Chapter 19: Carboxylic Chapter 19: Carboxylic AcidsAcids

CarboxyCarboxy group: -COOH, -CO group: -COOH, -CO22H, H,

Naming: Alkanoic AcidsNaming: Alkanoic AcidsIUPAC: Replace –IUPAC: Replace –ee of alkane name with of alkane name with –oic –oic acidacid O

OH 4-Methylhexanoic 4-Methylhexanoic acidacidC1C1

Cyclic: Cyclic: Cycloalkanecarboxylic Cycloalkanecarboxylic acidsacids O

OH

Cyclohexanecarboxylic Cyclohexanecarboxylic acidacid

OHO

1-Naphthalenecarboxylic 1-Naphthalenecarboxylic acidacid

C1, as in C1, as in cyclic cyclic aldehydesaldehydes

Common NamesCommon Names

Carboxylic acids take Carboxylic acids take precedenceprecedence over other over other groups:groups:

Include as many functions as possible in stemInclude as many functions as possible in stem

(Better than 4-acetylheptanoic acid)(Better than 4-acetylheptanoic acid)

Physical PropertiesPhysical Properties

PlanarPlanar structure, structure, trigonaltrigonal carbonyl carbonyl carboncarbon

The carboxy group is polar, The carboxy group is polar, undergoes hydrogen bonding, undergoes hydrogen bonding, and forms dimers:and forms dimers:

Dimerization causes Dimerization causes relatively high melting and relatively high melting and boiling pointsboiling points

11H NMR Chemical ShiftsH NMR Chemical Shifts

HOC

O

H10-13 10-13 ppmppm

2-2.5 2-2.5 ppmppm cf. cf. aldehydes aldehydes and ketonesand ketonesAldehyde likeAldehyde like

HC

O

OH

1313C NMR Chemical C NMR Chemical ShiftsShifts

Not quite Not quite as low field as low field as as aldehyde aldehyde or ketoneor ketone

IR SpectroscopyIR Spectroscopy

Two important bands: Two important bands: ννO-H O-H = 2500-3300 cm= 2500-3300 cm-1-1, , ννC=OC=O = 1710 cm= 1710 cm-1-1

ResonanceResonance

~200 ppm~200 ppm

~180 ppm~180 ppm

AcidityAcidityThe carboxy group is relatively acidic:The carboxy group is relatively acidic:

AcetateAcetate

Reasons: 1. Carbonyl Reasons: 1. Carbonyl carboncarbon is inductively strongly is inductively strongly electron withdrawingelectron withdrawing, 2. , 2. CarboxylateCarboxylate ion is stabilized ion is stabilized by by resonanceresonance

Compare …Compare …

H

2-Propenyl 2-Propenyl (allyl)(allyl)

CH2 H2CBBH H ++

ppKKa a ~ 40~ 40

B++

Electron withdrawingElectron withdrawing groups groups increaseincrease the acidity (decrease the acidity (decrease ppKKaa): ):

CFCF33COOH COOH ppKKaa ~ 0.23 ~ 0.23

DistanceDistance affects acidity: affects acidity:COOH

COOH

Cl

ppKKaa 4.194.19 ppKKaa 3.98 3.98

BasicityBasicity

Protonated on the Protonated on the carbonyl carbonyl oxygenoxygen: Allows for : Allows for allylic allylic resonanceresonance

1. 1. OxidationOxidation of primary alcohols and of primary alcohols and aldehydesaldehydes

With KMnOWith KMnO44; or CrO; or CrO33, H, H22O; or HNOO; or HNO3;3; or H or H22OO2;2; or Cu or Cu2+2+, or , or AgAg++. .

Recall Cr(VI) oxidation:Recall Cr(VI) oxidation:

PreparationPreparation

In H2O: Hydrate, which oxidizes to acid

2. 2. CarbonationCarbonation: : Organometallic reagents and Organometallic reagents and carbon dioxidecarbon dioxide

Example: Example:

Synthetic strategy: Synthetic strategy: RH RH → → RX RX → → RMgBr RMgBr → → RCORCO22HH

3. 3. Nitrile hydrolysisNitrile hydrolysis

Mechanism:Mechanism:

Tautomerization

COOH

Cl

CN

Cl

1.NaOH, H2O2. H+, H2O

90%

Cyanohydrin-hydrolysis: Cyanohydrin-hydrolysis: αα-Hydroxy acids-Hydroxy acids

ReactionsReactions

Nucleophilic substitution Nucleophilic substitution occurs by occurs by addition-eliminationaddition-elimination

Lead to carboxylic acid derivatives:Lead to carboxylic acid derivatives:

General:General:

:Nu:Nu

EE++

LeavinLeaving groupg group

Elimination

Nucleophilic Substitution Nucleophilic Substitution by Addition- Eliminationby Addition- Elimination

Tetrahedral Tetrahedral intermediateintermediate

Addition

:

:

Potential problem: AcidityPotential problem: Acidity

Acid or base catalyzedAcid or base catalyzed

Base Catalyzed MechanismBase Catalyzed Mechanism

Must not compete Must not compete with :Nuwith :Nu--

Acid Catalyzed MechanismAcid Catalyzed Mechanism

Synthesis of Carboxylic Synthesis of Carboxylic Acid DerivativesAcid Derivatives

A. A. Alkanoyl Alkanoyl HalidesHalides::

RC

O

OH

X=X= Cl, Br Cl, Br

+ -Cl + -OHRC

O

Cl

More More stablestable

Less Less stablestable

Poor Poor NuNu

Bad leaving Bad leaving group, group, strong base, strong base, good Nugood Nu

uphiluphilll

Therefore use other reagents: Therefore use other reagents: SOClSOCl22, PCl, PCl55, PBr, PBr33

SOClSOCl22: :

Mechanism: Mechanism: First step is to convert First step is to convert the bad leaving group OH into a good the bad leaving group OH into a good oneone

Good Good leavinleaving g groupgroup

Same as ROH Same as ROH RCl, except addition- RCl, except addition-elimination and not Selimination and not SNN22

Then it is addition-elimination:Then it is addition-elimination:

PClPCl55::

90%90%

O

OHPCl5

O

ClPCl3O

HCl+ ++

PBrPBr33::

PBrPBr33 Mechanism:Mechanism:

1.1.

