chem 215-216 hh w13 notes chapter 15: carboxylic acids …chem215/215-216 hh w13-notes-ch 15.pdfchem...

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013

Chapter 15: Carboxylic Acids and Their Derivatives and 21.3 B, C/21.5 A

“Acyl-Transfer Reactions”

I. Introduction

R Z

Oan acyl group bonded to

an electronegative atom (Z)

R O

O

R, R', R": alkyl, alkenyl, alkynyl, or aryl group

H

Examples:

R X

O X = halogen

R O

O

R S

O

R N

O

R O

O

R F

O

R Cl

O

R Br

O

R I

O

carboxylic acidR'

R'

R"R'

R'

O

acid halide*

acid anhydride

ester

thioester

amide

note: R could be "H"

one of or both of R' and R"could be "H"* acid halides

acid fluoride acid chloride acid bromide acid iodide

R Z

O

sp2 hybridized; trigonal planar making it relatively "uncrowded"

The electronegative O atom polarizes the C=O group, making the C=O carbon "electrophilic."

Resonance contribution by Z

RC

Z

O

RC

Z

O

RC

Z

O

The basicity and size of Z determinehow much this resonance structurecontributes to the hybrid.

RC

Z

Oδ

δ

hybridstructure

*

* The more basic Z is, the more it donates its electron pair, and the more resonance structure * contributes to the hybrid.

Trends in basicity:Cl

O

O R'OH OR' NR'R"

similar basicity

weakest base

strongestbase

increasing basiciy

Check the pKa values of the conjugate acids of these bases.

Chem 215-216 HH W13 Notes –Dr. Masato Koreeda - of 17. Date: March 18, 2013

O

R

H3C OH

O

H3CO

H3C O

O

H3C O

O

H3C NH2

O

CH3

O

H3C Cl

O

• The group obtained from a carboxylic acid by the removal of the OH is called an acyl group, i.e.,

acetyl group;often abbreviated as Ac

• Names of the C2 C=O derivatives [IUPAC names in parentheses]

H3C O Na

OCH2

CH3

ethyl acetate(ethyl ethanoate)

acetic acid(ethanoic acid)

sodium acetate(sodium ethanoate)

acetamide(ethanamide)

acetyl chloride(ethanoyl chloride)

acetic anhydride(ethanoic anhydride)

• C N cyano group: considered to be an acid derivative as it can be hydrolyzed to form an amide and carboxylic acid

H3C C NThe suffix -nitrile is added to the name of the hydrocarbon containing the same numberof carbon atoms, including the carbon atom of the CN group.

acetonitrile [IUPAC name: ethanenitrile]

C NH3C-CH2-CH2-CH2-C5 4 3 2 1

benzonitrile[IUPAC name]

pentanenitrile[IUPAC name]

For example,

e.g.,

N

Relative stabilities of carboxylic acid derivatives against nucleophiles

O

R Z

As the basicity of Z increases, the stability of increases because of added resonance stabilization. O

R Z

R Cl

OR OR'

O

R OH

O

R NR'R"

O R O

O

R O

O

R'

Oacid halide acid

anhydride

ester carboxylicacid

amidecarboxylate

less stable(i.e., more reactive)

toward nucleophiles

Relative stabilities of 's against nucleophiles

A few naming issues

C6H5

Obenzoyl group;often abbreviated as Bz

[abbreviated as Ac2O]

most stable(i.e., least reactive)

toward nucleophiles

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013 II. Acyl-transfer Reactions – Acylation Reactions

R C Z

O

Nu

"acylating" agent

Nucleophilic attackR C

O

Nu

Z

For this reaction to occur, Z must be a better leaving group than Nu.

Two possible leaving groups

The better the leaving group, the more reactive is in nucleophilic acyl substitution.R C ZO

Cl O C R'O

OR, OH NH2> >> >>

better leaving group

Cl

O

O

O O

OCH2CH3

O

SCH2CH3

O

O

O

O

NH

OCH3

OH

O

H3O+

Represents an acylation reaction of H2O.

SOCl2

CH3NH2(2 or more mol. equiv.*)

CH3CH2OH/baseor CH3CH2ONa

NaSCH2CH3 or HSCH2CH3

HO

O

O

Oor

Na

Most reactive!

