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by: Michelle Gulgowski DVM


Marketplace > University of Kentucky > Chemistry > CHE 232 > ORGANIC CHEMISTRY II
Michelle Gulgowski DVM
GPA 3.91

Robert Grossman

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Robert Grossman
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This 13 page Class Notes was uploaded by Michelle Gulgowski DVM on Friday October 23, 2015. The Class Notes belongs to CHE 232 at University of Kentucky taught by Robert Grossman in Fall. Since its upload, it has received 68 views. For similar materials see /class/228294/che-232-university-of-kentucky in Chemistry at University of Kentucky.

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Date Created: 10/23/15
Chapter 21 Addition of Soft Nucleophiles to Aldehydes and Ketones l W 4 UI Nomenclature a Aldehydes i Systematic Alkanal Ethanalhexanal propenal ii Trivial Formaldehyde acetaldehyde acrolein benzaldehyde b Ketones i Systematic Alkanone Propanone 2butanone 5hexen3one lphenyllethanone 3 Oxobutanoic acid ii Trivial Acetone acetophenone benzophenone Relative stability of aldehydes and ketones Sterically and electronically aldehydes more reactive Nucleophilic addition to aldehydes and ketones a Under basic conditions nucleophiles usually anionic except for amines add to neutral carbonyl compounds After the addition the former carbonyl O is protonated to give the product i Lone pair nucleophiles HO RO RCEC CEN H3N RNH2 ii Already talked about sigma bond nucleophiles b Under acidic conditions nucleophiles always neutral add to protonated carbonyl compounds H20 ROH H3N RNH2 After the addition the nucleophilic atom is deprotonated to give the product Reversible nucleophilic addition to aldehydes and ketones a Carbonyl H20 acid or base lt gt hydrate Slow in pure H 20 Equilibrium favors hydrate only for carbonyl r A with 1 tr 1 quot39 39 groups on ocC s eg Cl3CCHO chloral b Carbonyl ROH acid or base lt gt hemiacetal Slow in pure ROH Equilibrium favors hemi acetal only for carbonyl r A with 1 tr 1 quot39 39 groups on ocC s e g carbo hydrates c Carbonyl HCEN cat base lt gt cyanohydrin Equilibrium favors product in aldehydes Ketones are more ilTy but can buy acetone cyanohydrin Another way to make C C bond E g almonds make mandelic acid from benzaldehyde in this way Nucleophilic addition followed by substitution Acetal formation a RCHO or R2CO R OH cat H4r Z RCHOR 2 or R2COR 2 H20 i Proceeds through hemiacetal Equilibrium toward acetal by removal of H20 pushed toward carbonyl by addition of H20 ii Most convenient with diols such as ethylene glycol Entropy favors second reaction iii Can be selective for aldehydes over ketones Thermodynamically controlled iv Does not work well for esters or acids b Who cares i Polysaccharides are made and broken down in this way Glucose 4OH of glucose gt maltose gt gt starch Glucose fructose anomeric centers linked gt sucrose 6 gt1 9 ii Unlike carbonyl compounds acetals are inert to bases and nucleophiles So ketone or aldehdye can be converted to acetal then reaction carried out on another functional group in molecule eg carboxylic ester then ketone or aldehyde freed up Eg ethyl 4oxo pentanoate to 5hydroxy2pentanone Nucleophilic addition followed by dehydration a Carbonyl RNH2 or NH3 lt gt imine a N analog of a carbonyl compound H20 i Nucleophilic addition to give a hemiaminal carbinolamine is followed by El elimination of H20 H4r comes from N O is protonated before it leaves ii Equilibrium favors imine for R hydroxy alkoxy or amino groups Products called oximes oxime ethers or hydrazones When R alkyl equilibrium usually favors carbonyl but can be pushed toward imine by removal of H20 iii Fastest at nearneutral pH acidic pH protonates starting material and slows