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.

Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 7 of 17. Date: October 5, 2012

V. Esterification (1) Esterification reactions O O H+ + H3C-CH2-O-H CH2CH3 + H2O H3C OH Δ H3C O acetic acid ethanol ethyl acetate

The experimental equilibrium constant for the reaction above is:

[ethyl acetate] x [H2O] Keq = = 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 Châtelier’s principle).

Equilibrium compositions O O H+ + H3C-CH2-O-H CH2CH3 + H2O H3C OH Δ H3C O ______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].

O O H+ + 18 + H O H C OH H3C-CH2- O-H 18 CH2CH3 2 3 Δ H3C O

18 not cleaved in this reaction. Suggesting H3C- CH2 --- OH

Also, this bond this bond O not cleaved not cleaved O HO + H3C H H O H + + H2O H C OH CH 3 3 Δ CH3 optically active optically active

i) Overall, the Fischer esterification consitutes an acyl transfer from an OH to an OR' group.

O H - OR O H C H C 3 OH H+ 3 O R ii) Esterification of a carboxylic acid can't take place in the presence of base. Base deprotonates the carboxylic acid, forming a carboxylate anion, thus preventing a nucleophile (i.e., ROH) from attacking the carbonyl carbon. Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 8 of 17. Date: October 5, 2012

V. Esterification (cont’d) Mechanism for the acid-catalyzed esterification

O O H+ + H3C-CH2-O-H CH2CH3 + H2O H3C OH Δ H3C O acetic acid ethanol ethyl acetate

resonance stabilized alcohol H B H H O O O C2H5OH H3C O H H C O H H C O H H2SO4 3 3 acid [acetic acid] (acid catalyst)

C2H5-OH Use H-B for the Brφnsted acid. tetrahedral, sp3 H H O O O intermediate note: H3C C O H H3C C O H H3C O C2H5 H O O O H C H B O S O pKa -9 ester [ethyl acetate] H5C2 H 5 2 H O B ester hydrate

H pK -6 O a lone pair- B assisted H3C O H H H ionization! O O H H + H O pKa - 2.4 2 H3C C O H C2H5-O-H H3C O C2H5 O H5C2 ------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).

"more H B H H basic" O O O O X H3C O H H3C O H H3C O H H3C O H H The charge stabilized by the two H B identical resonance contributors. no resonance stabi- lization of the charge 2 iii) Direct SN2-like substitution not possible at an sp center

H O δ+ O C2H5-OH C2H5-O H3C O H H3C O H Not feasible δ+ H H

Chem 215 F12 Notes 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.)

O O CH CH H O+, Δ H 2 3 3 O + CH CH HO 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.

H B H H O O H O O CH2CH3 CH CH CH2CH3 CH2CH3 2 3 O H O H H H B O B Use H-B for the Brφnsted acid. H H tetrahedral intermediate CH2CH3 B H HO good old lone pair-assisted H O O O ionization! CH CH H H 2 3 O O H O H

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.

O O CH2CH3 1.NaOH, H O CH CH 2 OH + HO 2 3 + 2.H3O (pH ~1-2)

Mechanism: tetrahedral O intermediate O CH CH O CH2CH3 2 3 CH CH 2 3 H O or OH OH O H

H O O O acidification to pH ~1-2 H H H O O

Chem 215 F12 Notes 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 (diazomethane) O O H2C N N ester [methyl benzoate] O H HOCH3 O CH3 (solvent) benzoic acid H C N N 2 N N S 2! O N (gas) H3C N N O b. With base and reactive alkyl iodide [usually CH3I or CH3CH2I] or sulfate [usually (CH3)2SO4 (dimethyl sulfate) or CH3CH2SO4 (diethyl sulfate)]

O O O H3C I O H O CH3 O SN2! H H H Na H CH3I H H NaHCO H H 3 H H H H (weak base) HO NaI HO HO + HO DMA* (solvent) HO HO OH OH OH 91%

O * N,N-dimethylacetamide: polar aprotic solvent that can dissolve NaHCO3 N(CH3)2 ------O O S O O O H O (diethyl sulfate) CH2CH3 O O Na CO (weak base) O O N 2 3 N DMF* (solvent) O O 88% O * N,N-dimethylformamide: polar aprotic solvent that can dissolve Na2CO3 H N(CH3)2

(2) With Acid Anhydrides and Acid Chlorides from Alcohols

O O [acetic anhydride] O H CO [Ac2O] H CO 3 H3C O CH3 3 OH O CH3 H3CO [pyridine: solvent] or OAc N 99% O Ac=acetyl The reaction mechanism involves CH3 the initial formation of O N CH3 Chem 215 F12 Notes 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.