N CH3

O

H H

H3CN

H

H

*2nd mol equiv needed to do

R C Nu

O

"The acyl group, R-C(=O)-, has been transferred from Z to Nu."Overall,

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)

Compare pKa values of the conjugate acids of these leaving groups:

Leaving group ability and pKa values of the conjugate acids of leaving groups

Acyl-transfer reactions of carboxylic acid derivatives

CH3NH2(1 mol. equiv.)

[can be prepated from any of the aboveby treatment with OH]

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013 III. Synthesis of Carboxylic Acids (1) With the same number of carbon atoms as the starting material:

R OH

H Ha.

1°-alcoholR

H

O R

OH

Ocarboxylic acidaldehyde

oxidationoxidatione.g., pyridinium chloro-

chromate (PCC)or Swern method

e.g., Jones' reagent[CrO3, H2SO4, H2O, acetone] *A potential byproduct in the Jones oxidation of a

primary alcohol:

R

O

O

CH2-R(ester)

R

H

O R

O

Osodium

carboxylatealdehyde

b.Ag2O, NaOH, H2O(Tollens reagent)

R

OH

Ocarboxylic acid

Na H3O+

(to pH ~2)

Selective for aldehyde!

R

H

O

OH

R

H

OOH

Ag O Ag R

H

O

OH

Ag

OH

Ag0(silver mirror)

H

OHH

HH-O H

Ag2O, NaOH, H2O(Tollens reagent)

H3O+

(to pH ~2) O-H

OHH

HH-O H

An example of the selective oxidation of an aldehyde group:

(2) Fewer carbon atoms than the starting material:

1. O3

2. oxidative work-up(e.g., Ag2O, HO-

then H3O+)

O

OH+

O

OH

(3) One more carbon atom than the starting material:

a. Use of organometallic reagents

Br MgBrδ

δMg

CO

O

OC

MgBrO

OC

O-HH3O+

(to pH ~2)

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013 III Synthesis of carboxylic acid (continued)

(3) b. By an SN2 reaction with , followed by hydrolysisC N

Cl

benzyl chloride

CN

phenylacetonitrileNa C Nethanol

NH2

Ophenylacetamide

H2O, HCl

OH

OH2O, H2SO4, 100 °C(NH4)2SO4+

phenylacetic acid

or directly withH2O, H2SO4, 100 °C

C N

Mechanism for the acid-catalyzed hydrolysis of nitriles:

Rδδ

H OH

H

C NR H H O H

H OH

pKa ~ -10R C N H

OH H

H O HR C N H

OH

H OH

H

R C N H

OH

HR C

N HOH

HR

C NH2

Oamide

nitrile

R CN H

OH

HH O

H

OCR NH2

OH

H H OCR NOH

H OCR NH3

OH

H

From an amide:H O

H

HH

H OH

H

R CO

O H

HR C

O

O H

HOH

amide

carboxylicacid

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.


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:

C NR

H O

R C O

OH

RC N H

OH

amide

H OH

H O

H OH

R C NH

H

H O

HO

H O

R C NH

H

H O

OH O

H

H O

RC N

H

OHH O

RC N

H

O

RC N

H

O

H OH

R C O

O

nitrile

carboxylate

Alternatively,

RC NH2

O

* *

* 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. a.With SOCl2:

H3C OH

O+ SOCl2 H3C Cl

O+ SO2 + HCl

(gas) (gas)Δ

mechanism:

R OH

O

ClS

Cl

O

R OH

OCl

SCl

O

R OH

O ClSO

Cl

R OHCl

OS Cl

O

R Cl

O H Cl

R Cl

O-SO2

-Cl

-HCl

b. With PCl3:

(more common)

H3C OH

O+ PCl3

H3C Cl

OΔ3 3 + H3PO3

H3C OH

O2 Δ

high temperatures

(800 °C)H3C O CH3

O O+ H2O removed by

heating at ~100 °C

bp higher than H2O

OH

O(H2C)10H3C2 O

O(H2C)10H3C

(H2C)10H3CH3C O CH3

O O

Omp 42 °C (decanoic anhydride)

H3C OH

O2+ +

Δ

bp 118 °C(can be selectively distilled

off from the mixture)An "acyl transfer reaction" at C=O carbons via intermediate

OO

H3C

OH3C (H2C)10 (mixed anhydride)

R-COOH becomes highly acidic uponheating at hight emperatures, thuscatalyzes anhydride formation by protonating the C=Os.

