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126 Cards in this Set
- Front
- Back
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aldol
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3-hydroxybutanal / b-hydroxy aldehydes
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aldol addition
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rxn of 2 aldehyde mlcs to form b-hydroxy aldehyde
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base cat aldol addition involves
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enolate ion as intermediate - enolate ion formed by rxn of acetaldehyde w aqueous NaOH adds to a 2nd mlc acetaldehyde
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how is aldol addition like cyanohidrin formation?
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is aldol addition reversible?
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yes
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like many other carbonyl addition rxns, equil for aldol addition is
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more favorable for aldehydes than for ketones
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in aldol addition rxn of acetone, equil favors
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ketone reactant rather than addition prod, diacetone alcohol - prod can be isolated in good yield only if an apparatus used that allows prod to be removed from base cat as formed
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under more severe conditions (higher B conc, heat, both)
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prod of aldol addition undergoes dehydration rxn
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aldol condensation
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sequence of rxns consisting of aldol addition followed by dehydration
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condensation
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rxn in which 2 mlcs combine to form larger mlc w elimination small mlc, often H2O
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dehydration part of aldol condensation
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b-elimination rxn catalyzed by B, enolate ion intermediate
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how is dehydration diff from E2
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not concerted b-elim
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base cat dehydration rxn of simple alcohols
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unknown
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do ordinary alcohols dehydrate in base
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no
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why do b-hydroxy aldehydes & b-hydroxy ketones dehydrate?
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a-H are relatively acidic (B-promoted b-eliminations are fast when acidic H involved) & prod conjugated, particularly stable
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to extent that TS of dehydration rxn resembles a,b-unsaturated ketone
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it too is stabilized by conjugation & elim rxn accelerated (Hammond's postulate)
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product of aldol condensation
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a,b-unsaturated carbonyl cmpd
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aldol condensation important method for
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preparation a,b-unsaturated carbonyl cmpds
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acid cat aldol condensations give
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a, b unsaturated carbonyl cmpds (addition prod cannot be isolated)
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key reactive intermediate in acid-cat aldol condensations
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conj A of aldehyde/ ketone
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roles of protonated ketone
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source of enol & protonated ketone is electrophilic species in the rxn - reacts as electrophile w pi e of enol to give a-hydroxy carbocation, which is also conj A of addition prod
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a-hydroxy carbocation loses proton to give b-hydroxy ketone prod - under acidic conditions, material spont undergoes acid-cat dehydration to give a,b-unsat carbonyl cmpd
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aldol condensation driven to completion by
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dehydration
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nuc species in acid cat aldol condensation
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enol, not enolate ion
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enolate ions are too ___ to exist in acidic soln
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basic
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although enol is much less nuc than enolate ion,
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reacts @ useful rate bc protonated carbonyl cmpd (an a-hydroxy carbocation) with whih it reacts is potent electrophile
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nuc in base-cat aldol rxn
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enolate ion
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is a protonated carbonyl cmpd an intermediate
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no - too acidic to exist in basic soln
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electrophile that reacts w enolate ion is
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neutral carbonyl cmpd
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crossed aldol rxn
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2 diff carbonyl cmpds used
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result of crossed aldol rxn is
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difficult-to-separate mixture
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crossed aldol rxns that provide complex mixtures
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are not very useful bc prod not formed in high yield & isolation of 1 prod mostly tedious
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altho conditions that favor 1 prod or another in crossed aldol rxns have been worked out in specific cases under usual conditions (aq. or alcoholic A/B) useful crossed aldol rxns limited to situations in which
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a ketone w a-H is condensed w an aldehyde that has no a-H
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Claisen Schmidt condensation
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a ketone w a-H is condensed w aromatic aldehyde w no a-H
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can addition prod be isolated?
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no
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condensation prod
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most stable isomer of highly conj condensation prod
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why can't aldehyde in Claisen-Schmidt rxn act as enolate cmpd component of aldol condensation?
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has no a-H => 2/4 possible crossed aldol prod cannot form
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possible side rxn doesn't occur, why?
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aldol add rxn of ketone w itself - enolate ion from acetone can react either w another mlc of acetone or w benzaldehyde
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add to ketone occursmore ___ than add to aldehyde
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slowly
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even if addition to acetone does occur
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aldol add rxn of 2 ketones is reversible & add to aldehyde has more favorable equil constant than add to ketone
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rate & equil for add to benzaldehyde are more __ than add to 2nd mlc acetone
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favorable
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when a mlc contains 1+ aldehyde / ketone group
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intramlclr rxn possible
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intramlclr aldol condensations particularly favorable when
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5/6 membered rings formed bc of proximity effect
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questions to ask if you want to prepare particular a,b-unsat aldehyde/ ketone by aldol condensation
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what sm required by aldol condensation? with sm, is aldol condensation of cmpds feasible?
