View
43
Download
5
Category
Tags:
Preview:
Citation preview
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:
Recommended