2.2.

R

O

OHPBr2Br

R

O

OPBr2HBr++

::

R

O

OPBr2

++ H+ Br -

R

OH

OPBr2

R

O

Br+HOPBr2

Br

:

:

::: :

: :

1

2

B. B. AnhydridesAnhydrides

Cyclic anhydrides: Just heat, or SOClCyclic anhydrides: Just heat, or SOCl22

C. C. Esters:Esters:

Alcohols + carboxylic acids, cat. mineral acid, Alcohols + carboxylic acids, cat. mineral acid, reversiblereversible

Example:Example:ΔΔH H º ~ 0, º ~ 0, ΔΔS S º ~ 0, º ~ 0, ΔΔG G º ~ º ~ 00

Reverse: Reverse: Ester hydrolysisEster hydrolysis, driven by excess H, driven by excess H22O. Can also be O. Can also be effected by aqueous NaOH (Chapter 6: RX + Naeffected by aqueous NaOH (Chapter 6: RX + Na+-+-OO22CR). CR).

EsterHydrEsterHydr

GallagGallag

MechanismMechanism:: HH++ mineral acid, e.g., H mineral acid, e.g., H22SOSO44, HCl, proceeds initially , HCl, proceeds initially like acetalizationlike acetalization of aldehydes and ketones of aldehydes and ketones

Note: Carbonyl oxygen is always Note: Carbonyl oxygen is always more basicmore basic than hydroxy oxygen, because of than hydroxy oxygen, because of resonanceresonance in the protonated product.in the protonated product.

EsterEster

Intramolecular esterification: Intramolecular esterification: LactonesLactones

Even without removing the water the equilibrium Even without removing the water the equilibrium is favorable because of entropy (is favorable because of entropy (positivepositive). As ). As always in reversible reactions (thermodynamic always in reversible reactions (thermodynamic control), cyclization is best for five and six control), cyclization is best for five and six membered rings.membered rings.

D. D. AmidesAmides

This method is rarely used. Problem: Fast This method is rarely used. Problem: Fast (although reversible) salt formation (although reversible) salt formation (reverse is slow, hence (reverse is slow, hence ΔΔ needed) needed)

Heat carboxylic acid with an amine:Heat carboxylic acid with an amine:

Note: MNote: M++ --NHNH2 2 are are also called amides.also called amides.

Mechanism:Mechanism:

Highly pHighly pH H dependent profile. We shall dependent profile. We shall see in Chapter 20 that amide formation is see in Chapter 20 that amide formation is better accomplished by “activation” of better accomplished by “activation” of the carboxy group, as in alkanoyl halides the carboxy group, as in alkanoyl halides or anhydrides or even esters.or anhydrides or even esters.

Cyclic amides: Cyclic amides: ImidesImides from dioic from dioic acids, or acids, or lactams lactams fom amino acidsfom amino acids

Imide formation:Imide formation:

Lactam formation:Lactam formation:

Penicillins are lactams:Penicillins are lactams:

N

S

OCOOH

HHRHN

OHR'

R’OH stands for transpeptidase, R’OH stands for transpeptidase, the enzyme necessary for all cell the enzyme necessary for all cell wall construction. Osmotic wall construction. Osmotic pressure in a cell is enormous, 10-pressure in a cell is enormous, 10-20 atm. Penicillin causes literally 20 atm. Penicillin causes literally an explosion. an explosion.

Other Reactions of Other Reactions of Carboxylic AcidsCarboxylic Acids

1.1. ReductionReduction by LiAlH by LiAlH44

Mechanism complex, Mechanism complex, not clear, possibly not clear, possibly via:via:

C

O

O

H

R

Al

Li

H:

2. 2. Hell-Volhard-Zelinsky Hell-Volhard-Zelinsky Reaction: Reaction: Makes Makes αα--bromocarboxylic acidsbromocarboxylic acids

P + BrP + Br22 PBr PBr33

Important functionalization; can be exploited to Important functionalization; can be exploited to access access αα-amino acids. Mechanism is reminiscent of -amino acids. Mechanism is reminiscent of acid catalyzed halogenation of aldehydes and acid catalyzed halogenation of aldehydes and ketones.ketones.

Jakob Volhard Jakob Volhard (1834-1910)(1834-1910)

Nikolaj Zelinski

(1861-1953)

Carl Magnus von Hell (1849-1926)

Mechanism:Mechanism:

As in the acid catalyzed halogenation of aldehydes and As in the acid catalyzed halogenation of aldehydes and ketones, this needs ketones, this needs enolizationenolization of RCH of RCH22COOH. However, the COOH. However, the COOH group is too stable to enolize sufficiently, hence it COOH group is too stable to enolize sufficiently, hence it requires requires activationactivation to RCH to RCH22C(O)Br.C(O)Br.

pKa ~ 16!

Detailed mechanisms of steps 2 and 3:Detailed mechanisms of steps 2 and 3: