Week$1$Mechanisms$ $

CHEM$S220ab$

Alex$Engler$

101:$Alkene$+$H2X$ $ $
H Br

Br

Br

102:$Alkene$+$H3O+$ $ $ $103:$Alkene$+$ROH,$H+$ $ $ 104:$Alkene$+$X2$ $ $ 105$&$106:$Alkene$+$X2$+$*2OH$(*$=$H$or$R)$$
Br
Br Br Br
H OHMe

H

OH2
O H OH

H

OH2

OH2

OHMe OHMe
O H OMe

Br

Br

Br

Br

$ $

Br

Br

Br

OH2

OH2

OH

OH2

107:$Alkene$+$H2,$Pd/C$ $ $ $
H2C H H CH2 H3C CH3

H Pd C Pd C

H Pd C

108$&$109:$(Alk)Oxymercuration/reduction$of$Alkenes$ $ $ $ $
Hg AcO OAc

OH2
HgOAc Hg OAc OH2

+ NaBH4

OH2

OH

$

$

1/28$

Week$1$Mechanisms$ $

CHEM$S220ab$

Alex$Engler$

110:$Hydroboration/Oxidation$of$Alkenes$ $ $
B H H H H BH2

H2O2 NaOH
OH

111:$Ozonolysis$w/$reductive$workup$ $ $ 112:$Ozonolysis$w/$oxidative$workup$ $ $ 113:$Alkene$+$HBr,$ROOR$ $RO $
OR

H O

O3

Me2S

+

O

OH O

O3

H2O2

+

O

Br

H

Br Br Br

RO

H

Br

+ Br

$

$

2/28$

Good if 2o. NaOCH . N3-. HCN. NH3 Poor Nuc: Cl-. KOH) -OR (KOtBu.Week$2$Mechanisms$$ $ H H H H H H H H H H CH3 CHEM$S220ab$ Alex$Engler$ 200:$Ring$Flip$for$Chair$Conformations$ $ $ $ $ H H H H H H H H H H CH3 201:$SN2$Substitution$ $ $ $ Nuc: Rc Rb Rb Ra LG nNuc -> σ*LG Nuc Ra Excellent Nuc: CN-. H2O. HOR Rc STERICS: Excellent if Me. HOSO2R. Poor if 3o 202:$E2$Elimination$ $ $ $ $ B: R1 R2 LG R2 R4 H R4 R3 R1 R3 Strong Bases: -OH (NaOH. NaOEt) 3 -H (NaH) -C (R-MgBr) R1 R2 LG H R4 R3 nB -> σ*C-H σC-H -> σ*C-LG Br anti-periplanar has best overlap Br KOEt EtOH 71% Zaitsev $ $ $ $ $ Br Br + 29% Hofmann KOtBu tBuOH + 28% Zaitsev 72% Hofmann 203:$SN1$Substitution$+$E1$Elimination$ EtOH EtOH H O O EtOH H SN1 product (solvolysis) E1 product 204:$E1$Elimination$only$ $ $ $ $ $ $ 3/28$ OH H-OSO3H OH2 HOSO3 H . F-. HCl. H2S. H3O+ Poor LG: HF. H2O Excellent LG: HI. IGood Nuc: OH-. HBr. 1o. CH3O2-. Br-. SH-.

3:$Making$Alcohols$good$LGs$w/$SOCl2$ O O N Cl HO S Cl O O O OH S Cl S Cl S O $ $ $ + Cl + Cl Cl 207.2:$Making$Alcohols$good$LGs$w/$Tosylates$ $ $ $ 207.2:$Simmons2Smith$Reagent:$Carbenoid$ R' Zn-Cu CH2 I ZnI CH2 R R (+/-) R' 207.1:$Dichlorocarbene$ $t Cl Cl Cl Cl C Cl R R' R Cl Br Mg MgBr MgBr H H2O Grignard Formation Cl C Cl Grignard Quenching Cl Cl BuO: H C $ $ $I $ I (+/-) R' 206.4:$Making$Alcohols$good$LGs$w/$PBr3 OH P Br Br Br PBr2 HO Br O + Br H P Br Br $ $ 4/28$ .1:$Making$Alcohols$leave$with$Acid$(conc$HBr$or$conc$HI)$ $ See#201#for#1o#alcohols#and#203#for#3o#alcohols# O O OH Cl S O CH3 R N HO O S OTs 207.Week$2$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 205.122:$Grignard$Formation$&$Quenching$ $ $ 206.