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determine sm for aldol condensation
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mentally split a,b unsat carbonyl cmpd
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work backward from desired synthetic objective
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replace db on carbonyl side by 2 H & other by carbonyl O
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is condensation one that works, or one that is likely to give
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troublesome mixtures
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ethyl acetate undergoes Claisen condensation
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in presence of 1 equiv of sodium ethoxide in ethanol to give ethyl 3-oxobutanoate (ethyl acetoacetate)
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b-keto ester
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cmpd w ketone carbonyl group b to ester carbonyl group
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Claisen condensation
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B-promoted condensation of 2 ester mlcs to give a b-keto ester
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first step in mech of Claisen cond
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formation of enolate ion by rxn of ester w ethoxide B
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Why is ethoxide ion used as a B w ethyl esters in Claisen cond?
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ethoxide ion is nuc, also reacts at carbonyl group of ester to give usual nuc acyl sub rxn - products are same as reactants
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Although ester enolate ion formed in low conc, strong B & good nuc, undergoes
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nuc acyl sub rxn w 2nd mlc ester- usual 2 step sub mech (formation of tetrahedral add intermediate followed by loss of LG)
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overall equil lies far on side of
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reactants: all B-keto esters are less stable than esters from which derived
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Claisen cond must be driven to complete by applying
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Le Chateliers
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most common technique
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use one full equiv ethoxide catalyst
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In b-keto ester prod H on C adjacent to both carbonyl groups are especially
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acidic & ethoxide removes one proton to form quantitatively conj B of product
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un-ionized B-keto ester prod formed when
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acid is added subsequently to rxn mixture
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ethoxide ion is catalyst for rxns but
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eventually consumed (reactant, not catalyst overall, so 1 full equiv of ethoxide must be used)
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if Claisen condensation attempted w ester that has only 1 a-H
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no condensation prod is formed - desired cond prod has quaternary a-C, so no a-H acidic enough to react completely w ethoxide (if prod subject to conditions of Claisen, readily decomposes back to sm bc Claisen is reversible)
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Claisen condensation is example of
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nuc acyl sub
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nuc is
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enolate ion derived from an ester
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How is Claisen similar to saponification?
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How does aldol compare to Claisen cond?
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aldol is add of enolate ion/enol w aldehyde/ket followed by dehydration, Claisen is nuc acyl sub rxn of enolate ion w ester group, aldol cat by B & A Claisen full equiv B but no A, aldol requires 1 a-H, 2nd for dehydration step - Claisen: ester sm must have at least 2 a-H, one for each ionization
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Dieckmann cond
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intramclr Claisen cond in 5/6 membered rings
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Dieckmann requirements
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one full equiv of B to form enolate ion of prod & to drive the rxn to completion
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Claisen cond of 2 diff esters
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Crossed Claisen cond
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Not synth useful - crossed Claisen condensation of 2 esters that both have a-H
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mixture of 4 cmpds, diff to separate
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Crossed Claisen cond are useful if
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one ester is esp reactive or has no a-H (formyl -CH=O groups readily intro w esters of formic acid such as ethyl formate) -- Formate esters fulfill both criteria for crossed Claisen cond no a-H, greater reactive carbonyl than other esters bc formate ester is part aldehyde & aldehydes particularly reactive toward nuc
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less reactive ester w/o a-H can be used if present in excess i.e. ethoxycarbonyl group w diethyl carbonate - enolate ion of ethyl phenylacetate condenses preferentially w diethyl carbonate rather than another mlc of itself bc
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much higher conc of of diethyl carbonate & excess diethyl carbonate must then be separated form prod
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in rxn of ketones w esters, enolate ion of ketone
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reacts @ carbonyl group of ester - enolate ion derived from ketone cyclohexane is acylated by ester ethyl formate
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enolate ion of ketone acetophenone
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acylated by ester
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Several side rxns are possible but
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do not interfere
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Possible side rxn of cyclohexanone w itself
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equil for aldol add of 2 ketones favors reactants, whereas Claisen cond is irreversible bc 1 equiv of B used to form enolate ion of prod
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Ester cannot condense w itself bc
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no a-H
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Ester has a-H but self-condensation isn't a side prod bc
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ketones are far more acidic than esters => enolate ion of ketone formed in greater conc than enolate ion of ester
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ketone enolate ion can react w another mlc of ketone (unfavorable equil) OR
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intercepted by excess of ethyl acetate to give observed prod, B-diketone
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even tho esters less reactive than ketones, B-diketone is esp acidic (like B-keto ester) &
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ionized compeltely by one equiv NaOEt => B-diketone formation observed bc ionization makes irreversible rxn
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Planning synth of B-dicarbonyl cmpd
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examine target mlc, work backward to reasonable sm, analyze rxn of sm to see whether desired rxn is reasonable or other rxns will occur instead
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to determine sm for Claisen cond
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mentally reverse cond by adding elements of ethanol (or another ROH) across either C-C bonds btwn carbonyl groups
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Because there are 2 such bonds, we will generally find 2 possible
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disconnections & 2 corresponding sets of sm
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analyzing B-diketone
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sm for biosynth of fatty acids
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thiol ester of acetic acid called acetyl-CoA - complex functionality in mlc required for its recognition by enzymes but has no direct role in chem transformations
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In biosynth of fatty acids, acetyl CoA converted into
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malonyl Co-A by carboxylation of a-C
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-SCoA group in both acetyl & malonyl CoA replaced in nuc acyl sub rxn by
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-SR: acyl carrier protein
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In rxn closely resembling Claisen cond, malonyl & acetyl thiol esters react in enzyme catalyzed rxn to give
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acetoacetyl thiol ester
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nuc e pair made available by loss of
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CO2 from malonyl CoA, which drives Claisen cond to completion
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In laboratory, Claisen cond driven to completion by
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ionization of prod w strong B like ethoxide
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Strong base cannot be used in living cells
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all rxns must occur near neutral pH
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acetoacetyl thiol ester then undergoes successively
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carbonyl reduction, dehydration, & db reduction, each cat by enzyme
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net result is
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acetyl thiol ester converted into a thiol ester w 2 additional C
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sequence of rxns repeated, adding another 2 C to chain
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4 rxns repeated w 2 C to the C chain @ each cycle until
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fatty aid w proper chain length obtained
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fatty acid thiol ester then
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transesterified by glycerol to form fats & phospholipids
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why do common fatty acids have an even # C atoms?