first reaction basic pH slows protonation of O in hemiaminal and prevents second reaction 6 V Carbonyl R2NH lt gt enamine a N analog of an enol H20 i Nucleophilic addition to give a hemiaminal is followed by El elimination of H20 H4r comes from C O is protonated before it leaves ii Equilibrium usually favors carbonyl but can be pushed toward enamine by removal of H20 c Who cares i Imines Schiff bases are important biological intermediates Enamines too will see later 39 Retinal makes imine with lysine residue of rhodopsin 39 Conversion of pyruvate to alanine catalyzed by pyridoxal vitamin B6 ii Hydrazine N2H4 carbonyl gt hydrazone Hydrazone KOH in DMSO gt alkane Wolff Kishner reduction Nucleophilic addition followed by elimination Wittig reaction Another way to make C C bond a RCHO or R2CO Phg R39z gt RCHCR 2 or R2CCR 2 Byproduct is Ph3PO b Mechanism Via betaine Questions about existence of betaine but don t worry about it c Ph3P BrCHR 2 gt Ph3JPLCHR 2 Br BuLi gt Ph3 jR 2 Thus half of an alkene can come from an alkyl bromide and the other half from a ketone or aldehyde d Useful for making mono di and trisubstituted alkenes but not for tetrasubstituted alkenes Thus RCHCHR gt RCHO BrCH2R or RCH2Br R CHO And remember RBr gt ROH e Better than addition of Grignard followed by dehydration because dehydration follows Saytzeff s rule 7 thermodynamic ratio of products more substituted favored 7 while Wittig reaction gives only one product Oxidation of aldehydes and ketones a Ketones to esters in BaeyerVilliger reaction RCOR mCPBA gt RCOZR ester 0 atom inserts between carbonyl C and ocC Chapters 1718 Benzene and Aromaticity Naming Benzenoid Compounds Arenes a One small substituent i Nitro bromo propyl isopropyl etc ii Trivial names toluene phenol aniline benzaldehyde benzoic acid benzonitrile b Large substituents Phenyl xxx Ph Aryl xxx Ar Benzyl c Two substituents ortho meta para d Two or more substituents Numbering Structure of benzene Fact All bonds equivalent a Resonance description Toilet bowl description b Molecular orbital description Six AOs therefore six MOs i butadiene acyclic 0 1 2 3 nodes Hexadiene acyclic 0 to 5 nodes ii benzene cyclic can t have one three or five nodes Two possibilities for two nodes or four nodes one for none or six Thus six energy levels of which two pairs are degenerate Frost mnemonic Reactivity of benzene Fact Not a triene a Only substitution not addition Hard to hydrogenate Unusually unreactive b Huckel rule Odd number of pairs of electrons in continuously overlapping cyclic system is unusually stable Even number of pairs of electrons is unsually unstable c Examples of aromatic compounds i benzene pyridine ii cyclopentadienyl anion cycloheptatrienyl cation iii not cyclopentadiene itself not hexatriene iv furan pyrrole v naphthalene anthracene C60 d Examples of anti aromatic compounds i cyclobutadiene Elongates the bonds Not isolable ii cyclopentadienyl cation iii cyclopentadienone iv cyclooctatetraene Folds to avoid overlap e Energy of aromaticity i Extremely hard to hydrogenate benzene Doesn t do Diels Alder reactions Ca 30 kcalmol more stable than expected ii cyclopentadiene 20 orders of magnitude more acidic than pentadiene iii can buy cycloheptatrienyl cation iv some more aromatic than others Anthracene furan do Diels Alder reactions C60 does addition reactions 01 Chapter 14 Chemistry of Arenes Electrophilic Aromatic Substitution Reactivity of Benzene a Relatively unreactive b Substitution of electrophiles not addition Typical alkene reactions like hydrogenation hydroboration dihydroxylation are difficult or don t go at all c Nucleophile Bromination and other halogenation reactions a C6H6 Brz gt NR but FeBr3 promotes reaction gives C6H5Br b Mechanism Addition of electrophile gives cation Br