3:$Alkene$(3o)$$Ether$(3o2other)$ H $ R OH O sol H O $ $ 5/28$ .4:$Neighboring$Participation$ $ S Br H S OH OH2 S $ $ Br S Br 307.1:$Thiol$$Disulfide$ $ $ $ $ S S I I S I H S S OH S 305.2:$Thiol$$Sulfide$ $ H S OH S Br S 305.Week$3$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 301:$Alcohol$$Alkoxide$ $ $ H O H O 302:$Thiol$$Thiolate$$ $ H S OH S 305.1:$Alcohol$$Ether$(1o21o/2o)$ $ $ 307.2:$Alkene$$Ether$(2o22o)$ $ $ $ Hg(OAc)2 NaBH4 OH O O Br O 307.

Week$3$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 308.1:$Ether$(1o)$$Dihalide$ $ O H H Br HO Br Br Br Br $ $ $ H O Cl H O Br Br Br H2O 308.1:$Opening$of$Epoxide$in$Acid$ $ $ $ H3C OH sol H O CH3 O CH3 H O OH OH OH 310.2:$Alkene$$Epoxide$(2$steps)$ $ $ $ $ O H O O Br Br Br Br Br H O H OH2 OH Br OH Br Rac 310.2:$Ether$(3o)$$Alcohol$(1o)$+$Halide$(3o)$ $ $ $ Cl H O Cl + HO + HO $ $ $ O O H 309.2:$Opening$of$Epoxide$in$Base$ $ $ $ O CH3 O CH3 O O H OCH3 OH CH3 O $ 6/28$ .1:$Alkene$$Epoxide$(1$step)$ R O O H H2O O R + O 309.

NaOH H H $ $ 7/28$ . H2O2.5:$Alkyne$$Enol$$Aldehyde$ $ $ $ $ $ H BR2 H C CH BR2 H O OH O O 2.122:$Alkyne$$Alkene$Halide$$Geminal$Dihalide$ $ C CH H Br C Br CH2 Br H Br Br $ Br Br C CH Br Br Br 314.1:$Epoxide$$Vicinal$Diol$(anti)$ H2O $ $ O H O H OH H OH OH OH2 OH 312.324:$Alkyne$$Trans$Vicinal$Dihalo$Alkene$$Tetrahalo$Alkane$ $ $ Br H Br Br Br Br Br Br Br Br Br Br Br Br Br 314.Week$3$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 311:$Epoxide$$C2C$bond$via$Grignard$ $ $ O BrMg CH3 HO H O OH 312.2:$Alkene$$Vicinal$Diol$(syn)$ $ $ O O Os O O O O Os O CH3 O O O O H O H2O OH + OH 313:$Vicinal$Diol$$Ketone$&$Aldehyde$ $ $ OH HIO4 O I O = H O CH3 OH O 314.

Week$3$Mechanisms$$ $ Hg2+ C CH C CHEM$S220ab$ Alex$Engler$ 314.2:$Allylic/Benzylic$Hydrogen$$Bromine$ O Br $ $ $ H Cl + Br + Cl Cl Cl (NBS) O 319:$Benzylic$Hydrogen$$Carboxylic$Acid$ $ $ H H H O KMnO4 OH OH O $ $ 8/28$ .1:$Benzylic$Hydrogen$$Bromine$ $ $ $ H Br H Br Br Br Br + Br 318.6:$Alkyne$$Enol$$Ketone$ $ $ $ $ $ OH OH Hg Hg Hg2+ CH Hg H OH2 H2O OH2 OH H O H O OH2 316:$Alkyne$$trans2Alkene$ H NH2 $ $ $ $ H NH2 C C 317:$Alkyne$(terminal)$$Acetylide$$C2C$bond$ $ C NH2 CH C C Br $ Br 318.

