Organic Chemistry II - Chem 231 S'12
Organic Chemistry II - Chem 231 S'12
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Reviews for Organic Chemistry II - Chem 231 S'12
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Date Created: 04/01/14
EAS 0 Must proceed through privileged systems 0 m E V e 1 35 tri substituJ ted m Eu5 m 0 E4 124 lbst39M d EAS in su Itute TM TH E n l m I 1235 I39i sufbs tmed 2 D 1 EAS A m I 1m 0 EAS Rules Can stop each EAS after one reaction Only op disubstituted isomers can be seperates no tritetra separation Proceed only through privileged systems substituents symmetric or all direct to same positions No Friedel Crafts alkylacylation alkyl and acyl halide rxn through carbocationacylium intermediate if RNO2 present too deactivating No Friedel Crafts alkylation alkyl halide rxn through carbocation if carbocation rearrangements are possible 0 Strategies Sulfonationsulfonation is reversible can block 5 position of 123 trisub NO2 directs m reduction and Sandmeyer converts to op director NH2 or from Sandmeyer OH Cl Br I Alkyl directs op converted to acyl via KMnO4 oxidation Acyl directs m can be converted to corresponding alkyl via Clemmenson reduction III Ground Rules for Synthesis 0 Any inorganic starting materials 0 Any organometallic reagent RMgX or R2 CuLi where R a Allyl group b Phenyl ring c Saturated alkyl chain with 4 carbons 0 Organic reagents a Any saturated alcohol aldehyde ketone carboxylic acid alkyl halide with 4 carbons b Any ylide with 4 carbons phenyls in PPh3 don t count c Any ester which acid component contains 4 carbons don t count ester s carbons 0 ONLY ONE functional group per molecule ex no Michael acceptors bc contains both alkene and carbonyl no vinyl halides allyl permitted Allowed reagents 0 Diethyl carbonate starting ester to make diesters from ketones Ethyl acetoacetate acetoacetic ester synthesis 0 O l l Aug Diethyl malonate malonic ester synthesis 0 O O39KkO 12 ethanediol carbonyl protecting group HoOH Diethyl oxalate only 12dicarbonyl not too sure 0 E1O39HJOET 0 Allyl bromide substitutionalkene B Hzc I r Benzyl bromide substitution Br Cyclohexanone ketone 6 ring D Cycloopentanone ketone 5 ring Tosyl Chloride TsCl alcohols gt ROTs O H3CCl 0 Pyridine weak base proton sink mCPBA epoxidation rxn agent CIJH O O C Dimethyl sul de ozonolysis reducing agent S H3C CH3 Mercuric acetate oxymercuration rxn agent 0 C CH3 O Hg O H3C C O Brpmobenzene EAS w m 69 enzaldehyde EAS O D I P1 gt U W OW D W 19 O 93 9 Q enzene EAS H I Q09 O to an 5 an E1 gt m Synthesis Study Guide Feynman Liang CHEM231 Spring 2012 Amherst College I Substitution 0 S2 single step 100 inversion 1 electrophile else E2 dominates DMSO or acetone solvent polar aprotic 0 Snl rate determined by carbocation formation shifts possible racemic product 3 electrophile E1 will always be present H20 or compatible will not generate other products ROH solvent polar protic 0 Good nucleophile sterically unhindered basic 0 Good leaving group strong conj acid Making alkyl halides RX 0 Alcohol using acid from ROHl39 protonation followed by halide substitution of H2 O 522 IHLI Fl 1 HUIHI IHICIIHI SN1 unless 1 SN2 competes with elimination unhindered substrate and good Nu to favor substitution 0 Alcohol using TsCl tosylate OTs L group instead of OHl39 PM I1 TEEH p1rriIIlliInE IFh 2 wX N Br I UIHI IE2 ILIIHF acetone A 2 Ph Fl 39 Two step