deprotonates cation to reestablish aromaticity Doesn t add c Polybromination can occur if xs Brz is used d C12 FeC13 reacts same way 12 CuClz reacts same way e Use Can convert to Grignards which can react with all sorts of electrophiles especially aquot bond electrophiles Sulfonation a C6H6 H2S04 or S03 oil of vitriol gt gives C6H5SO3H b Mechanism Nature of S20 bonds c Use Sulfa drugs Saccharin OZ Nitration a C6H6 HNO3 gt gives C6H5NOZ b Mechanism Active species is NOf c Not reversible Second nitration is a lot harder Why d Use TNT to make anilines will discuss later Friedel Crafts alkylation a C6H6 RX gt gives C6H5R Requires catalytic amount of strong Lewis acid AlCl3 to make reaction go b Mechanism Active species is R c Limitations i Second alkylation is easier Why To control use excess of arene esp as solvent Sterics sometimes prevents second alkylation Eg anisole t BuCl gives mostly one product ii Works only with Csp3 X Aryl and vinyl halides don t work iii Works best with 3 halides doesn t work well for 1 halides nPrCl gt cumene nBuCl gt sBuC6H5 65 nBuC6H5 35 neopentyl chloride gt 11 dimethylpropylbenzene 0 9 only d Useful to make C C bonds Friedel Crafts acylation a C6H6 RCOX gt gives C6H5COR Requires at least two equivalents of strong Lewis acid A1C13 to make reaction go b Mechanism Active species is RCO Stabilized cation c Acylation always stops after occurring once d Useful to make C C bonds e Can be reduced with ZnH or N2H4 then KOH and A to give 1 alkylbenzenes Regiochemistry and reactivity of electrophilic aromatic substitution a 0p directing activating groups MeO RZN alkyl b m directing deactivating groups COX SO3H CN N02 13113 c 0p directing deactivating groups Hal d strongly acidic conditions of F C reactions turns NHZ 0p director into NH3 m director do psubstitution by acetylating N first with AcZO remove the Ac group with aq NaOH Electrophilic aromatic substitution of heteroarenes a Pyridine reacts at C3 meta to the N atom b Furan and pyrrole react at C2 next to the heteroatom c All can be explained by looking at the relative stability of the different carbocationic intermediates and their resonance structures Further transformations of aromatic substituents a Diazonium ions i C6H5NOZ H2 PdC gt C6H5NH2 NaNOZ HCl gt C6H5N2 ii C6H5N2 CuCl gt C6H5Cl iii C6H5N2 CuBr gt C6H5Br iv C6H5N2 KI gt C6H51 v C6H5N2 H3P02 gt C6H6 vi C6H5N2 CuCN gt C6H5CN Useful to make C C bonds a CN can be converted to COZH with aq NaOH viiC6H5N2 H20 CuO gt C6H50H viiiC6H5N2 HBF4 gt C6H5F b Metal catalyzed couplings i C C bond forming reactions a ArCl RMgCl cat Ph3P2NiC12 gt ArR Kumada coupling b ArX RM cat Pd0 phosphine ligand gt ArR M SnBu3 or SnMe3 BOH2 ZnCl Stille Suzuki Negishi couplings c ArX C0 MeOH base cat Pd0 phosphine ligand gt ArCOZMe d ArX RCECH base cat Cul cat Pd0 phosphine ligand gt ArCECR Sonogashira coupling e use Cspz with BOH2 Cspz or Csp3 with Sn or Zn Csp3 can be primary secondary or tertiary no rearrangements unlike F C chemistry f most widely used methods these days for attaching Csp3 and Csp2 to aromatic rings g Disconnection Ar R gt Ar Br R M 1 If R is CEC M H is best 2 If R is CC M BOH2 is best 3 If R is C C M ZnCl or SnMe3 is best F C alkylation is also an option watch for rearrangements when working forward 4 If in doubt M SnMe3 which works with all kinds of C 5 If R is CO use F C acylation ii C N and C 0 bond forming reactions Buchwald Hartwi g couplings a ArX ROH base cat Pd0 phosphine ligand gt ArOR b ArX R2NH base cat Pd0 phosphine ligand gt ArNRZ c Cannot do these reactions by 8N2 or 8N1 c Comparison of diazonium ions vs cross couplings i Diazonium ion chemistry starts with H gt N02 gt NHZ gt N2 whereas metal catalyzed reactions start with H gt halogen Diazonium chemistry has a meta director intervene before