2:$Phenyl$Hydrogen$$Bromine$ Br $Br Br Br Br H Fe Br Br Fe $Br $ Br Br solv H Br Br + FeBr4- 401.1:$CrO3$mech:$2o$Alcohol$$Ketone$ pyr pyr H O O Cr O OH O $ $ $ OH O O Cr O O OH O Cr O proton transfer 400.1:$Phenyl$Hydrogen$$Chlorine$ Cl $Cl $Cl $ Cl Cl H Al Cl Cl Cl Al Cl Cl solv H Cl Cl + AlCl4- 401.2:$CrO3$mech:$1o$Alcohol$$Aldehyde$$Carboxylic$Acid$ H2O H H O Cr O O O OH O Cr O O OH O O Cr O OH O H-pyr $ $ $ $ $ $ $ $ HO H OH H+ transfer H3O+ HO OH2 OH2 HO OH O H H H H O Cr O H2O H2O O Cr O O H O O HO O OH Cr O OH H+ transfer + H3O+ + H2CrO3 OH 401.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 400.3:$Phenyl$Hydrogen$$Nitro$ O $ $ O H OSO3H OH O N O OH2 N O H H NO2 solv NO2 N O $ $ 9/28$ .

6:$Friedel2Crafts$Acylation$ $ $ R O O Cl Al Cl R Cl Cl O Cl Al R H R Cl Cl R solv H O O $Cl 402.2:$Elimination2Addition$via$Benzyne$ $ $ $ $ $ NH2 NH2 NH2 H Br Br NH2 NH2 NH2 NH3 NH2 NH3 403.1:$Addition2Elimination$w/$Aryl$Halides$ $ $ $ O N O O2N Cl O2N Cl OH O2N OH OH O N O O N O 402.5:$Friedel2Crafts$Alkylation$ $ $ $ Cl Cl Al Cl Cl Cl Cl Al H Cl Cl solv H 401.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 401.01:$Aldehyde/Ketone$$Cyanohydrin$ $ $ $ O HCN H O CN HO CN H H CN $ 10/28$ .4:$Phenyl$Hydrogen$$Sulfonic$Acid$ $ $ $ O S O H OSO3H O O S O OH H H SO3H solv SO3H 401.

M. OH $ $ 11/28$ .06:$Protecting$Ketones$and$Aldehydes$using$Acetals$ $ $ $ $ $ $ $ $ O H2O H OH H O HO OH H H OH O OH HO H+ O OH HO H2O H H+ O H H OH H OH transfer OH OH solv H+ O O O OH O OH H H H H OH2 $ $ OH2 H+ transfer OH S.04:$Aldehyde$or$Ketyone$in$Base$$Hemiacetal$ $ $ $ $ $ OH HO H O solv-H O OMe HO OMe H H H OMe HO-H O O H O O O O OH 403.02:$Ketone$$Alcohol$&$C2C$via$Grignard$ $ $ MgBr O OH H+ w/u 403.05$&$403.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 403.03:$Aldehyde/Ketone$$Geminal$Diol$or$Hydrate$ HO 2 $ $ $ O H+ OH HO OH2 HO OH H H H H H2O 403.

