310-15 - CH 310 N T Th 2-3:30 LECTURE 15 Textbook...

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Unformatted text preview: CH 310 N T Th 2-3:30 LECTURE 15 Textbook Assignment: Chapter 17 (begin) Homework (for credit): POW 7 posted Today's Topics: Derivatives of Carboxylic Acids& Reactions Notice & Announcements: Exam II: Monday, 10/20; 7-9 PM Last Name: A-L WEL 1.308 Last Name: M-Z WEL 1.316 Use the same arrangements (as exam I) for conflict schedule. Organic Lecture Series Functional Derivatives of Carboxylic Acids 2 Organic Lecture Series Reaction with Alcohols Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification O OCH 3 + Methyl propenoate (Methyl acrylate) (bp 81C) HO 1-Butanol (bp 117C) O O + CH 3 OH Butyl propenoate Methanol (Butyl acrylate) (bp 65C) (bp 147C) 3 HCl 1 Organic Lecture Series Reaction with Ammonia Acid halides react with ammonia, 1amines, and 2amines to form amides 2 moles of the amine are required per mole of acid chloride O Cl + 2 NH3 Hexanoyl Ammon ia chloride O NH 2 + NH4 Cl Hexanamid e Ammon ium chlo ride + - 4 Organic Lecture Series Reaction with Ammonia Acid anhydrides react with ammonia, and 1and 2amines to form amides 2 moles of ammonia or amine are required O O CH3 COCCH3 + 2 NH3 Acetic Ammon ia anh yd rid e O O + CH3 CNH2 + CH3 CO NH4 Acetamid e Ammon ium acetate 5 Organic Lecture Series Reaction with Ammonia Esters react with ammonia, and 1and 2 amines to form amides esters are less reactive than either acid halides or acid anhydrides O Ph OEt + NH3 Ph O NH2 + Et OH Ethanol Ethyl p henylacetate Phenylacetamide Amides do not react with ammonia, or 1 or 2amines 6 2 Organic Lecture Series Acid Chlorides with Salts Acid chlorides react with salts of carboxylic acids to give anhydrides most commonly used are sodium or potassium salts O O + CH 3 CCl + N a OC Acetyl chloride Sodium benzoate O O CH 3 COC Acetic benzoic anhydride + N a+ Cl - This is a method to prepare mixed acid anhydrides 7 Organic Lecture Series Interconversions 8 Organic Lecture Series Reactions with Grignard Reagents treating a formic ester with 2 moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2alcohol O HCOCH3 + 2 RMgX An ester of formic acid OH magn esium H2 O, HCl alkoxide HC-R + CH3 OH salt R A 2 alcohol 9 3 Organic Lecture Series Reactions with Grignard Reagents treating other esters with 2 equivalents of Grignard reagent followed by hydrolysis in aqueous acid gives a 3alcohol O CH3 COCH3 + 2 RMgX An ester of an y acid other than formic acid magnesiu m H O, HCl 2 alk oxid e salt OH CH3 C-R + CH3 OH R A 3 alcohol 10 Organic Lecture Series Reactions with Grignard Reagents 1. addition of 1 mole of RMgX to the carbonyl carbon gives a TCAI 2. collapse of the TCAI gives a ketone (an aldehyde from a formic ester) 1 O MgX 2 O [MgX] + CH3 -C-OCH3 + R 1 CH3 -C OCH 3 R 2 A magnesiu m s alt (a tetrahed ral carbonyl addition intermediate) O + CH3 -C + CH3 O [ MgX] R A ketone 11 Organic Lecture Series Reactions with Grignard Reagents 3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI 4. treatment with aqueous acid gives the alcohol 3 O + 3 CH3 -C R A k eton e R MgX OH H2 O, HCl CH3 -C-R (4) R R Magnesiu m salt A 3 alcohol CH3 -C-R O [ MgX] - + 12 4 Organic Lecture Series Reactions with Organolithium Organolithium compounds are even more powerful nucleophiles than Grignard reagents they react with esters to give the same types of 2and 3alcohols as do Grignard reagents and often in higher yields O RCOCH3 1 . 