ortho para director can be useful for synthesis E g m bromotoluene ii Metal catalyzed route is much shorter can often buy aryl halides iii Metal catalyzed reaction is much more versatile for making C C bonds Very mild conditions Nonaqueous so more compatible with organic reagents iv Diazonium chemistry can replace N02 with F or OH neither easy to do with metal catalyzed couplings v Two methods can complement one another eg 135 tributylbenzene 10 Nucleophilic aromatic substitution Trinitrochlorobenzene H0 gt picric acid a Can t be 8N2 because backside attack can t occur Can t be SNl because aryl cations are way unstable Can t be electrophilic substitution because H0 is a nucleophile b The nitro groups make benzene 339 bonds electrophilic Negative charge upon attack of H0 is stabilized by N02 groups What other electrophilic 339 bonds do we know about c For aromatic ring to be electrophilic enough to react at room temperature need at least one preferably two N02 groups or other strong electron withdrawing groups 11 Aromatic side chain oxidation a KMnO4 converts alkyl chains attached to benzene rings into COZH groups b All alkyl side chains that contain benzylic H atoms are oxidized 12 Birch reduction a Li liquid NH3 converts benzene into 14 cyclohexadiene b Alkyl and alkoxy groups prefer to end up on the Cspz of the cyclohexadiene product c COZH group prefers to end up on the Csp3 of the cyclohexadiene product 13 Note Many ways to make ArCOZH a ArH X2 Lewis acid gt ArX Mg gt AngX C02 gt ArCOZH b ArH X2 Lewis acid gt ArX CuCN gt ArCN aq NaOH gt ArCOZH c ArH X2 Lewis acid gt ArX C0 MeOH cat Pd0 phosphine ligand gt ArCOZMe d ArH CH3C1 A1C13 gt ArCH3 KMnO4 gt ArCOZH 14 Note ACE does not ask quotdesign a synthesisquot questions Do the book homework Chapter 23 Alpha Substitution of Carbonyl Compounds N l Enolates a Carbonyl compounds are acidic at the CL C can be deprotonated by bases to give enolates i Ketones and aldehydes have pKa 18720 about as acidic as alcohols Acidity of simple carbonyls is directly related to energy of carbonyl the lower in energy the less acidic So aldehydes are more acidic than ketones Acetone a typical ketone has pKa 20 ii Two carbonyl groups are even better than one Generally 13dicarbonyl compounds have pKa of 914 more acidic than alcohols Diethyl malonate has pKa l3 ethyl acetoacetate and malononitrile have pKa ll ethyl cyanoacetate and 24 pentanedione have pKa 9 b Choice of base for deprotonation of carbonyl compounds i Simple carbonyl compounds can be completely and irreversibly deprotonated by a strong base in an aprotic solvent The base most widely used for this purpose LDA is derived by deprotonating i Pr2NH pKa Z 37 with BuLi LDA will deprotonate ketones esters or 30 amides in this way ii LDA deprotonates unsymmetrical ketones on less hindered side steric hindrance iii Limitations to LDA 39 Not useful for aldehydes and acyl chlorides 7 side reactions occur 39 Not useful for deprotonating CH3COX methyl ketones acetonitrile ethyl acetate other esters and amides of acetic acid 7 side reactions occur 39 With 10 or 20 amides deprotonates N iv A moderate base such as EtO cannot deprotonate a simple carbonyl compound irreversibly However a small amount of enolate is generated when NaOEt or another alkoxide is added to a ketone or ester in EtOH or another alcohol and this small amount of enolate can react with some electrophiles EtO deprotonates ketones on more substituted side 7 reversible deprotonation so two di erent enolates are in equilibrium and more substituted enolate is lower in energy v 13Dicarbonyl compounds are completely and irreversibly deprotonated by moderate bases such as NaOEt LDA is not used for 13dicarbonyl compounds overkill c Enolates are nucleophilic at the former a C Reaction of