H O H + H2O OH O 27% 73%

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.

H p-TsOH (catalytic) + H2O benzene O O (continuously (reflux) removed by using OH 95% a Dean Stark 9-hydroxynonanoic apparatus) 9-hydroxynonanoic acid acid lactone

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.

O O R"OH, acid or base catalyst R' R" R O R O R'OH, acid or base catalyst

acid-catalyzed: H O CH + HO-CH3 3 p-TsOH (catalytic) O Δ O base-catalyzed: (CH2)16CH3 H NaOCH3 (catalytic)* O (CH2)16CH3 O H C (CH2)16CH3 H + 3 3 HOCH3 O O (excess) (CH2)16CH3 H O glycerol tristearin (a fat) *Speculate as to why only a catalytic amount of NaOCH3 is needed here.

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 Notes – Dr. Masato Koreeda - Page 12 of 17. Date: October 5, 2012

VIII. Acylation of ammonia and Amines: Synthesis of Amides

Amides: cf. 1715 cm-1 O O R' R' CH3 R N R N O -1 ketone R" R" IR: νC=O ~1670 cm CH3 An extremely significant resonance contributor to All atoms except for the structure of amides. O the methyl hydrogens are on the same plane. C CH3 H N 1H NMR: δ 2.98 ppm (singlet) CH 3 2.89 ppm (singlet) This C-N 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 O O O O H C NH + H C N CH3 + 3 2 3 CH H3C O CH3 H HO 3

acyl group transferred from OC(=O)CH3 to ArNH Mechanism: O O O O O H3C O CH3 H3C CH3 O CH3 * H3C N H C NH H C N H H 3 2 3 H O H

tetrahedral O CH3 intermediate * or B *These two steps could be reversed in order. O O + H3C N CH3 or H-B X O O H HO CH3 H3C NH2 H3C O CH3

Not an S 2!! N

Chem 215 F12 Notes 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

O O (acetic anhydride) H CH3 NH2 N NH3 O H3C O CH3 2 O + O CH3 OH OH OH

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.

O O (acetic anhydride) H CH N 3 NH2 2 O H3C O CH3 O + 2 N O CH3 OH O CH3 H (pyridine) N O

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).

O O CH Cl N 3 + 2 HN(CH3)2 + H2N(CH3)2 CH 3 Cl

Mechanism:

O O O HN(CH3)2 O Cl CH Cl N 3 H2N(CH3)2 N H N H + CH3 H C CH Cl HN(CH3)2 H3C CH3 3 3 extremely acidic! Cl

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.

O O CH3 Cl N(CH2CH3)3 N + HN(CH3)2 + HN(CH2CH3)3 CH3 Cl O Note: Even if a tertiary amine reacts with an acid halide, N(CH2CH3)3 the resulting quaternary amine product undergoes reaction with a halide anion to recover the original acid halide. Cl

Chem 215 F12 Notes 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.

O O CH + NH2CH3 3 + HOCH2CH3 OCH2CH3 N H

Mehanism: O O O O

OCH2CH3 CH3 CH3 OCH2CH3 N N H N H H H H NH2CH3 + CH3 OCH2CH3 HOCH2CH3

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) O O H2O Cl + NH3 Cl + HOCH2CH3 OCH2CH3 -10 °C, 1 hr NH2

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) O O O O

O N O N Br NH3 0 °C Br

(CH3)3COH/THF (solvent) One of the key steps used in the synthesis of O OH Tamiflu. O O NH2

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.

O 225 °C! O 225 °C! O + H2NPh + H2O Ph OH Ph O H NPh Ph NHPh 3

Chem 215 F12 Notes 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.

LiAlH4: reacts with a protic solvent (i.e., R-O-H); use a non-polar solvent such as diethyl ether and THF; requires acidic workup. highly reactive; reduces virtually all C=X bonds and cyano group.