2 R' Li 2 . H2 O, HCl OH R- C-R' + CH3 OH R' 13 Organic Lecture Series Reactions with Organocuprate Reagents Acid chlorides at -78 react with Gilman C reagents to give ketones under these conditions, the TCAI is stable, and it is not until acid hydrolysis that the ketone is liberated O 1 . ( CH 3 ) 2 CuLi, ether, -78 C Cl 2 . H O 2 Pentanoyl chloride 2-Hexanone O This is analgous to Gilman coupling with alkyl halides. Experimental note: -78oC is dry ice & acetone or IPA 14 Organic Lecture Series Reactions with Organocuprate Reagents Gilman reagents react only with acid chlorides they do not react with acid anhydrides, esters, amides, or nitriles under the conditions described O H 3 CO O 1 . ( CH3 ) 2 CuLi, eth er, -78C Cl 2 . H O 2 O H 3 CO O 15 5 Organic Lecture Series Reduction - Esters by LiAlH4 Most reductions of carbonyl compounds now use hydride reducing agents esters are reduced by LiAlH4 to two alcohols the alcohol derived from the carbonyl group is primary O Ph OCH 3 1 . LiAlH4 , et her 2 . H 2 O, HCl Ph OH + CH 3 OH M ethanol Methyl 2-phenylpropanoate 2-Phenyl-1propanol 16 Organic Lecture Series Reduction - Esters by LiAlH4 Reduction occurs in three steps plus workup Steps 1 and 2 reduce the ester to an aldehyde O R C OR' + H O O (2) R C OR' R C + H H A tetrahedral carbonyl ad dition intermed iate (1) OR' Step 3 reduction of the aldehyde followed by work up gives a 1alcohol O R C H (3) O R C H H (4) OH R C H H A 1 alcohol + H 17 Organic Lecture Series Reduction - Esters & NaBH4 NaBH4 does not normally reduce esters, but it does reduce aldehydes and ketones Selective reduction is often possible by the proper choice of reducing agents and experimental conditions O O OEt NaBH4 EtOH OH O OEt (racemic) 18 6 Organic Lecture Series Reduction - Esters by DIBAlH Diisobutylaluminum hydride (DIBAlH) at -78 C selectively reduces an ester to an aldehyde at -78 the TCAI does not collapse and it is not until C, hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated O 1 . DIBALH , toluen e, -78C OCH 3 2 . H2 O, HCl Methyl hexanoate O H + CH3 OH Hex anal 19 Organic Lecture Series Reduction - Amides by LiAlH4 LiAlH4 reduction of an amide gives a 1 , 2 or 3amine, depending on the degree , of substitution of the amide O NH 2 Octanamide O NMe 2 1 . LiAlH 4 2 . H2 O N,N -D imethylben zamide NMe2 1 . LiAlH4 2 . H2 O NH 2 1-Octanamine N ,N-D imeth ylb enzylamine 20 Organic Lecture Series Reduction - Amides by LiAlH4 The mechanism is divided into 4 steps Step 1: transfer of a hydride ion to the carbonyl carbon Step 2: a Lewis acid-base reaction and formation of an oxygen-aluminum bond O R C NH2 + H AlH3 (1) O R C NH2 + AlH3 H AlH3 O R C NH2 H (2) 21 7 Organic Lecture Series Reduction - Amides by LiAlH4 Step 3: redistribution of electrons and ejection of H3AlO- gives an iminium ion Step 4: transfer of a second hydride ion to the iminium ion completes the reduction to the amine O AlH3 (3) H R C N H H H An iminium ion (4) R-CH2 -NH 2 A 1 amine 22 R C N H H H Organic Lecture Series Reduction - Nitriles by LiAlH4 The cyano group of a nitrile is reduced by LiAlH4 to a 1amine 1 . LiA lH4 CH3 CH= CH( CH 2 ) 4 C N 2 . H2 O 6-Octenenitrile CH 3 CH= CH ( CH 2 ) 4 CH 2 N H2 6-Octen-1-amine 23 Organic Lecture Series STOP HERE FOR EXAM MATERIAL 24 8 Organic Lecture Series Enolate Anions and Enamines 25 Organic Lecture Series Acidity of -Hydrogens Hydrogens alpha to a carbonyl group are more acidic than hydrogens of alkanes, alkenes, and alkynes but less acidic than the hydroxyl hydrogen of alcohols Type of Bond pKa CH3 CH2 O-H 16 O CH3 CCH2 -H 20 CH3 C C-H 25 CH2 =CH-H CH3 CH2 -H 44 51 26 pKa = -log Ka Sec 16.12 Organic Lecture