(2) Acid Anhydrides


V. Esterification (1) Esterification reactions

+H3C OH

O

acetic acid

H3C-CH2-O-H

ethanol

H+

Δ H3C O CH2CH3O

H2O

ethyl acetate

+

The experimental equilibrium constant for the reaction above is:

[ethyl acetate] x [H2O] [acetic acid] x [ethanol]Keq = = 3.38

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

+H3C OH

O

acetic acid

H3C-CH2-O-H

ethanol

H+

Δ H3C O CH2CH3O

H2O

ethyl acetate

+

____________________________________________________________________________________________________________________ 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].

+

+ +

+

H3CO

H3C-CH2-18O-HH+

Δ H3C 18O CH2CH3

OH2O

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

H3CO

CH3

HO H

optically activeCH3

O H

optically active

H+

Δ

H3CO

H2O

this bond not cleavedthis bond

not cleaved

Also,

OH

OH

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

H3C OH

O

H3C O R

O

H+

H - OR

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 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013 V. Esterification (cont’d) Mechanism for the acid-catalyzed esterification

H3C O

O

H

BH

H3C O

O

H

SO

OO O

HH

H

H3C O

O

H

H

resonance stabilized

C2H5-OH

CH3C OO

O H

H5C2

H CH3C OO

O H

H5C2

H

tetrahedral, sp3 intermediate

Hester hydrate

CH3C OO

O H

H5C2

HH

H3C O

O

C2H5+ H2O

H3C O

O

C2H5

ester [ethyl acetate]

acid [acetic acid]

H

alcohol

H2SO4

C2H5OH

(acid catalyst)

pKa -9

C2H5-O-HH

pKa - 2.4

H3C O

O

H

H pKa -6

note:

+H3C OH

O

acetic acid

H3C-CH2-O-H

ethanol

H+

Δ H3C O CH2CH3

OH2O

ethyl acetate

+

Use H-B for the Brφnsted acid.

B

BH

Blone pair-assisted

ionization!

---------------------------------------------------------------------------------------------------------------------------- Notes: 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 C=O lone pairs are more “basic” than those of the ether oxygen of an ester (i.e., -OR).

H3C O

O

HH3C O

O

H H3C O

O

H

H

H3C O

O

H

H HBH

BH no resonance stabi-lization of the charge

"morebasic"

The charge stabilized by the twoidentical resonance contributors.

X

H3C O

O

H

H

C2H5-OHH3C O

O

HH

C2H5-OHδ+

δ+

iii) Direct SN2-like substitution not possible at an sp2 center

Not feasible


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.)

+CH2CH3

O

O HO

HO CH2CH3H3O+, Δ

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.

CH2CH3O

Use H-B for the Brφnsted acid.

BH

B

BHB

CH2CH3O H

H O H

CH2CH3O H

OH

H

CH2CH3O H

OH

tetrahedralintermediate

CH2CH3O H

OH

H

OH

O H

O

O H

HO CH2CH3 good oldlone pair-assisted

ionization!

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.

+CH2CH3

O

OH

O

HO CH2CH31.NaOH, H2O

2.H3O+ (pH ~1-2)

CH2CH3

O

CH2CH3O

OH


O

O H

OH

CH2CH3O

O H OHor

O

OH

O H

H

acidification to pH ~1-2

Mechanism:

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013 Chapter 15: Carboxylic Acids and Their Derivatives.

VI. Ester Formation: Some of Other Commonly Used Methods (1) From carboxylic acids a. With diazomethane

O H

O

benzoic acid

H2C N NHOCH3(solvent)

O CH3

O

H2C N N

O

OH3C N N

N N(gas)

ester [methyl benzoate](diazomethane)

SN2!

b. With base and reactive alkyl iodide [usually CH3I or CH3CH2I] or sulfate [usually (CH3)2SO4 (dimethyl sulfate) or CH3CH2SO4 (diethyl sulfate)]

+

OHHOHO

O

O HH

H

H H

OHHOHO

O

OH

H

H H

OHHOHO

O

O CH3H

H

H H

CH3INaHCO3

(weak base)DMA* (solvent)

N,N-dimethylacetamide: polar aprotic solvent that can dissolve NaHCO3

Na

H3C I

NaI

SN2!