an enolate with an electrophile gives a carbonyl compound with a new bond d Ketones and aldehydes with ocstereocenters racemize readily under acidic or basic conditions Enols a Carbonyl compounds are in equilibrium with enols Enols and carbonyl compounds are tauto mers b Carbonyls are converted to the enols under both acidic and basic conditions i Under acidic conditions protonation then deprotonation Any strong acid in a protic solvent such as EtOH or H20 can be used Sometimes no solvent is used ii Under basic conditions deprotonation to give an enolate then protonation The base is O V typically H0 in H20 EtO in EtOH or t BuO in t BuOH The equilibrium constant for the carbonyl Z enol reaction usually lies far on the side of the carbonyl Cyclohexanone Keq 10396 acetone Keq 1039s The lower in energy the carbonyl the less enol is present at equilibrium Among simple carbonyl compounds only ketones aldehydes and acyl chlorides have enough enol present at equilibrium to be detected chemically Esters and amides have negligible amounts of enol present However all types of l3 dicarbonyl compounds have large amounts of enol present at equilibrium Enols are nucleophilic at the C 5 to the HO group ie at the former CL C Reaction of an enol with an electrophile gives a protonated carbonyl compound Although enols are formed under both acidic and basic conditions they are reactive intermediates under acidic conditions only Under basic conditions the enolate is the reactive species Alkylation of enolates with alkyl halides Forms CiC bonds a U V Alkylation of simple carbonyl compounds Ketones are treated with LDA then with l alkyl halide iodide is best Overall substitution of QC H of carbonyl with alkyl group 39 RCH2COR LDA then R39I gt RCHR39COR Mechanism of substitution is 8N2 of enolate on alkyl halide i V 1 iii Generally useful only for l alkyl iodides allyl bromide or benzyl bromide latter two are particularly reactive toward 8N2 For 2 alkyl halides better to use the l3dicarbonyl approach see below iv Retrosynthesis A CiC bond between the CL C and the 5 C of a carbonyl compound can be made from the simpler carbonyl compound and the alkyl iodide lt V When NaOEt is used as base to alkylate simple carbonyl compounds multiple alkylations occur uncontrollably because the base cannot discriminate between starting material and product as it goes around making small amounts of reactive enolates This does not happen with LDA because all of the starting material is cleanly converted to enolate before the alkylation is carried out vi Not useful for aldehydes because of competing aldol reactions vii If the starting nucleophile is a CH3CO compound better to use the l3dicarbonyl approach below otherwise aldolr eactions can interfere with clean alkylation Alkylation of l3dicarbonyl compounds i CH2CORC02Et NaOEt gt NaCHCORC02Et then R39Br gt R39CHCORC02Et ii Can be done twice R39CHCORC02Et NaOEt gt NaCR39CORC02Et then R Br gt R39CR CORC02Et iii The alkylating reagent can be l or 2 alkyl bromide chloride or iodide 7 much more general than alkylation of simple carbonyl compounds iv The C02Et group can be replaced with H Use the Krapcho decarboxylation H20 DMSO 4 V39 LiCl heat V Retrosynthesis A ketone RCHR39COR can be made from RCHCOR C02Et and R39Br Especially useful for making ii substituted acetone derivatives c Clean monoalkylation of carbonyl compounds requires complete deprotonation of carbonyl compound LDA for simple carbonyls EtO for 13dicarbonyls Reaction of enols with X2 ocHalogenation reactions a Ketone Br2 gt ochaloketone HBr Takes place under acidic conditions C12 can be used too Enol is key intermediate Reaction stops after rst substitution unlike under basic conditions because the electronwithdrawing halogen makes the enol of the product