10:$Wittig$Alkene$Synthesis$ $ $ $ $ $ $ Ph H H O O PPh3 PPh3 Br PPh3 O H Ph H Ph3P: n-Bu: + O PPh3 PPh3 Ph H Ph H 403.07:$Aldehyde$or$Ketone$$Imine$ $ $ $ N H+ O OH HO H H2O NH2Me H H H H+ transfer NHMe NH2Me Me Me solv HN $ $ solv: H N H H 403.08:$Aldehyde$or$Ketone$$Enamine$ $ $ $ O H as above w/ LPP + N N 403.14:$Baeyer2Villiger$Oxidation$ $ $ $ $ R RCO3H O O OH O O R R' R R' RR R' R OH O O H+ O OH R O R' O RR OH RR O R' O R O OH :solv R' 404:$Grignard$+$CO2$$Carboxylic$Acid$ O $ $ $ O MgBr C O O H+ O OH $ 12/28$ .09$&$403.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 403.

4:$Acid2cat$tert2butyl$ester$formation$ $ $ Br OH O O :solv O OH O 405.3:$Esterification$with$halide$in$presence$of$K2CO3$ $ $ $ O O O H3C O I O OH O O OCH3 405.5:$Carboxylic$Acid$$Acid$Chloride$ $ $ $ $ O S O Cl Cl O O S Cl O O S Cl O S O + Cl OH :solv O OH OH OH Cl Cl Cl Cl 405.6:$LAH$Reduction$of$Cbx$Acid$ H O H $ $ $ $ $ O H Al H H2 (g) O H H O Al H Al H H H H H H H H Al H H O OAlH2 H OH O H+ OH O O w/u $ $ 13/28$ .1:$Fischer$Esterification$ $ $ O H+ OH OH H+ OH OH OHR OH OH :solv O OH transfer OR OH2 OR OR ROH 405.2:$Diazomethane$Esterification$ $ $ $ O O H3C O H2C N N N N OCH3 O OH + N2 (g) 405.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 405.

3:$Basic$hydrolysis$(preferred$to$acidic)$ $ $ O O O -OH OH O O H+ O -OH OR OR OH workup OH 406.4:$Dry$Hydrolysis$of$tert2butyl$ester$ $H+ $ O H OR Al H H OR H H O OH O + O OH O H 406.2:$Acidic$Hydrolysis$of$Esters$ $ $ O H+ OH OH H+ OR OH2 OH OH :solv O transfer OR OR OHR OH OH OH H2O 406.1:$Transesterification$ $ $ 406.6:$Reduction$with$DIBAL$at$278oC$$aldehyde$ $ $ Al Al O O H3O+ O $ $ H OR OR H H 406.5:$LAH$reduction$to$primary$alcohol$ $ $ O H O H Al H H H workup H OH O H+ 406.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 406.7:$Grignard$Addition$to$Ester$ $ $ $ $ $ $ 14/28$ Ph O O O O OH H+ OR Ph OR Ph Ph workup Ph BrMg Et BrMg Et .

2# 408.1:$Acidic$hydrolysis$of$amides$ $ same#mech#as#406.1:$Acid$Chloride$with$water$ $ $ $ O O OH OH OH2 O H+ Cl Cl OH2 transfer Cl OH OH OH OH2 OH2 407.2$Basic$hydrolysis$of$amide$ $ same#mech#as#406.4:$LAH$reduction$of$amide$ $ $ $ $ $ H+ workup N $ 15/28$ .1# H Al H H H N H O R H Al H H N H R R N H H R H NR H H Al H H H R H O Al H H H N OAlH2 408.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 407.2:$Acid$Chloride$with$Alcohols$ $ $ $ O O OH OH O H+ Cl Cl OHR transfer Cl OR OR OR OHR 407.3:$Acid$Chloride$with$Amines$ $ $ $ O O OH H+ Cl H2NR Cl NH2R OH Cl NHR pyr O transfer NHR NHR 407.3$Alcoholysis$of$amide$(not$very$effective)$ $ O R N H H same#mech#as#405.3# 408.4:$Acid$Chlorides$with$organozinc$reagents$ $ $ $ O BrZn Cl O O Cl 408.