(i) esters, carboxylic acid, and lactones

R OR' R OH 1. LiAlH4 1. LiAlH4 R-CH2OH + HO-R' R-CH2OH + + O R' ≠ H 2. H3O O 2. H3O ester workup carboxylic acid workup O OH

O 1. LiAlH4 OH 2. H O+ lactone 3 diol workup

mechanism: Far more electrophilic Thus, the aldehyde gets reduced R OR' R OR' than the ester C=O carbon. faster than the starting ester does. H H H O O R H + ester H Al H H Al OR' H Al H O Li H Li H Li H H H Al Y H + H3O H Li R O Al Y workup R OH H [Y = H or OR'] H H Li H H The aldehyde intermediate above can't be isolated as this gets quickly reduced.. + R'OH + 2 H2 + Al(OH)3 + LiOH

carboxylic acid H H R O H R O Al H R O Al H R H H H H O H H O Li O Li O + H Al H H Al Y H Al Y aldehyde + H2 H H H H Li Li Li H O Al H Y Al + H Li [Y = H or O(C=O)R] H3O workup Li H R-CH2OH

Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 16 of 17. Date: October 5, 2012

IX. Reactions of Carboxylic Acid Derivatives

(1) Reduction with hydride reagents: (ii) LiAlH4 reduction of amides

R' R' R N R" 1. LiAlH4 R N R" O 2. aqueous workup H H amine!

Unlike an OR group, the N of an NR'R" group is basic and nucleophilic. Thus, it donates its lone-pair electrons to kick out Al-O- species. mechanism:

R NR'R" R NR'R" R' H H R N H O O R" H Al H + H Al O Li amide H Al H H Li H Li H Li H H H Al Y H2O R NR'R" workup R NR'R" + 2 H2 H Li H H H H + Al(OH)3 + LiOH

(2) Reactions with Organometallic Reagents: Grignard Reagents

(i) esters

Ph OCH3 aqueus workup Ph OH + 2 CH3MgBr + HOCH3 + 2Mg(OH)2 THF (usually with saturated O H3C CH3 (solvent) aqueous NH4Cl) + 2Br

Ph OCH3 aqueus workup Ph OH Ph OCH3 + CH3MgBr + + HOCH3 THF (usually with saturated H C CH3 O 3 O + Mg(OH)2 (solvent) aqueous NH4Cl) ca. 1 : 1 + Br

virtually no Ph CH3 obtainable. (acetophenone) O

Mechanistic interpretation:

H3CO MgBr Ph OCH3 H C MgBr δ 3 Ph OCH3 Ph CH3 H3C O Ph MgBr slow fast fast H3C O MgBr O H3C O MgBr δ H3C *As soon as a small amount of an ester ketone C=O carbon: aqueous reacts with the Grignard reagent, the adduct far more electrophilic work-up immediately produces a ketone, which than ester C=O carbon reacts quite rapidly with the Grignard reagent Ph OH in solution, thus not accumulating the ketone product. H3C CH3

Chem 215 F12 Notes Notes – Dr. Masato Koreeda - Page 17 of 17. Date: October 5, 2012

IX. Reactions of Carboxylic Acid Derivatives: (2) Reactions with Organometallic Reagents (ii) Reaction 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. Ph O Ph O MgBr H3C MgBr H x + CH4 O O H3C MgBr δ δ C=O C too non-electrophilic to reaction with an additional equivalent of a Grignard reagent

In contrast, more nucleophilic organolithium reagents can add to the intially produced lithium salt. OLi Ph O Ph Ph O H + + + + 2 H3C-Li OLi CH4 H2O 2 LiOH O acidic workup CH3 CH3 carboxylic (pH 1 - 2) ketone acid H H mechanism: O Ph + CH4 Ph O OLi H O+ OH H Ph O Li Ph 3 Ph OH OLi OH H C O 3 H C Li O CH3 CH3 3 H3C Li δ δ δ δ reaction end-product Ph O Ph O H

CH OH2 3 CH3 (iii) Reactions with amides: In general, amides are not quite reactive with most organometallic reagents (RM), but under forcing conditions, they react similarly as esters.

N-Methoxy-N-methylamides (Weinreb amides): special class of amides that react with most RMs and the initially formed addition products exist as stable chelate, thus affording ketones upon acid hydrolysis.

CH3 CH3 Ph N CH3 Ph O CH H3C MgBr O 3 Ph N CH3 + O H C N CH3 3 O acidic workup CH H O O Mg (pH 1 - 2) 3 H Br N-methoxy-N-methylamide 5-membered, stable chelate; does not fragment to a C=O species mechanism for the hydrolysis:

CH3 Ph O H Ph O CH3 CH3 Ph N CH3 H OH2 O Ph N CH3 CH3 CH3 H C O Ph N CH3 3 H C O + O Mg 3 OH H3C Br H CH3 CH3 H OH H O H N CH3 H N CH3 O H H O H O O H H H H

Note: Even if excess RM 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).