less nucleophilic toward more X2 b HellVolhardZelinskii reaction RCH2C02H PBr3 Br2 gt RCH2COBr gt RCHBrCOBr H20 gt RCHBrCOZH Conversion of acid to acyl halide occurs rst the acyl bromide unlike the acid enolizes rapidly because it is high in energy the enol of the acyl bromide reacts with Br2 Then aqueous workup gives the ochaloacid or addition of alcohol gives the ester c Why useful i ocHalogenation accomplishes umpolung at CC C Addition of Nu e g CN N3 gives substitution reactions at CC C ii ocHaloketones are dehydrohalogenated with pyridine heat to give 0L5unsaturated ketones iii OLChloroacetone is riot control agent tear gas Aldol reaction a We have already discussed reaction of enols and enolates with alkyl halides and elemental halogens A third important class of electrophiles is carbonyl compounds b 2 RCH2CHO cat acid or base gt RCH2CHOHCHRCHO Also works for ketones Requires ocH s or can t occur So PhCHO doesn39t undergo the reaction Equilibrium reaction Favors product for RCH2CHO but favors starting material for R2CHCHO es and ketones due to steric hindrance Both ocalkylation and aldol reactions use carbonyl compound base How do we differentiate D V i ocAlkylation requires alkyl halide In absence of alkyl halide aldol can occur ii Aldol reaction requires undeprotonated carbonyl compound If all carbonyl compound is rapidly and completely deprotonated aldol cannot occur iii For simple carbonyls slow addition of carbonyl to slight excess of LDA ensures that all carbonyl is deprotonated quickly and prevents aldol iv On the other hand for simple carbonyls Eth generates small amounts of enolate in presence of excess of carbonyl so EtO promotes aldol v For 13dicarbonyls EtO deprotonates completely f Forms new CiC bond g Intrarnolecular aldol reactions 6 Aldols can be dehydrated to give 0L5unsaturated carbonyls gt1 9 gt0 a Occurs under either acidic or basic conditions b Can only occur if the aldol product has an ocH Possible for butyraldehyde or cyclohexanone aldol but not for isobutyraldehyde aldol c For ketones aldol reaction is unfavorable but CiC bondforming reaction can be driven toward completion by favorable dehydration Eg cyclohexanone But not for diisopropyl ketone or isobutyraldehyde Mixed aldol reactions a Two different ketones or aldehydes can give four different products upon aldol reaction b The mixed aldol reaction can proceed cleanly i One of the components is an aldehyde lacking ocH s eg PhCHO or CHZO and the other is a carbonyl compound that is resistant to being an electrophile ketone or ester Cyclohexanone PhCHO dehydration follows ethyl hexanoate xs CHZO gives two aldols One is I A 4 1 I r r r 39J with LDA and then the other component is added directed aldol reaction Very useful for esters as nucleophiles Doesn t work well for aldehydes aldol competes with LDA deprotonation iii One of the components is a l3dicarbonyl compound A l3dicarbonyl compound doesn39t act as an electrophile and it is so acidic that only it and not the other carbonyl is deprotonated iv The reaction occurs in an intramolecular fashion So 25hexanedione 26heptanedione and 6oxohexan 2one all cleanly undergo aldoldehydration reactions Regiochemistry questions c Possible to do mixed aldols with esters or amides as the nucleophiles using strategies i or ii above Evans oxazolidinones for enantioselective aldol reactions Retroaldol reaction a A 5hydroxycarbonyl compound can undergo a retroaldol reaction under acidic or basic conditions i Under acidic conditions protonate carbonyl O cleave C bond to give enol and protonated carbonyl do a couple of H4r transfers and deprotonate ii Under basic conditions deprotonate OH cleave CiC bond to give enolate and carbonyl protonate enolate b Retroaldol reaction often occurs to relieve strain c