process 1 convert 2 substitute Could have also eliminated OTs after step 1 in E2 Saytzeff s rule m Na EI I heat 0 Alcohol using SOCI2 IE 7 I 39I j39 lwl QIJITFE s2 ROH soon H0 1 soIgI HGI One step process hydroxyl attacks S and SO2 Cl is displaced by C1 nucleophilic substitution Pyridine should be used to neutralize HCl Will also convert all COOH to COCl Williamson ether synthesis ROR S Fl I F139 I he FIl39 I JH I K 0 S N2 inversion of con guration Alkoxide Ro formed by ROH NaH Na OR 0 Electrophile must be 1 E2 predominates 2 and 3 0 Intramolecular forms cyclic ethers bridged rings epoxides etc 0 Unlike acid C1 or Fisher esteri cation does not require carbonyl group Alkylation of amines RxNH NIH3 GIHI3 I IIZ3H339IH3 I 0 SN2 inversion 0 Possible deprotonation of amide product by NH3 gtNHi39 may result in multiple alkylations 0 1 substrate required or else E2 predominates Other nucleophiles for CC bond making 0 Cyanide CN SW2 2INEC3 FI 39E IIII3 FI I Moderate basegood Nu favors SN2 Can hydrolyze CN to COOH 0 Acetylide anion CECR E IEEEH 1 Fi L 1quot Fl39 ICEICIH Lquot Anion generated from deprotonation pKa25 NaNH2 is good base for this Strong Nu SN2 0 Any decent nucleophile organometals metal hyrdides enolatebased doubly ozC II Alkene addition 0 Formed by eliminaton Alcohol dehydration RROH H3O A gt RR 2 H2O reversed using strong base E2 occurs between antiperiplanar H and L favored over SN2 with strong base steric hindrance higher temp E1 has unselective stereochemistry always accompanies S N1 Regiochemistry follows Saytze quots rule product favors more highly substituted alkene bc hyperconjugation of transition state 0 General Rules for Addition Markovnikov s rule positively charged adding reagant usually H attaches to alkene to create more stable carbocation intermediate to less substituted C so the carbocation has charge on higher substituted C Dimerizepolymerize the carbocation formed can be attacked by the nucleophilic 7rbond Br2 and C12 form trans dihalides through halonium ion Halonium can also be attacked by other Nu Note Nu will attack carbon with more positive charge which is usually more substituted one bc hyperconjugation stabilized Hydrogenation K H H2 Williquot I I GFIS TI GEr I I I I 0 H2 gas and metal catalyst PdC rxn on surface of metal Hydrob oration oxidation III EH3THIF H EEI39 quotla HI39I39l I309 lfl QH an I I I I 0 Two step antiMarkovnikov syn addition of water across double bond with no rearrangements 1 Hydroboration x I 39I39 III IEZEK II EI3THF an E I A I I Concerted single step no rearrangements of carbocation possible Regioselective BH2 adds to less substituted end Markovnikov s rule Synaddition H and BH2 on same face of alkene consistent w concerted Product RBH2 reacts 3x more until trialkylborane BR3 is formed 2 Oxidation of alkylboranewith peroxide IHEDIE NEIDH EFII3 IsIoIIIII3 3 HDIHI BR3 attacked by OOH to form BOR3 which is then substituted by OH Stereochemistry of carbon with BH2 is retained Oxymercuration reduction 1 IHIgI Ac g39HgDI 3 6 2 Mia BlI4 I3s an I 0 0 Threestep Markovnikov antiaddition of water across double bond with no rearrangements 0 Preferred way vs acid catalyzed to hydrate alkene 1 Oxymercuration H P Hgl la 39IIIequot 1 ME Mercurinium prevents rearrangements can form on both faces of alkene 2 Opening of mercurinium ion mmIIIg ME ME IIEII IIIgnIII aInIII p 9 mg DIHI HUI MIR If not