 ) ( 3 ) 2 extremely acidic! ( 3 ) 2 ternatively, 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. ( ) 3 ( 3 ) 2 3 ( 2 3 ) 3 ( 2 3 ) 3 ote: Even if a tertiary amine reacts with an acid halide, the resulting quaternary amine product undergoes reaction with a halide anion to recover the original acid halide.

14 hem W13 otes Dr. Masato Koreeda - Page 14 of 17. Date: March 18, 2013 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 ( 3 ) is used Mehanism: 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 generated in the reaction intermediate (see above). More examples: (1) , 1 hr 2 In the example shown above, the low reaction temperature as well as short reaction time are necessary in order to avoid the S 2 reaction at the - site. (2) r d. With carboxylic acids 3 0 ( 3 ) 3 /TF (solvent) r 2 ne of the key steps used in the synthesis of Tamiflu. An amide can also be prepared directly from a carboxylic acid and a 1 - or 2 -amine. owever, the reaction mixture needs to be heated at high temperatures in order to form an amide bond from the initially formed ammonium carboxylate salt ! 225! 3 2

15 hem W13 otes Dr. Masato Koreeda - Page 15 of 17. Date: March 18, 2013 IX. eactions of arboxylic Acid Derivatives [hapter 21.3, and 21.5 A] (1) eduction with hydride reagents a 4 : typically in a protic solvent that serves as a proton source (e.g., 3, and 3 2 ) reduces: aldehydes, ketones, imines, acid halides (to 2 ), acid anhydrides [(=)] 2 [to 2 and (=) - ] ut, does not reduce esters, acids, or amides. 4 : reacts with a protic solvent (i.e., --); use a non-polar solvent such as diethyl ether and TF; requires acidic workup. highly reactive; reduces virtually all =X bonds and cyano group. (i) esters, carboxylic acid, and lactones ' ' ester workup - 2 -' carboxylic acid workup - 2 lactone workup diol mechanism: ' ' Far more electrophilic than the ester = carbon. Thus, the aldehyde gets reduced faster than the starting ester does. ester ' Y [Y = or '] Y 3 workup The aldehyde intermediate above can't be isolated as this gets quickly reduced.. ' 2 2 () 3 carboxylic acid Y 2 Y aldehyde [Y = or (=)] 3 workup - 2 Y

16 hem W13 otes Dr. Masato Koreeda - Page 16 of 17. Date: March 18, 2013 IX. eactions of arboxylic Acid Derivatives (1) eduction with hydride reagents: (ii) 4 reduction of amides " ' aqueous workup ' " amine! mechanism: amide '" '" Unlike an group, the of an '" group is basic and nucleophilic. Thus, it donates its lone-pair electrons to kick out -- species. Y ' " '" (2) eactions with rganometallic eagents: Grignard eagents (i) esters Mgr 3 Mgr TF (solvent) TF (solvent) 2 workup '" 2 2 () 3 aqueus workup 3 2Mg() 2 (usually with saturated 3 3 aqueous 4 ) 2r aqueus workup 3 3 (usually with saturated 3 3 aqueous 4 ) Mg() 2 ca. 1 : 1 r virtually no 3 (acetophenone) obtainable. Mechanistic interpretation: 3 3 Mgr 3 3 Mgr 3 Mgr slow fast fast *As soon as a small amount of an ester reacts with the Grignard reagent, the adduct immediately produces a ketone, which reacts quite rapidly with the Grignard reagent in solution, thus not accumulating the ketone product. 3 Mgr 3 ketone = carbon: far more electrophilic than ester = carbon 3 3 Mgr aqueous work-up 3 3

17 hem W13 otes Dr. Masato Koreeda - Page 17 of 17. Date: March 18, 2013 IX. eactions of arboxylic Acid Derivatives: (2) eactions with rganometallic eagents (ii) eaction with carboxylic acids: Grignard reagents react to form carboxylate salts and the resulting salts do not undergo a further reaction with the Grignard reagents at room temperature. 3 Mgr Mgr 4 3 Mgr x = too non-electrophilic to reaction with an additional equivalent of a Grignard reagent In contrast, more nucleophilic organolithium reagents can add to the initially produced lithium salt. carboxylic acid mechanism: acidic workup 3 (p 1-2) 4 3 reaction end-product ketone (iii) eactions with amides: In general, amides are not quite reactive with most organometallic reagents (M), but under forcing conditions, they react similarly as esters. -Methoxy--methylamides (Weinreb amides): special class of amides that react with most Ms and the initially formed addition products exist as stable chelate, thus affording ketones upon acid hydrolysis methoxy--methylamide 3 Mgr mechanism for the hydrolysis: Mg r Mg r 5-membered, stable chelate; does not fragment to a = species acidic workup (p 1-2) ote: Even if excess M reagents are used, the chelated adduct does not react further with the reagent. This is an extremely convenient method for the synthesis of ketones from carboxylic acids (via Weinreb amides).