Series -Hydrogens are more acidic because the enolate anion is stabilized by: 1. delocalization of its negative charge 2. the electron-withdrawing inductive effect of the adjacent electronegative oxygen O CH3 -C-CH2 - H + :A - O CH3 -C CH2 O - CH3 -C=CH2 + H-A Resonance-stabilized en olate anio n 27 9 Organic Lecture Series Enolates in Use Base-promoted -halogenation Step 1: formation of an enolate anion OH R'-C-C-R + :OH R slow O C R O: C C R + H2 O C R' R R' R Res on ance-stab ilized enolate anion Step 2: nucleophilic attack of the enolate anion on halogen O: C R' C R R + Br Br fast R' O C Br C R + R Br 28 Organic Lecture Series Formation of an Enolate Anion Enolate anions are formed by treating an aldehyde or ketone with base O CH3 -C-H + NaOH O -Na+ O H C C-H + H2 O H C C-H H H An en olate anion most of the negative charge in an enolate anion is on oxygen 29 Organic Lecture Series Enolate Anions Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions O R R + R' Br n ucleophilic s ubstitu tion SN 2 O R R R R' + Br R An enolate A 1 haloalkan e anion or su lfonate O R O R + nucleophilic addition R' O R O R' R' R' R An enolate anion R R A tetrahedral carbonyl ad dition intermediate 30 A ketone 10 Organic Lecture Series The Aldol Reaction The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound although these reactions may be catalyzed by either acid or base, base catalysis is more common The reaction results in a new C--C bond 31 Organic Lecture Series The Aldol Reaction The product of an aldol reaction is a -hydroxyaldehyde O H O NaOH CH3 -C-H + CH2 -C-H A cetaldehyde A cetaldehyde OH O CH 3 -CH-CH2 -C-H 3-Hydroxyb utanal (a -hydroxyaldehyde; racemic) or a -hydroxyketone O H O CH3 -C-CH 3 + CH2 -C-CH3 Acetone Acetone Ba(OH) 2 OH O CH 3 -C-CH2 -C-CH3 CH3 4-Hydroxy-4-meth yl-2-p entanone (a -hydroxyketone) 32 Organic Lecture Series The Aldol Reaction Base-catalyzed aldol reaction Step 1: formation of a resonance-stabilized enolate anion H-O - O + H-CH2 -C-H pK a 20 (w eak er acid) H-O-H + pK a 15.7 (s tronger acid) O CH2 -C-H O CH2 =C-H - An enolate an ion Step 2: carbonyl addition gives a TCAI O CH3 -C-H + O CH2 -C-H O O CH3 -CH-CH2 -C-H A tetrahed al carbon yl addition intermediate Step 3: proton transfer to O- completes the aldol reaction 33 11 Organic Lecture Series The Aldol Reaction-Acidic Reaction Acid-catalyzed aldol reaction Step 1: acid-catalyzed equilibration of keto and enol forms O CH 3 - C-H HA OH CH 2 = C- H Step 2: proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone O CH3 -C-H + H A H O CH3 -C-H + A 34 Organic Lecture Series The Aldol Reaction-acidic Reaction Step 3: attack of the enol of one molecule on the protonated carbonyl group of another molecule Step 4: proton transfer to A- completes the reaction H H O O CH3 -C-H + CH 2 =C-H + :A OH O CH3 -CH-CH2 -C-H + H-A (racemic) (Steps 3 & 4 are combined here) 35 Organic Lecture Series The Aldol Products-H2O Products aldol products are very easily dehydrated to ,-unsaturated aldehydes or ketones OH O CH3 CHCH 2 CH warm in either acid or base O CH3 CH= CH CH + H2 O An , ,-unsaturated aldehyde aldol reactions are reversible and often little aldol present at equilibrium Keq for dehydration is generally large if reaction conditions bring about dehydration, good yields of product can be obtained 36 12 ...
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This note was uploaded on 10/18/2008 for the course CH 310M taught by Professor Iverson during the Fall '05 term at University of Texas.

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