symmetric OH adds to more substituted end bc more charge think halonium attack 3 Reduction M3 39 39 3939E Hg c lIaEHII IIIIIe X H 739quotIn H I H I39IIIlIII H9 39III1Ie Stereochemistry of reduction is random Alkene epoxidation alkene gt GPOXICIG gt I OsO4 is similar Intermed can be isolated but generally 0 Can also treat diazonium with KI to form RI transformed to diol with sodium sul te 1hydroxy2substituted RV JV VLQEDVQ HE W U Vv 3 E V V H G1 J CH 2 NEEEGJHEED I I 0 Can also hydrolize with H3O to form R OH fiECVV jib quot I I 0 Use OsO4 if you do not want to oxidize aromatic alkyls to COOH lH P E 39 lI Clemmensen reduction of acyl to alkyl III EAS 0 Singlestep formation of epoxide 3 membered ring with O i H stereochemistry preserved H V H VEI H H EHdHh 39 H lE EWHQ 0 g H m 0 Epoxides can be opened by Nu to give alcohol H H H H H H H l Hj areniumian NIIE quot393 H35 H0 mi v 1 0 Res stabilized arenium intermed substitution trumps addition i Nun Mug bc deprotonation restores aromaticity Under nomacidic Nu attacks 1esshindered Carbon 0 To determineVrVate and directing effects of substituents I think SN 2 with inversion f30mP3 139e Stablhty res hyPe139C0na lnductl of Posslble arenlum O Requires strongly acidic conditions Allows for EAS alkylation lntermed H3 mm0T1d P0St1113 te using acyl groups which won t undergo carbocation shifts and Examples of possible Nu NC HS I RCEC can be reduced to alkyl and many other pathways HO RO Br N3 NH3 Organometals metal 0 In general EDG op activating and EVJWG m deactivating hydrides exgzeption halogens are op deactivating due to induct res Ozonolysis alkene gt two carbonyls 0 Not limited to just benzene EAS also possible on Oxidation of alkyl to n 0 Ozone cleavage of alkene to generate two separate carbonyls 5 J 4 V 3 GH 101 A p quot3 i H Hquot 2 3 H H39 5 H V 3 5 ll 1quot E l V1 lMnD4 lNJ UlHl iii VVV 2 VV IN 2 H 3 VVc iVV anA an D CV 1 H3 Pyridine Pyrrole 0 Alkene gt Molozonide unstable gt Ozonide Diazoniurn ion RNO2 gt RNH2 gt RN Er 0 V m 0 Eitrii lgTCCti rneta directing can be reduced to amino NH2 0 5 J H 1 rH h 9 r gun V Fri if P 3 V HE E Hui E HEVHTJR fin 0 Reverse of Clemmenson basic rxn conditions mechanism Ha Ha mgllumnid 4 H Eli HE Mama I likely through benzylic V EV 2zunlde Hb di V V i V 0 Reduction of Ozonide commonly M62 S yields two carbonyls i I n V l IV Mug Summary of EAS A Me 2iIH32S ID IVI Cllll3IUllJiUIII ilon R5quot V M A H Ugkhg E 0 Careful Hg with Pd C will also hydrolyze alkenes HNU3 H CE 39C 3 B quot2 39Bquot3 Hm ll H2501 l 250quot EL lFeClL3 Elm lFeClL3 G39 quot 39C 39 Flam 0 Amine R NH2 can be converted to diazonium ion 39 l M O H 0 Note reaction can also be intermolecular resulting in only one RN EN which can be further substituted through SN 1 D2 503quotquot Gquot Bquot H I dicarbonyl product v 39 39 Dihydroxylation alkene gt 12diol V Ni P6 P Jjam O Alkene oxidation to 12 diol using KMnO4 or OsO4 H I NJH2 H GDZH H2G39H V V ml D Hg QH I see specrilcnexamiplea E E V R N if quot39 4 39 39 fomnndntlunsaj O I I fC CV E l3 dl l llllllml inn I I I j I I 0 Concerted rst step forms unstable intermediate followed by Reactlons from dlazonlum y N gt v N u J 2 removal of MnO2 0 Sandmeyer reaction Cuprous salt substitution of diazonium GQVM fD 55 D fD H3 5 VDVVV VD K ion srele summary for reactants V I1 MI 0quotquotquotViquotQ D E14 D 2 K 1quot quotquot B Qiu iwi 0ucu louiar leicm S Kl