ORGO M5

[CHP 21: Carboxylic Acid Derivatives]

Compounds w/ func group that can be converted » CA via simple acidic/basic hydrolysis

Lactones: cyclic ester

Amide: composite of CA & ammonia/amide

Ammonium salt » amide @ high temp

Lactams: cyclic amide

Nitrile: cyano group

a) Hydrolysis » acid

• H3O+ excess (nitrile » 1 amide » acid)

b) Synthesis « acid

• NH3 + heat (» 1 amide)

• POCl3 (» nitrile)

Electronic structure of nitrile

sp hyb w/ 180 bond angle

Acid Halide aka acyl halides: activated deriv used in synthesis of other acyl cpd like ester

Anhydride: 2 MC of acid w/ H2O loss

Mech) Nucleophilic Acyl Substitution

Interconversion of acid deriv via add/elim mech

★ Reactivity of acid derivatives

1) Reactivity of acid derivatives ↓ as basicity of L.G. ↑

• Bc less basic L.G. means more stable as a L.G. » ↑ reactivity of acid derivatives

2) ↑ loss of resonance stability ↓ reactivity

• Amide have strong resonance stabilization followed by weak ester and even weaker anhydride

• Tetrahedral intermediate has no resonance stab after nuc attack » amide less reactive

* Easy to go from more reactive » less reactive

★ Interconversion of acid derivatives

Acid chloride > anhydride > ester > amide > carboxylate

Mech) Acid chloride » anhydride

Mech) Acid chloride » ester

Mech) Acid chloride » amide

+ Ammonia → 1 amide

+ 1 amine → 2 amide

+ 2 amine → 3 amide

Mech) Acid anhydride » ester

Mech) Acid anhydride » amide

Mech) Ammonolysis of ester » amide

* Nuc needs to be NH3 // 1 amine

* Req. prolonged heat → normally just hydrolyze ester so need to make acid chloride add amine

★ L.G. in nuc acyl substitution vs SN2

• Diff in mech: SB may serve as L.G. in acyl subs even though it cannot in alkyl subs

SN2’s 1 step mech)

• Not strongly endo/exo

• Bond of L.G. ½ broken in the TS so rxn is sensitive to nature of L.G.

Acyl Subs)

• L.G. leaves in separate 2nd step after tetrahedral interm

• 2nd step is highly exo: converting tetra int. → more stable MC

• bond to methoxide just begun to break

Mech) Acid anhydride

Transesterfication

• One alkoxy group can be replaced by another w/ acid/base catalyst

• w/ large excess of desired alcohol

Mech) Transesterfication (base cat vs acid cat)

Hydrolysis of CA Derivatives

a) Hydrolysis of acid halide & anhydride

• Occur quickly even under neutral condition

b) Hydrolysis of ester aka base catalyzed Saponification

ex) saponification

c.b) Hydrolysis of amides (basic)

c.a) Hydrolysis of amides (acidic)

d.b) Hydrolysis of nitriles (basic)

HEAT w/ H2O/EtOH

d.a) Hydrolysis of nitriles (acidic)

HEAT w/ H2O/EtOH

Reduction of acid derivatives w/ hydrides

a) Hydride reduction to alcohol

• LiAlH4 & H3O+ reduce » 1 alcohol

  • Acid chloride

  • Anhydride

  • ester

• NaBH4 reduce acid chloride » 1 alcohol

  • acid chloride more reactive than other deriv

Mech) Hydride reduction to alcohol

b) Reduction to aldehyde from acid chloride // nitrile // ester

Acid chloride)

• LiAlH(O-t-Bu)3 DIBAL-H

Ester

1. (i-Bu)2AlH

2. H2O

c) Reduction to amines from amide // nitrile

1. LiAlH4

2. H2O

(For nitrile H2/Pt)

Mech) Hydride reduction of amide » 1 amine

Reduction of acid derivatives w/ Organometalic Reagents

a) acid chloride // ester » alcohol via GR adding twice

a)