N(CH3)2

O*

91%

--------------------------------------------------------------------------------------------------

OHO

NO

O

O S OO

O (diethyl sulfate)

N,N-dimethylformamide: polar aprotic solvent that can dissolve Na2CO3

Na2CO3 (weak base)DMF* (solvent)

OCH2CH3

O

NO

O

H N(CH3)2

O*

88%

(2) With Acid Anhydrides and Acid Chlorides from Alcohols

OHH3CO OH3CO CH3

OH3C O CH3

O O[Ac2O]

[acetic anhydride]

N[pyridine: solvent] OAcH3CO

or

Ac=acetylCH3

O99%

The reaction mechanism involvesthe initial formation of

NCH3

O

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - 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.

+O

OH O

H

H2OH

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.

OH

O O+ H2O

9-hydroxynonanoic acid 9-hydroxynonanoic acid lactone

p-TsOH (catalytic)

benzene(reflux)

95%(continuously

removed by using a Dean Stark apparatus)

H

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.

R O R' R O R"

O OR"OH, acid or base catalyst

R'OH, acid or base catalyst

acid-catalyzed:

+O CH3O O

HO-CH3p-TsOH (catalytic)

Δ

H

base-catalyzed:

+

(CH2)16CH3

(CH2)16CH3

(CH2)16CH3

O

O

O H3CO (CH2)16CH3

O

NaOCH3(catalytic)*

HOCH3(excess)

3

tristearin (a fat)

H

H

Hglycerol

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 215-216 HH W13 Notes – Dr. Masato Koreeda - of 17. Date: March 18, 2013 VIII. Acylation of ammonia and Amines: Synthesis of Amides

Amides:

R N R'O

R"

R NR'

O

R"An extremely significantresonance contributor tothe structure of amides.

HC

NCH3

CH3

OAll atoms except for

the methyl hydrogens are on the same plane.

This C-N bond almost like a double bond. does not undergo free rotation at room temperature.

1H NMR: δ 2.98 ppm (singlet)2.89 ppm (singlet)

IR: νC=O ~1670 cm-1 CH3

CH3O

1715 cm-1cf.

ketone

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

++NH2H3CH3C O CH3

O ONH

H3C HO CH3

OCH3

O

acyl group transferredfrom OC(=O)CH3 to ArNH

Mechanism:

NH2H3C

H3C O CH3

O O

NH3C

H3C O CH3

O O

HH

B

NH3CCH3

O CH3

O

OHH

or

+NH

H3C HO CH3

OCH3

O

or H-B

*

*

*These two steps could be reversed in order.


NH2H3C H3C O CH3

O O

Not an SN2!!

X

Chem 215-216 HH W13 Notes – Dr. Masato Koreeda - 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

+

OH

NH2 H3C O CH3

O O

OH

HN

CH3

OO CH3

O(acetic anhydride)

2OH

NH3

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.

+OH

NH2 H3C O CH3

O O

O

HN CH3

OO CH3

O(acetic anhydride)

N (pyridine)CH3

O

2

NH

2

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).

+Cl

O

HN(CH3)22 +N

O

H2N(CH3)2CH3

CH3

Cl

Mechanism:

Cl

O

HN(CH3)2

ClO

NH3C CH3

H

O

NH3C CH3

H

HN(CH3)2

+N

O

H2N(CH3)2CH3

CH3

Cl

Cl extremely acidic!

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.

+Cl

O

HN(CH3)2 +N

O

HN(CH2CH3)3CH3

CH3

Cl

N(CH2CH3)3

N(CH2CH3)3

ONote: 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.

Cl


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.

++OCH2CH3

ONH2CH3 N

HCH3

OHOCH2CH3

OCH2CH3

O

NH2CH3

OCH2CH3O

NH HCH3 OCH2CH3

N CH3O

H H

NHCH3

O

+HOCH2CH3

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 H+ generated in the reaction intermediate (see above).

More examples: (1)

Cl OCH2CH3

OCl NH2

O++ HOCH2CH3NH3

H2O-10 °C, 1 hr

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)

N

OO

OBr

OO

NH3(CH3)3COH/THF

(solvent)

0 °CN

OO

OBr

OH O NH2

One of the key steps used in the synthesis of Tamiflu.

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.

++

Ph OH

OH2NPh Ph O

O

H3NPh Ph NHPh

OH2O

225 °C! 225 °C!