1:$Weinreb$amide$w/$Grignard$addition$ MgBr Br O O O CH3 R CH3 CH3 N CH3 R CH3 N N Mg O CH3 R $ $ $ $ O O H3O+ O BrMg R 409.3:$Formation$of$Weinreb$amides$ $ $ $ $ Cl CH3 O OCH3 HN O O N CH3 CH3 + pyr 410.2:$Basic$Hydrolysis$of$Nitrile$ $ same#mech#as#406.3:$Nitrile$to$Amine$via$LAH$ $Me $ add "H:-" C N H+ workup twice Me NH2 $ $ 16/28$ .1:$Acidic$Hydrolysis$of$Nitrile$ OH2 OH $ $ $ $ Me C N Me C NH Me NH H+ transfer Me NH2 Me OH OH2 H+ H2O NH2 O same mech as before OH O NH2 410.2:$Weinreb$amide$w/$LAH$reduction$ $ $ $ $ H O O N CH3 CH3 H CH3 N O O O CH3 H CH3 N Al H H3O+ O CH3 O H AlH4 409.3# H H 410.Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$ 409.

1:$Protecting$an$Amine$with$Boc2O$ O $H N 2 O O O O H N O $ Me OH O O OH O Me (Boc) Boc2O $ $ 17/28$ .Week$5$Mechanisms$$ $ HO HO CHEM$S220ab$ Alex$Engler$ 501:$Carbohydrate$$Saccharide$OR$Hemiacetal$$Acetal$ HO $ HO $ $HO $ $ OH H+ O HO HO O HO & deprotonate HO O OH OH HO O HO OH HO O HO OH O O HO OH OH2 HO OH OH HO OH OH 502:$Strecker$Synthesis$of$Amino$Acids$ $H $ $ $N $ $ $ H2N NH2 C Ph Ph OH H2N NH2 H2O OH H2N NH3 Ph HO OH H2N OH O H-NH3 H3N H OH H NH3 H OH NH2 OH2 H NH2 H NH H+ transfer :sol Ph OH2 H2N H2N NH2 Ph OH Ph Ph Ph N Ph NH H2N C H3N-H H NH HN C H2N H2O-H C N OH2 Ph OH Ph NH H+ transfer Ph O H2N OH :sol H+ OH2 Ph Ph transfer Ph Ph 503:$Forming$Peptide$bonds$with$the$Coupling$Agent$DCC$ $ C N R N H R N O R O H2N H N R N H NH2 N R C N N R O O N Ph R $ $ $ $ R OH H+ O sol: R O H N H H+ R N H HO NH N R O transfer O N H OH N R O O O $ $ + N H N H N H N H 504.

1:$Keytone$to$Enol$via$Enolate$in$base$ $ $ $ H O O H-OH OH OH O O OH enolate enol H-OH 506.2:$Keytone$to$Enol$in$acid$ $ $ $ $ sol: H-sol H O H+ OH OH OH :sol O $ 18/28$ .324:$Protecting/Deprotecting$Cbx$Acid$with$acidic$alcohol$/$NaOH$ $ $ $ Boc N H O O O O H2N OH Me MeOH. DCC H N Boc N H O O HF 506.Week$5$Mechanisms$$ $ O CHEM$S220ab$ Alex$Engler$ 504.2:$Deprotecting$an$Amine$with$TFA$ O H2N OH F3C O Me OH Me O $ $ $ O H N OH 504. H+ H2N OMe Me NaOH (aq) H2N OH Me 505:$Solid$Phase$Synthesis$ $ $ Boc OH Cs2CO3 Boc N H O O Cl O N H O $ $ $ $ $ $ H2N Boc TFA O H2N O O OH N H O O OH N H O Cmpd A Cmpd A.

1:$Aldol$Reaction$in$base$ O O O H H H H $ $ $ $ $ O HO-H O O OH O H H OH OH O OH O O aldol addition intermediate H H H H OH aldol condensation product 507.2:$Aldol$Reaction$in$acid$ H+ H $ $ $ $ OH H OH H OH H H+ O O OH H :sol :sol OH O OH O OH OH O sol: H $ Aldol condensation product H2O HO H+ HO HO $ $ Aldol addition intermediate $ $ 19/28$ .5:$Bromoform$from$Methyl$Ketone$ $ $ Ph O O O OH Ph OH O CBr3 Ph O + HCBr3 Ph CBr3 Ph CBr3 HO 507.3:$Ketone$in$acid$to$Alpha2halocarbonyl$via$enol$ $ $ $ 506.4:$Ketone$in$base$to$saturated$Alpha2Halocarbonyl$via$enol$ O O O O O O OH H OH2 OH Br Br OH OH2 Br O Br $ Ph Ph H H H Br Br Ph $OH O Ph H Br Br Br Br Ph Br Br OH 506.Week$5$Mechanisms$$ $ H+ CHEM$S220ab$ Alex$Engler$ 506.

2:$Hydrolysis$&$Decarboxylation$of$β-keto$esters$ $ $ $ $ $ $ 509.Week$5$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 508.2:$Alkylation$and$Decarboxylation$ $ $ $ $ $ $ $ $ $ 20/28$ O Me O H EtO OEt O O OH O O O O OEt OEt H OEt OH Hydrolysis & Decarboxylation O Me OEt H3C OEt I O O O .1:$Claisen$Condensation$ $ $ H O O O O OEt O OEt OEt OEt OEt $ $ $ OEt O O O O O O H+ workup OEt OEt OEt stable enolate O O O O OH O O O H O 508.1:$Alkylation$of$β2dicarbonyl Enolate$Ions$ $ $ $ OEt OMe OMe OH O OH OH O H+ workup H OH OH OH H+ + O C O O O O O O O O O O EtO H OEt EtO OEt EtO Br OEt OEt 509.

2:$Slight$deficit$of$LDA:$Thermodynamic$Lithium$Enolate$ $ $ O Li O + O OLi O + R2N: -78oC H 0.2:$Opening$Epoxides$with$LDA$ O $ OEt O O O OEt O O H+ OEt HO OEt $ workup H :NR2 512.4$Conjugate$Addition$with$R22CuLi$ $ $ $R Li Cu R R R O O O H+ workup $ $ 21/28$ .β2unsataturated$carbonyls$with$Grignards$ O $Ph-MgBr Ph O Ph OH O O O H+ workup Ph-MgBr H+ workup kinetic product Ph Ph $ $R-Li $ $ O R 512.1 eq 510.Week$5$Mechanisms$$ $ O OLi CHEM$S220ab$ Alex$Engler$ 510.9 eq 0.1:$R2Li$or$LiAlH4$addition:$1.1 eq H 0.2$addn$ONLY$ O R OH thermodynamic product H+ workup 512.1 eq Li Me-I $ $ $ LDA -78oC + LiI 511.9 eq O 511.9 eq O 0.3:$1.1:$Alkylation$at$alpha$position$with$LDA$(Ester$or$Nitrile)$ O 0.1:$Slight$excess$of$LDA:$Kinetic$Lithium$Enolate$ $ Li -78oC H $ R2N: 1.1:$α.

β− unsaturated carbonyl O O Me O Aldol Condensation O Me Me O Polycyclic system where new ring has α.β− unsat.4:$Conjugate$additions$with$NaOH. carbonyl.5 dicarbonyl H-OEt $ $ 22/28$ .$NaCN$(in$alcohol$solvent).Week$5$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 512.$or$primary$and$secondary$amines$ $ $Nu: $ $ $ 513:$The$Michael$Reaction$ O O O O O CuLi O O O O sol-H 512.4$Addition$and$Alkylation$ Br O O Nu Nu 2 (+/-) O EtO-H OEt O $ $ OEt H + OEt + O OEt O $ $ $ $ OEt 5 1 2 3 4 O O 5 O 514.$$ $ $$Thiolate$(NaSR). 1.$The$Robinson$Annulation$ $ $ $ $ $ $ $ $ O O HO O O O O H Me OEt O Me O O Me O O Me O H-OEt O O EtO O H β-dicarbonyl O Me Michael Acceptor: α.5:$Tandem$1.

4$ H2 N H N 601.Week$6$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 601. LiAlH4 2.3:$Aryl$Amine$Synthesis$via$Nitro$Reduction$ $ $ $ HNO3 H2SO4 Sn HCl O2N H2N 601. Pd NH2 601.2:$1o$Amine$Synthesis$via$Nitrile$Reduction$ $ $ Br C N C N 1.1:$1o$Amine$Synthesis$via$Azide$Reduction$ $ $ N N N Br N N N N N N H2. H+ w/u NH2 601.4:$2o/3o$Amine$Synthesis$via$Amide$Reduction$ # See#408.5:$2o/3o$Amine$Synthesis$via$Reductive$Amination$ $ $ $ $ 602:$The$Mannich$Reaction:$Making$β2amino$carbonyls$ $ $ $ Ketone/Aldehyde $ $H $ $ $ $ $ 23/28$ Aldehyde H+ O OH HO H O O H+ OH HO H+ transfer H2O HN H2N HN H H B H C N H+ OH OH iminium intermediate HN OH :sol HN :sol H enol intermediate H2 N H2O H N H H2N H H O HN 1o or 2o amine .

22Alkyl$Migration$to$Nitrogen)$ $ $ $ $ $ $ $ $ O H N NH O O Br N N O Br O C N 1o amide H OH Br Br H OH rearrangement step HO-H HO-H NH H N O H N O N O N C O O NH2 OH OH HO OH "amide enolate" 1o amine $ $ 24/28$ .1:$Beckmann$Rearrangement$(1.22Alkyl$Migration$to$Nitrogen)$ O O N N Cl N N N H N Ph OH Ph N N N Ph N N N Ph N Ph C N O $ Ph $ $ $ $ rearrangement step H+ OMe Ph N OMe N OHMe H N Ph O N Ph C O OMe H+ transfer Ph O :sol OH MeOH amide tautomer 603.22Alkyl$Migration$to$Nitrogen)$$OH OH sol: $ $ $ $ $ $ H+ $ N OH OH O H+ OH H2N OH HO H2N OH H2O HN OH HN N H+ H+ transfer oxime intermediate end step 1 ketone (cyclic or acyclic) OH2 :sol OH2 N N OH2 N N N :sol O rearrangement step HN HN $ tautomer of amide "enol form" O O Cl amide 603.3:$Hofmann$Rearrangement$(1.Week$6$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 603.2:$Curtius$Rearrangement$(1.

like SM "Endo" diastereomer "ortho" isomer.2:$Suprafacial$cycloaddition$ $ $ $ $ $ 6 π e∆ ψ1 −> π∗ ∆ π∗ −> π∗ hν NOTE: the UV light excites an electron in the π orbital of one cyclopentene into the π∗ orbital.Week$6$Mechanisms$$ $ O N CHEM$S220ab$ Alex$Engler$ 604. CN) N2 OH H2O 605. allowing suprafacial cycloaddition.1:$Diels2Alder$Reaction$ OMe $ $ NC OMe CN CN H CN H $ $ OMe (+/-) OMe OMe O (+/-) OMe O CN "trans" w/ CN.224:$Reactions$of$Aryl$Diazonium$Salts$ X CuIX H O P H OH (X = Cl. not "meta" 605. hν 4 π eO 605. like SM OMe "cis" w/ OMe. I. Br.3:$Antarafacial$cycloaddition$ $ $ O C O C CH2 O O C CH2 CH2 ∆ CH2 O C O CH2 C CH2 C CH2 ∆ O $ $ $ 25/28$ .1:$Synthesis$of$Aryl$Diazonium$Salts$ $ $ $ N N N N OH2 O H+ O N OH H+ O N OH2 O N NH2 H2 N N O H+ t/f H+ H N N H N N OH OH transfer $ $ $ $ $ N2 N2 Cl 604.

