318-17 - Textbook Assignment: Chapter 18 Homework (for...

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Unformatted text preview: Textbook Assignment: Chapter 18 Homework (for credit): POW 8 posted Today’s Topics: Derivatives of Carboxylic Acids Exam 2: 3/24; 7-9PM; WEL 2.122 acetaminophen Reactions with Grignard Reagents –treating a formic ester with 2 moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2°alcohol O HCOCH3 + 2 RMgX An ester of f orm i c aci d OH magn esium H O, HCl 2 alkoxide HC-R + CH3 OH s alt R A 2° alcohol Reactions with Grignard Reagents – treating other esters with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3°alcohol O CH3 COCH3 + 2 RMgX An ester of an y acid othe r than fo rmi c ac i d magnesiu m H2 O, HCl alk oxid e salt OH CH3 C-R + CH3 OH R A 3° alcohol 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 2 O [MgX] + O + CH3 -C + CH3 O [ MgX] CH3 -C-OCH3 + R MgX 1 CH3 -C OCH3 R2 A magnesiu m s alt (a tetrahed ral carbonyl addition intermediate) R A ketone 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 O [ MgX] MgX CH3 -C-R R Magnesiu m salt + O CH3 -C 3 3 +R OH (4) CH3 -C-R R A 3° alcohol H2 O, HCl R A k eton e Reactions with Organolithium Reactions Organolithium Organolithium compounds are even more powerful nucleophiles than Grignard reagents – they react with esters to give the same types of 2°and 3°alcohols as do Grignard reagents – and often in higher yields O 1 . 2 R' Li RCOCH3 2 . H2 O, HCl OH R- C-R' + CH 3 OH R' Reactions with Organocuprate Reagents Reactions Organocuprate 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 . ( CH3 ) 2 CuLi, ether, -78° C 2-Hexanone O Cl 2 . H O 2 Pentanoyl chloride This is analogous to Gilman coupling with alkyl halides. Reactions with Organocuprate Reagents Reactions Organocuprate – Gilman reagents react only with acid chlorides – they do not react with acid anhydrides, esters, amides, or nitriles under these conditions O H 3 CO O 1 . ( CH3 ) 2 CuLi, e th er, -78°C Cl 2 . H2 O O H 3 CO O Reduction - Esters by LiAlH4 Reduction 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 + CH3 OH M ethanol Methyl 2-phenylpropanoate 2-Phenyl-1propanol Reduction - Esters by LiAlH4 Reduction • Reduction occurs in three steps plus workup – Steps 1 and 2 reduce the ester to an aldehyde O R C OR' + H R C OR' RC+ H H A tetrah edral carbon yl ad di ti on i nte rme d i ate (1) O (2) O OR' – Step 3 reduction of the aldehyde followed by work up gives a 1°alcohol O RC H +H (3) O RCH H (4) OH RCH H A 1° al co ho l Reduction - Esters & NaBH4 Reduction • 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) * Reduction - Esters by DIBAlH Reduction • 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 OCH3 2 . H2 O, HCl Methyl hexanoate 1 . DIBALH , toluen e, -78°C O H + CH3 OH Hex anal Reduction - Amides by LiAlH4 Reduction • LiAlH4 reduction of an amide gives a 1° , 2° or 3°amine, depending on the degree , of substitution of the amide O 1 . LiAlH4 NH2 2 . H O 2 Octanamide O NMe2 NMe2 1 . LiAlH4 2 . H2 O N ,N-D imeth ylb enzylamine N,N -D imethylben zamide NH2 1-Octanamine Reduction - Amides by LiAlH4 Reduction • 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 (1) R C NH2 + H AlH3 O R C NH2 + AlH3 H (2) AlH3 O R C NH2 H Reduction - Amides by LiAlH4 Reduction – 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 RC NH HH An iminium ion (4) R-CH2 -NH2 A 1° ami ne RC NH HH Reduction - Nitriles by LiAlH4 Reduction • The cyano group of a nitrile is reduced by LiAlH4 to a 1°amine 1 . L iA l H4 CH3 CH= CH( CH 2 ) 4 C N 2 . H2 O 6-Octenenitrile CH3 CH= CH ( CH2 ) 4 CH2 N H2 6-Octen-1-amine Enolate Anions and Enamines and Enamines Acidity of α-Hydrogens Acidity 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 16 20 25 44 51 CH3 CH2 O-H O H CH3 CC 2 -H CH3 C C-H CH2 =CH-H CH3 CH2 - H pKa = -log Ka Sec 16.12 α-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 OCH3 -C=CH2 + H-A Re so nanc e -stabi l i z e d e n ol ate ani o n Enolates in Use • Base-promoted α-halogenation Step 1: formation of an enolate anion enolate OH R'-C-C-R + :OH R - slow O C -R •• C O: C C R + H2 O R' R R' R Re s on ance -stab i l i z e d e no l ate ani o n Step 2: nucleophilic attack of the enolate anion on halogen O: R' C C R R + Br Br fast R' O C Br C R+ R Br 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 e n ol ate ani o n + – most of the negative charge in an enolate anion is on oxygen 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 RR R' + Br R An en olate A 1° h aloalkan e anion or su l fo nate O R – O R + nu cleophilic add ition R' O R O R' R' R' R An enolate an ion RR A tetrahedral carbonyl ad di ti on i nte rme d iate A ketone The Aldol Reaction The Aldol • 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 The Aldol Reaction The Aldol • The product of an aldol reaction is – a β-hydroxyaldehyde O H O NaOH CH3 -C-H + CH2 -C-H A cetaldehyde A cetaldehyde OH O α β CH3 -CH-CH2 -C-H 3-Hydroxyb utanal (a β -hydroxyaldehyde; racemic) – or a β-hydroxyketone O H O CH3 -C-CH3 + CH2 -C-CH3 Acetone Acetone Ba(OH) 2 OH O βα CH3 -C-CH2 -C-CH3 CH3 4-Hydroxy-4-meth yl-2-p entanone (a β -hydroxyketone) The Aldol Reaction The Aldol • Base-catalyzed aldol reaction Step 1: formation of a resonance-stabilized enolate anion O H-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 OCH2 =C-H An enolate an ion Step 2: carbonyl addition gives a TCAI O CH3 -C-H + O CH2 -C-H O OCH3 -CH-CH2 -C-H A tetrahed al carbon yl addi ti o n i nte rm e di ate Step 3: proton transfer to O- completes the aldol reaction The Aldol Reaction-Acidic The Aldol • Acid-catalyzed aldol reaction – Step 1: acid-catalyzed equilibration of keto and enol forms O CH3 - C-H HA OH CH2 = 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 The Aldol Reaction-acidic The Aldol – 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 + CH2 =C-H + :A O CH3 -CH-CH2 -C-H + H-A (racemic) OH (Steps 3 & 4 are combined here) The Aldol Products-H2O The Aldol – aldol products are very easily dehydrated to α,β-unsaturated aldehydes or ketones OH O CH3 CHCH 2 CH warm in either acid or base O β α CH3 CH= CH CH + H2 O An α,β-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 Crossed Aldol Reaction Crossed Aldol In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group O NaOH CH3 CCH3 + HCH O O CH3 CCH2 CH2 OH 4-Hyd roxy-2-b utanone Crossed Aldol Reaction Crossed Aldol Crossed aldol reactions are successful if: 1. one of the reactants has no α-hydrogen and, therefore, cannot form an enolate anion and 2. the other reactant has a more reactive carbonyl group, namely an aldehyde O HCH CHO CHO CHO O Furfural 2,2-D imethylprop anal Formald ehyde Benzaldehyde O O NaOH + HCH CH3 CCH3 O CH3 CCH2 CH2 OH 4-Hyd roxy-2-b utanone Crossed Aldol Reaction Crossed Aldol • Nitro groups can be introduced by way of an aldol reaction using a nitroalkane O HO + H-CH2 -N O N itromethane pK a 10.2 (stronger acid) Water p Ka 15.7 (w eaker acid) H-O-H + CH2 -N O O CH2 =N O O Resonance-stabilized an ion – nitro groups can be reduced to 1°amines O + CH3 NO2 Cyclohexan on e N itrometh ane NaOH ( aldol) HO CH2 NO2 H2 , Ni HO CH2 NH2 1-(N itromethyl)cyclohexanol 1-(A min omethyl)cycloh exanol Intramolecular Aldol Reactions intramolecular aldol reactions are most successful for formation of five- and sixmembered rings consider 2,7-octadione, which has two α-carbons α3 O α1 O KOH HO O α1 O KOH OH (n ot formed) O -H2 O (formed) O -H2 O O 2,7-Octanedione O α3 ...
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This note was uploaded on 03/23/2010 for the course CH 310n taught by Professor Iverson during the Spring '08 term at University of Texas at Austin.

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