Decarboxylation of a Sketo acid is a retroaldol reaction Conjugate addition a Alkenes are usually nucleophilic but when substituted with a carbonyl group they become electrophilic Acrolein MVK and more highly substituted analogs b An 0L5unsaturated ketone or aldehyde is electrophilic both at the carbonyl C and at the SC c Any reactions that a ketone or aldehyde can undergo at the carbonyl C an 0L5unsaturated ketone or aldehyde can undergo at the SC d Mechanism involves addition of nucleophile to TE bond to form enolate and protonation of enolate to give product e How do you know a priori whether a nucleophile will attack the SC l4addition or the carbonyl C 12addition You don t It s a matter of memorizing the reagents i Amines and CEN usually do l4addition attack SC Another way to make C C bond ii LiAlH4 tends to do l2addition while NaBH4 can do either 12 or l4addition depending on the structure of the substrate But NaBH4 always does l2addition in the presence of CeCl37H20 iii Grignard reagents can do either 12 or l4addition Another way to make C C bond However 39 Grignard reagents always do l2addition in the presence of anhydrous CeCl3 39 Dialkylcuprates Gilman reagents R2CuLi derived from alkyl halide RBr by addition of Li metal and then 12 CuI do l4addition preferentially to 0L5unsaturated ketones So RCOCH2CH2R gt RCOCHCH2 RBr And remember RBr gt ROH iv Good carbon acid e g EtOZCCHR also adds to electrophilic alkene eg CH2CH OMe in the presence of catalytic amounts of base to give product of addition across the TL bond of the alkene EtOZCCR7CH27CH2 OMe Nucleophile can be any enolate but works best with stabilized enolates eg N J s F 39 39 l339 1 quot Must be at least one H on the a carbon f Alkene must have electronwithdrawing group such as carbonyl attached if it is to undergo conjugate addition 10 Enamines a Enols and enolates are nucleophilic at the alkene C not attached to 0 because a resonance structure can be drawn in which that C has a lone pair and a formal negative charge Likewise enamines R2N RCR2 are also nucleophilic at the alkene C not attached to N b Enamines are intermediate in nucleophilicity between enols and enolates c Prepared from ketones or aldehydes and secondary amines e g CH3COCH3 Et2NH Z Et2NCCH3CH2 by removal of H20 d Enamines are not widely used in synthesis any longer they have been superseded by the use of enolates and LDA However enamines are the body39s way of making ketones into nucleophiles at the occarbon The body can t deprotonate ketones and aldehydes with a strong base so it converts them into an enamine which can undergo Michael or aldol reactions Example fructose biosynthesis Claisen and Dieckmann reactions ester and ketone enolates react with esters Makes a C C bond a Mechanism b Thermodynamics i driven by deprotonation of product ii requires one full equivalent of base unlike aldol reaction iii works only with esters with two ochydrogens if product can t be deprotonated doesn t go c Mixed Claisen works if one ester lacks OLhydrogens H7 Phi EtOZCi EtO OZEt d Dieckmann reaction is intramolecular Claisen double Michael adduct as one example e Retron is Soxocarbonyl Disconnect between ocC and carbonyl C f Multiple Claisens plus reductions and eliminations used to make polyketides like erythromycin Thioesters are used instead of esters because thioesters are more electrophilic and more easily deprotonated g RetroClaisen can occur when Sketo ester with quaternary center between carbonyls is treated with NaOEt Combining carbonyl condensation reactions in synthesis a The aldol and Michael reactions both form CiC bonds Can use them in combination to effect powerful synthetic transformations b The Robinson annulation Michael aldol dehydration


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