Hl3Uquot39 V H5 39IH I V m Ema ME ME EB 3 mg 5 h Cl Br GM 1 DH R a imr393i39 391 wad sjriawnddimiuin EH3 l IV Carbonyl chemistry Nucleophilic attack at carbonyl 0 To determine reactivity look at stability hyperconj res inductive of charge separated form of carbonyl nuethittmheeie nxygyuen etetmph ite eerbnn 0 Reactivity Acid Cl gt Aldehyde gt Ketone gt Ester gt Amide 0 Aldehydes and ketones undergo addition because no Lgroup 3 3 39 39 I EH1 HI 8NH3 39 Nu Nut 0 Acid Cl ester amide carboxylic acids undergo substitution iEiEJ Fiquot39lLquot L QNIUZ N 5 39i 39 F39 JJ irJ1u LE EHFEHTTEITEETFEquot 0 Nitriles react similarly to carbonyl V Ft GEN P iFt I3iN Addition reactions ketonesaldehydes 0 Hydrationdehydration carbonyl gt 11 diol acid or base catalyzed r Its DH JL i Hlgf H H hjrn tete 0 Acetal formation carbonyl gt acetal acid catalyzed 0 31 FIquotD DHquot JJJL EiFtquotDH P 1 H35 Ft Hquot Ft Pl enetat Hemiacetal intermed unstable only cyclic can be isolated EQ driven towards acetal w excess alcohol or removing H20 Reverse is acetal hydrolysis acid catalyzed No rxn in basic conditions can t eliminate from hemiacetal Addition W nitrogen nucleophile 0 All drived forwards by removing H20 reverse is hydrolysis 0 Imine formation from primary amine netural conditions 1 p5 p5 rm 2 H Ft A H Ft CH irm39ne pH24 prevent protonation of amine to ammonium hydrolysis pH 6 to prevent deprotonation to unreactive carboxylate ion Reductive amination can be achieved by reducing the resulting imine NaBH4 D Flu A FtquottlH2 Z ill H253 0 Enamine formation from secondary amine identical until last step i mi N HECI F H F 39 H In this tease there is HID prnn that can he lnet from the nitrngen Hll etiminie39tinn lrN H Ft tN H F enemtne 0 Tertiary amines are unreactive bc can t stabilize charge Substitution reactions prefer acid Cl unless multiple CO0H 0 Fischer esteri cation RCO0H gt RCO0R HUH t 2 3 iHJ E H D H39iL DH H D1i5t39 Acid catalyzed Kzl driven towards ester w excess RCO0H or R 0H or removing H20 No reaction in base deprotonate to carboxylate Can also be done by attacking acid chloride with alcohol Reverse is ester hydrolysis RCO0R gt RCO0H acid catalyzed but base induced deprotonate to carboxylate Transesteri cation RCO0R R 0H gt RCO0R R OH C H e t HquotCH H t ii5t39IEH FIl39JL DFl iHquotLL D1i5t39 0 Amide hydrolysis substitutes amide NH2 with 0H 3 n IJLL iH3 um JLDH wimp Ft NHE Ft Acid NH2R reacts with acid to form NHI and base NHR reacts with CO0H to form carboxylate induced Can also be done with NH3 nucleophile and acid Cl 0 Activating COOH gt acid Cl with SOCI2 converts CO0H to most reactive acid Cl u SUEIE u Ftquotquotu nH Ale Jr S glm N H Pyridine proton sink prevents excess HCl Acid Cl can be substituted to any other carboxylic acid derivative add weak base to neutralize superior way to form esters and amides o C CH3 CH 0 o l CH3 3 quotN Cl H0 e A 0 quot Clquot i i quot 39739 GI H f33J 0 NaOH 0 lL H2N Ph me A Hcquot o Cl 39 H20 H60 0 PM f3995quot5 i 0 Activating COOH gt anhydride by reacting with acid Cl or another anhydride 0 O O 0 0 i 2 H tc o LcHr ocHa Anhydrides react similarly to acid Cl except eliminates a carboxylic acid 0 0 AOL 0 i 2 H90 OH 74 Acetals carbonyl protecting groups H F Ejp ggt Email i JJN 2Hquot DH A F1 writ tilt Ftquot eeetai Formed via addition of alcohol to carbonyl Acid catalyzed driven towards acetal by removal of water