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'

O

O

O

R' ≠ Hester

lactone

1. LiAlH4

2. H3O+

workup

R-CH2OH + HO-R'R OH

Ocarboxylic acid

R-CH2OH1. LiAlH4

2. H3O+

workup

1. LiAlH4

2. H3O+

workup

OH

OH

diol

mechanism:R OR'

Oester

LiAlH

HH

H

R OR'

O H

AlHH

H

Li

R H

O LiAlH

HH

OR'

Li

AlH

HH

Y

Far more electrophilic than the ester C=O carbon.

+

Thus, the aldehyde gets reduced faster than the starting ester does.

[Y = H or OR']

R O

H H Li

AlH

HY

The aldehyde intermediate above can't be isolated as this gets quickly reduced..

R OH

H H

H3O+

workup

+ R'OH + 2 H2+ Al(OH)3 + LiOH

R O

O

carboxylic acid

LiAl

H

HH

H

H R O

O Li

AlH

HH

LiAlH

HH

Y

[Y = H or O(C=O)R]

R O

Li

AlH

HH

H

LiAlO

HH

Y

O

Li

AlH

HH

YLi

AlH

H+ H2

R H

O +

R-CH2OH

H3O+ workup

aldehyde


IX. Reactions of Carboxylic Acid Derivatives

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

mechanism:

R NR'R"

Oamide

LiAlH

HH

H

R NR'R"

O H

AlHH

H

Li

R N

H LiAlH

HH

O

Li

AlH

HH

Y

+

R NR'R"

H H

R NR'R"

H H

H2Oworkup + 2 H2

+ Al(OH)3 + LiOH

R N R"O

R'

R N R"

H

R'

H

1. LiAlH4

2. aqueous workup amine!

R'

R" Li

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.

(2) Reactions with Organometallic Reagents: Grignard Reagents

Ph OCH3

O+ 2 CH3MgBr

THF(solvent)

(usually with saturatedaqueous NH4Cl)

aqueus workup Ph OH

H3C CH3HOCH3 2Mg(OH)2

2Br

+

+

+

Ph OCH3

O+ CH3MgBr

THF(solvent)

(usually with saturatedaqueous NH4Cl)

aqueus workup Ph OH

H3C CH3HOCH3Mg(OH)2

Br

+

+

+

(i) esters

Ph OCH3

O+

ca. 1 : 1

virtually no Ph CH3

O(acetophenone) obtainable.

Ph OCH3

OPh OCH3H3C

MgBrδ

δ

H3C O MgBrPh

H3CO

H3C MgBr

Mechanistic interpretation:

Ph OH

H3C CH3

Ph CH3H3C O MgBrslow fast fast

aqueous work-up

ketone C=O carbon:far more electrophilicthan ester C=O carbon

*As soon as a small amount of an esterreacts with the Grignard reagent, the adduct

immediately produces a ketone, which reacts quite rapidly with the Grignard reagentin solution, thus not accumulating the ketone

product.

H3CO MgBr


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.

δδ

Ph O HO

H3C MgBr

Ph O

O

MgBrCH4+

C=O C too non-electrophilic to reaction with an additional equivalent of a Grignard reagent

H3C MgBrx

In contrast, more nucleophilic organolithium reagents can add to the initially produced lithium salt.

δδ

Ph O HO

H3C Li

Ph O

O

LiCH4+

Ph O HO

+ 2 H3C-Li PhOLi

OLi

CH3

+ CH4acidic workup

(pH 1 - 2)

Ph O

CH3

H2O 2 LiOH++

mechanism:

δδH3C Li

PhOLi

OLi

CH3

PhOH

OH

CH3

Ph O

CH3

reaction end-product

H3O+Ph

OH

O

H3C

HH

Ph O

CH3

HOH2

ketonecarboxylicacid

(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.

Ph N O CH3

O

CH3

N-methoxy-N-methylamide

H3C MgBr Ph N O CH3

O

CH3

H3CMg

Br

5-membered, stable chelate;does not fragment to a C=O species

acidic workup(pH 1 - 2)

Ph O

CH3N O CH3CH3

HH

+

Ph N O CH3

O

CH3

H3CMg

Br

Ph N O CH3

OH

CH3

H3C

O HH

H

Ph N O CH3

OH

CH3

H3C

H

O HH

H N O CH3CH3

H

Ph O

CH3

HOH2

+

O HH

H

Ph O

CH3

N O CH3CH3

HH

mechanism for the hydrolysis:

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).

chem 215-216 hh w13 notes chapter 15: carboxylic acids …chem215/215-216 hh w13-notes-ch 15.pdfchem...

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