1. 2 RMgBr

2. H3O+

b)

1. 2 RLi

2. H3O+

Mech) Rxn of ester w/ 2 moles of GR

b) Acid chloride react once w/ dialkylcuprate Reagent » ketone

R2CuLi

c) Nitrile » imine » ketone via GR

1. 2 RMgBr

2. H3O+

[Summary of Acid Chloride Chemistry]

• Bc so reactive, not found in nature

Synthesis: COOH » COCl

• SOCl2 // COCl2

Acid chloride » other acid derivatives

Rxn of acid chloride

Friedel Craft Acylation of Aro Ring

[Summary of Anhydride Chemistry]

Synthesis: Acid Chloride + CA (& pyr) // Carboxylate Salt

• Chloride + CA + pyr

• // Chloride + Carboxylate Salt

Rxn of Anhydride

★ Acetic formic anhydride react @ formyl group → more electrophilic & less hindered

Friedel Craft Acylation

★ FC to cyclic anhydride » only 1 acid react » 2nd acid free to undergo further rxn

[Summary of Ester Chemistry]

Synthesis

Reaction

Formation of Lactones via spontaneous fischer esterfication of stable 5-6 mem ring

[Summary of Amide Chemistry]

• Unlike amine NOT BASIC or NUC

• can only be protonated w/ SA

Synthesis

Bc amide is least reactive » made from any others

Reaction

• Not easily convert to other deriv w/ nuc aryl subs!

• Dehydration using POCl3 // P2O5

Formation of 5 // 6 mem Lactam via heat // Dehyd. agent

Reactivity of Lactam ★ B Lactam unusually reactive due to the 4 ring strain » acylate variety of nuc!

[Summary of Nitriles Chemistry]

Synthesis of nitriles

Reaction of Nitriles

Thioester

• > reactive toward NAS than ester but < reactive than acid chloride, anhydride

★ Enhanced reactivity of thioester

1. < Resonance stabilization of thioester

   • 2p orb C & 3p orb S diff size, distance from nuc

   • Weak overlap of p orb » weaker C-S bond vs C-O

   

2. - SR better L.G. vs - OR

   • Sulfide less basic & larger so (-) charge spread over > volume

   • S more polarizable vs O so more bonding as leave

Structure of Coenzyme A

• Biochemical acyl transfer reagent

• Thioester not prone to hydrolysis yet good selective acylation → common acylating agent in living system

  

Synthesis of Carbamate Ester

R-NCO (isocyanate) + HO-R (alcohol)

[CHP 22: Condensation & Alpha Subs of Carbonyl Cpd]

Alpha Substitution

Subs of 1 H attached to α C w/ Elec

** Enolate ion interm

Condensation of enolate w/ aldehyde // ketone

1. Ketone // aldehyde

2. ROH

Condensation of enolate w/ ester

Keto-Enol Tautomerism

• Interconv of isomer via migration of (1) proton & (2) double bond =

• Not resonance

• Keto form is favored » stronger C=O stable

  

a) Base-Cat (α H abstracted first by base)

b) Acid- Cat (O of carbonyl abstracts H from acid & then H on α abstracted)

★ Racemization

If α C that is chiral has enolizable H atom, acid // base allow α C to invert configuration w/ enol being intermediate » racemization

Acidity of α H (pka ~20)

• > acidic than alkane or alkene (pka > 40) or alkyne (pka = 25)

• < acidic than water (pka = 15.7) // alcohol (pKa = 16-19)

• Only small amount of enolate at EQ (key nucleophile)

Formation & Stability of Enolate Ion

• Even though keto-enol tautomerism EQ favor keto form addition of elec shift EQ to formation of more enol (bc enol attack elec)

  

However… EQ mis of enolate & base not work sometimes bc base react w/ elec faster than enolate