water Reversible hydrolyze with excess water and acid Stable in basic conditions unstable in acidic Allows reversible conversion of carbonyl to diester removing electrophilicity Examples Protecting carbonyl D Te H He DH 2 benzene Protecting alcoholdi alcohol b 39 Ht catalytic 25 G First acid catalyzed acetal formation H30 w protecting group do reaction then acid catalyzed hydrolysis in excess water 12 ethanediol protects carbonyl Diethyl carbonate protects diol Preparation of organometallic reagents using Metal hydride addition carbonyl A o Summary Use H2Cr2O4H20 fol all except making aldehyde iul Etg 2 H3l3 li i32 uli Reactions with organometallic reagents carbonyl A alcohol ketone D O O O O i i JL J H Rig HJLORquot H lL OH Fl H H HMgBrPmdm lFl quot39 OH H OH Hquot OH H OH NO O smflerwurkup HXKH RX H54 RXR REACTION I H VH HI OH mixture Hquot OH Hquot OH Hquot OH Hquot OH HXQL O Hquot OH lJ Pmduut i i quotquot 39iquotquotF39i FigtltII Flgtlt H39 Hgtlt39Hquot Hgtlt Hquot39 H uFlquot39 iHgtlt J quot H39quot Ouu Piuduufl HO HO O HO HO C Offer workup REACTION REACTION HJLNHH HEAOTIOH REACTION HJ39L x n Electron donating metal gives electrons to alkyl forming RCH2 which acts as nucleophile Carboxylic acid derivatives have L group are substituted aldehydeketone are reduced Summary Use organocuprate to make 14 addition on Michael acceptor and converting acid chlorides to ketone All else should use organolithium Don t forget acidic aqueous workup to protonate R0 to alcohol O R X alcohol amide from 1 alcohol p 0 Difference is due to hydration in aqueous conditions thus any 0 X halide Mg 1 HELH Win Rim Hjionl HEROH RJOLMH Hi Cr oxidation rxn w aqueous conditions will react siirnilar to 2 H2 CF04 H2 0 Reagents are Very basic reacts iike R b 3 metai is iAHmduc H OH H OH H OH H OH H H H H H OH 0 Reaction begins with carbonyl oxygen attacking CrO3 to form eieCtT0ii39d0iiatiiig and TeaCtiVe must be DRY iaquot 39iquot 39 i RAH HXH VHXH H H H KOiH Hlt NH2 H chomate ester intermed HCrO3 is eliminated in E2 by any base These nucleophiles are very strong and can participate in all NQBH4 Pm H oH H OH H OH M0 N0 N0 Vvittig reaction Carbonyl gt alkene the previous substitution addition reactions iaflerwurilwiii HXH Kai H94 H REACTION HEEETWN HEM3T0N mmm o Wittig reagent ylide prepared from alkyl halide via phosphonium ion formation and deprotonanion w strong base Grignard reagents RMgX Mg metal with alkyl halide Mia H V I 1 F39iFquoth3 ME EPA Mg inserted in between halide and carbon 0 Summary ALWAYS 1186 LiA1H4 A i m v ha 39 Me i ulLi M V H H3 pT H3CMgH o Electronidonating metal allows hydride H to act as E l Eiz nucleophlle 0 Converts aldehydes and ketones into alkenes by replacing carbonyl double bond 0 The Al metal is magical H RE i 39 H R3 M Organolithium reagents RLi Li R X 03 9 09 FA O s ou Ana q b 2lLi 08 quot39quot 39At MiCf 6 pp Ha PiJla H1 H2 Eta 393quot R OH H ALH I 0 I R 3 H H C 0 Reaction proceeds through 4 membered ring ylide carbon a H Al attacks carbonyl Organocuprate reagents R2CuLi First make R Li then f E 1 react with Cu X twice R H no ates 0 Properties of enolates H2 4 D V 0 iiA r3Ic R N quoti 39 Ff I NE H NH H g N H 39 39 quot H H a H131 llIIENH H 39 39l H3 2 H20 work39Lipv H R F H H o Nitriles can be hydrolyzed twice 9 CH H JlAH a carbon of ketonesaldehydes have weakly acidic H resonance with carbonyl deprotonation generates enolate