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They are formed from successive addition of 2 C acetate units
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What other cmpds in nature are synth from acetyl CoA?
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isopentenyl pyrophosphate, basic building block of isoprenoids & steroids + some aromatic cmpds found in nature
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malonic ester synth
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like other b-dicarbonyl cmpds has unusually acidic a-H so conj B enolate ion can be formed w alkoxide bases like Na ethoxide
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conj B anion of diethyl malonate is nuc & reacts w alkyl halides & sulfonate esters in sn2 rxns
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can be used to intro alkyl group @ a position of malonic ester - even secondary halides - can be extended to prep of CA
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saponification of diester & acidification of resulting soln gives
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substituted malonic acid derivative
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Heating any malonic acid derivative causes it to
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decarboxylate
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Result of alkylation, saponification, & decarboxylation
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CA that is conceptually a substituted acetic acid - acetic acid mlc w alkyl group on a-C
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malonic ester synth
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overall sequence of ionization, alkylation, saponification & decarboxylation starting from diethyl malonate
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Alkylation step of malonic ester synth results in
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formation of new C-C bond
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Anion of malonic ester can be alkylated twice in 2 successive rxns w
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diff alkyl halides to give after hydrolysis & decarboxylation a disubstituted acetic acid
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If alkyl halides R-X & R'-X are among those that undergo Sn2 rxn, target CA can be
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prepped by malonic ester synth
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why not avoid wasting a Co2Et group in synth of CA by malonic ester alkylation by directly alkylating the enolate ion of an acetic acid ester?
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enolate ions derived from esters, once formed, undergo another faster rxn: Claisen cond w parent ester
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What can be used to form stable enolate ions rapidly at -78 C from esters?
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very strong, highly branched N bases
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Amide
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conj B anion of an amine - has double usage as CA derivative
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Because esters have pKa values near 25, amide B are strong enough to
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convert esters completely into their conj B enolate ions
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Ester enolate anions formed w B can be
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alkylated directly w alkyl halides
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Esters w quaternary a-C atoms can be prepared by this method but not
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malonic ester synth
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N bases gen from corresponding
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amines & butyllithium at -78C in THF solvent
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ester alkylation is considerably more
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expensive than malonic ester synth & requires special inert atm techniques bc strong B used react vigorously w O2 & H2O
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Malonic ester synth useful for
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large scale syntheses
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Prep of lab samples or cmpds unavailable from mal ester synth
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prep & alkylation of enolate ions w amide B particularly valuable
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Why does use of strong amide B avoid Claisen cond?
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reaction is run by adding ester to B
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When a mlc of ester enters the soln
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can react w strong B to form enolate ion or w mlc of already formed enolate ion in Claisen cond
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Rxn of esters w strong amide B so much faster at -78C than Claisen cond that
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enolate ion is formed instantly & never has chance to undergo the Claisen cond
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Claisen cond is avoided bc
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ester & enolate ion are never present simultaneously except for an instant in rxn flask
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Potential side rxn
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uc rxn of amide base or conj A amine at ester carbonyl group
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Amines react w esters to give prod of aminolysis but conj B of amines, strong B, don't react more rapidly w esters bc
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competition - when an amide base reacts w the ester, can either remove a proton or react at carbonyl C
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Rxn at carbonyl C retarded by
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VDW repulsions btwn groups on carbonyl cmpd & large branched groups on B
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If amide b could be in contact w ester long enough would react @ carbonyl C but B reacts more rapidly by --
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abstracting a-proton
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Reaction w tiny H does not involve VDW that would occur if B were to react @ carbonyl C, so
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amide B takes path of least resistance: forms enolate ion
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