Soln: Use Lithium Diisopropylamide LDA

LDA Synthesis) akyllithium reagent to deprot diisopropylamine

** LDA convert carbonyl cpd » completely to enolate

ex) Enolate of cyclohexanone

Alkylation of Enolate Ion

1. LDA

2. R-X

• Rxn usually take place @ α C forming new C-C bond

  • LDA forms enolate » act as nuc & displace halide

• Enolate has 2 nuc sites (oxygen & α C) & can react w/ either of these sites

Enamine Formation

• Ketone // aldehyde react w/ 2° amine to form enamine

• Enamine has nuc α C » used to attack electrophiles

• Electrostatic potential map)

Mech of Enamine Formation

• Ketone // aldehyde

• 2° amine

• H3O+

★ Enamine > reactive vs enol but < than enolate

» Iminium ion unreactive

Alkylation of Enamine aka Stork Rxn

Acylation of Enamine aka Stork Rxn

α-Halogenation of Ketone

a) Base promoted α halogenation ★ base promoted MULTIPLE halogenation

• X2 (halogen)

• Base

• Base promoted and not catalyzed bc full equiv of base consumed in rxn

• α haloketone produced is > reactive than ketone bc enolate stab via EWG halogen

• 2nd halogenation faster than 1st

• Not useful in producing mono-halogenated ketones

Haloform Rxn

• Methyl Ketone react w/

• H2

• NaOH (under strongly basic condition)

• » carboxylate ion & haloform

• ** Trihalomethyl ketone interm (not isolated)

• NAS where -OH is nuc, -CX3 is L.G.

+ Iodoform (CHI3) Test used to identify Methyl Ketone

• Alcohol can give + iodoform test

• Iodoform (CHI3) is yellow solid that ppt out of soln

  

a) Acid catalyzed α halogenation ★ More control on multiple halogenation

• X2 (halogen)

• CH3COOH

• Acidic halogenation may replace one or more α H depending on amount of X2 (halogen) used

  • Bc halogen subs enol interm is stable

★ Unlike ketones… aldehydes are easily oxidized & X2 (halognes) are strong oxidizing agent

Attempt to halogenate aldehydes » oxidation of carboxylic acids

α-Bromination of Acid: Hell-Volhard-Zelinsky (HVZ) Rxn

• Carboxylic acid

• 1) Br2 & PBr3

• » α bromo acyl bromide

• 2) H2O

• » α bromo acid ★ Commonly used to convert to α amino acid via acess NH3

• α bromo acid » α amino acid

Aldol Condensation

& Subs Dehydration

• Ketone // aldehyde

• 1) H+ // -OH

• » aldol product

• 2) Heat & H+ // -OH

• » α, b- unsaturated ketone // aldehyde

Dehydration of aldol product)

• Produce α, b- unsaturated conjugated aldehyde // ketone

a) Base Cat Aldol Condensation

• NUC addition of enolate ion to another carbonyl group

a) Acid Cat Aldol Condensation

★ Driving Aldol Conden » Completion

• Reflux acetone using Ba(OH)2 while non volatile diacetone alcohol product not reflux

★ Crossed Aldol Condensation

When enolate of one aldehyde // ketone adds to carbonyl group of diff aldehyde // ketone » crossed aldol condensation

Use LDA to just make desired enolate ion » add cpd we want as electrophile (control which enolate add to which carbonyl group)

★ Problem Solving Strategy

Aldol Cyclization intra MC aldol rxn

ex)

+ Planning synthesis using aldol condensation

Claisen Ester Condensation

• 2 Esters

• 1) -OR

• 2) H3O+

• α H is weakly acidic

  • < acidic vs ketone & aldehyde bc C=O stab via reasonance w. other O » less capable of stab (-) charge of enolate ion

    

• Ester MC undergo NAS via enolate

Mech)

★ Good choice if one ester w/ α H and other w/out

Dieckmann Condensation aka Claisen cyclization »5-6 mem ring

★ If condensation btwn ketone // aldehyde & ester, ketone // aldehyde becomes enolate first bc > acidic & attack ester

Acidity of Carbonyl Cpd: capacity to stab (-) charge » which enolate nuc and which elec