Ketoenol forms equilibate keto is lower energy and favored at neutral Tautomerization to enol catalyzed by base or acid Must use LDA to forms enolate quantitatively and explicitly prevent multiple alkylations O H QlLi39 I Hi39iwltGl3 LN me HLgOH3 H H Ln IH CH gt we v C 2 H2E 1MarkiJ gt ILIIML o Enolate can then act as nucleophile in substitution reactions with alkyl halides a hydrogen A a substituted However this requires a strong base and can be avoided o If possible prefer the doubly a enolates only one possible enolate less reactive base required Acetoacetic ester synthesisdoubly d proton A d substituted carbonyl or 6 ketoester Chromium oxidants alcohol A carbonyl H H H H H H 3 Q In D i l L r 39i HBGH H H H DlH H Elll Fi V l l Ei EH3 i l3H3 EEg J L7g 5H3 2 Hi li H3 Eh aliiehjf e 1quotquotalOOiO 27 alOOiO 3 HlOOhii Eml l H W H CH 39 V EH3 0 ketoester stabilizes enolate and allows quantitative formation Gr zipwidin MD D E1 MD with mild bases OEtEtOH enolate itself is also less ftilrigrj lHEAGTlDli HJ H HJ39F lHEAGTDN Teaeti 39e 0 Synthetic equivalence ketoester decarboxylation note requires carbonyl to COOH generates same products as D D D 1 1 t tt k HEGFDIJHEDN LL P a M HEADN regu ar eno a e a ac lliii Dllell Fit ICIH Hi ilii 39 i 0 Multiple alkylations before decarboxylation possible as is stopping and extracting 13 dicarbonyl Malonic ester synthesis doublyozproton gt ozsubstituted carboxylic acid or Bketoester QC KZiTiEt G at An Y If U 1 J oE 3 J is U nr quotquotquot quotquot39quot quot LEE 1 NaDEtu39Elf39H 0 Same as acetoacetic except during acidic workup one COOEt wil decarboxylate and other will hydrolyze to carboxylic acid 0 Note any proton doublyoz to two anion stabilizing groups can react similarly Aldol condensation aldehyde gt Bhydroxy or ozBunsaturated ketone D 1 0 MaDH DH 3 39339 Hquotuquot H anuegpfbur Ijdhnnrl 0 Aldehyde acceptor aldehydeketone enolate donor 0 Crossed Aldol acceptor is aldehyde w no ozprotons and donor is symmetrical ketone or has protons on only one ozcarbon 0 Ketone acceptor possible only in intramolecular ring forming rxn Last step of Robinson annulation 0 Optional 8hydroxyl group can be eliminated in Elcb reaction 1 Deprotonate 2 Eliminate OH Lgroup and form oz Bunsaturated carbonyl 0 Reversible acid and base catalyzed Claisen condensation ketoester gt 13dicarbonyl 1 MaDltElEI DH EL El 2 p E El H CIEI p L o aIceptnr fdiunnrjli 0 Ester acceptor esterketone enolate donor 0 Crossed Claisen Donor symmetrical ketone with 23 protons on each ozC or unsymmetrical with 1 H on one ozC and 23 H on other 0 Crossed Claisen Acceptor ester w no ozC 0 Reversible Bketoester must deprotonate to drive EQ Michael addition ozBunsaturated carbonyl gt 15dicarbonyl in in 3 NaICIE1t not C EtCIH donor l EtEp1iDr I Em 39 D 0 Any good nucleophile enolate CN organometals etc attacks a Michael acceptor oz B unsaturated carbonyl 0 Competes with normal carbonyl addition increased by acid protonated ROH has res struct w on 8carbon 0 Ketoester can be decarboxylated to give 15dicarbonyl p l39f39 aCHI39H3C E1 H3U 5 7 D G E El Em quot tr Robinson Annulation Forms bicyclic ring from cyclic enolate donor and Michael acceptor Enolate adds in Michael addition proton shifts form enolate on other side of Michael acceptor s carbonyl enolate attacks in intramolecular aldol condensation
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