3]$Sigmatropic$Rearrangements$ $ $ $ $ 1 2 3 LUMO of "cation": ψ1 HOMO of "anion": ψ1 2 1 2 3 1 ∆ 3 2 2 3 1 3 1 1 6 π eSuprafacial 2 3 6 5 4 6 5 4 6 5 4 6 5 4 $ $ 26/28$ . 8 π eHOMO: ψ3 Antarafacial ∆ D+ D H3C H ∆ D CH3 D CH3 ∆ H CH3 + CH3 $607.Week$6$Mechanisms$$ $ HOMO: ψ2 6 π e∆ CHEM$S220ab$ Alex$Engler$ 606.2:$Conrotary$Electrocyclic$Opening/Closing$ HOMO: ψ3 8 π e∆ CH3 CH3 HOMO: ψ1 4 π eCH3 CH3 CH3 ∆ CH3 CH3 CH3 CH3 (+/-) CH3 CH3 ∆ H CH3 ∆ CH3 CH3 CH3 H 607.n]$Sigmatropic$Rearrangement$ $ $ $ $ $ $ H3C H H3C 5 p orbitals.1:$[1.1:$Disrotatory$Electrocyclic$Opening/Closing$ $ $ $ $ H3C CH3 CH3 CH3 CH3 CH3 HOMO*: ψ2 4 π eCH3 hν CH3 CH3 CH3 CH3 H CH3 CH3 ∆ CH3 H hν $ $ $ $ $ $ H3C CH3 (+/-) CH3 606.2:$The$Cope$Rearrangement:$[3. 6 π eHOMO: ψ2 Suprafacial H+ ∆ H 7 p orbitals.

3:$HSCoA$Cofactor:$Transesterification$or$Retro2Claisen$ NH3 O NH3 O O O CoAS O H3N OH NH3 aldehyde NADH NAD+ ethanol H-enz enz-H O O HO SCoA H-enz O + :enz enz: Acetyl CoA O enz: H-SCoA Glycine 608.3]$Sigmatropic$Rearrangements$ $ $ $ OH O CO2 6 π e-. Suprafacial CHEM$S220ab$ Alex$Engler$ 607. Suprafacial CO2 O2C ∆ ∆ O O CO2 OH O 608.Week$6$Mechanisms$$ $ 6 π e-.3:$The$Claisen$Rearrangement:$[3.1:$The$Thiamine$Cofactor$(TPP):$Turning$an$α2decarboxylation$into$$ $ a$β2decarboxyliation$ H-enz $ $ $ $ RN H OH S O RN RN O S O OH O O S H O H-enz enz: RN O Decarboxylation Product: Aldehyde α-ketoacid S TPP: Thiamine 2 608.4:$Lipoamide$Cofactor:$Addition$of$a$Leaving$Group$ $ $ $ $ $ $ $ HO S O enz-H R N O O R N OH O R N enz-H OH S S lipoamide R S O S TPP :enz SCoA R O :enz H-enz R OH R N S S SH S SH S R SH H-enz O enz: SH SH H-SCoA + SCoA R Acetyl CoA $ $ 27/28$ .2:$NADH$Cofactor$–$a$source$of$HR$ R H-enz N N $ O + HN 3 H O H H H2N + OH O H $ $ $ $ 608.

5:$ATP$Cofactor:$$ $ $ $ O O Me OH :enz P P P A O O Me O P O Me R R O R R $ $ 28/28$ .Week$6$Mechanisms$$ $ CHEM$S220ab$ Alex$Engler$ 608.