Reaction Mechanisms-Alex Engler

Week$1$Mechanisms$ CHEM$S220ab$ Alex$Engler$$

$ $ 1/28$

101:$Alkene$+$H2X$

$

$

102:$Alkene$+$H3O+$

$

$

$103:$Alkene$+$ROH,$H+$

$

$

104:$Alkene$+$X2$

$

$

105$&$106:$Alkene$+$X2$+$*2OH$(*$=$H$or$R)$$

$

$

107:$Alkene$+$H2,$Pd/C$

$

$

$

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

$

$

$

$

H BrBr Br

H OH2OH2 O H

H OH2

OH

H OHMe OHMe OMeO H

OHMe

Br Br Br

Br

Br

Br

Br Br Br

OH2

Br

OH2OH2

Br

OH

H H

Pd

C

Pd

C

H H

H2C CH2

Pd

C

H3C CH3

AcOHg

OAc

Hg

OAc

OH2

OH2

HgOAc

OH2

+ NaBH4

OH

Week$1$Mechanisms$ CHEM$S220ab$ Alex$Engler$$

$ $ 2/28$

110:$Hydroboration/Oxidation$of$Alkenes$

$

$

111:$Ozonolysis$w/$reductive$workup$

$

$

112:$Ozonolysis$w/$oxidative$workup$

$

$

113:$Alkene$+$HBr,$ROOR$

$

$

H2O2

NaOHH

BH

HBH2

H

OH

O3 Me2SO O

H

+

O3 H2O2O O

OH

+

RO OR H BrRO

Br

Br

H Br

Br + Br

Week$2$Mechanisms$$ CHEM$S220ab$ Alex$Engler$$

$ $ 3/28$

200:$Ring$Flip$for$Chair$Conformations$

$

$

$$

201:$SN2$Substitution$

$

$

$

202:$E2$Elimination$

$

$

$

$

$

203:$SN1$Substitution$+$E1$Elimination$

$

$

$

$

204:$E1$Elimination$only$

$

$

$

$

HHH

HH

H

CH3

H

H

H

H

H

CH3

H

H

H

H

H

H

H

HH

Ra

LGNuc:

RbRc

Ra

Nuc

RbRc

Excellent Nuc: CN-, SH-, I-

Good Nuc: OH-, Br-, N3-, NH3

Poor Nuc: Cl-, CH3O2-, F-, H2O

Excellent LG: HI, HBr, HCl, HOSO2R, H3O+

Poor LG: HF, H2S, HCN, H2O, HORSTERICS: Excellent if Me, 1o; Good if 2o, Poor if 3o

nNuc -> σ*LG

LG

H

R1

R3

R2

R4

B:

R2

R1

R4

R3

nB -> σ*C-HσC-H -> σ*C-LG

Strong Bases:-OH (NaOH, KOH)-OR (KOtBu, NaOCH3, NaOEt)-H (NaH)-C (R-MgBr)

LG

H

R1

R3

R2

R4

anti-periplanar hasbest overlap

Br KOEt

EtOH+

71% Zaitsev 29% Hofmann

BrKOtBu

tBuOH

+

28% Zaitsev 72% Hofmann

Br EtOHHO

EtOH

O

SN1 product(solvolysis)

Br

H

EtOH

E1 product

OH

H

HOSO3OH2H-OSO3H


$ $ 4/28$

205.122:$Grignard$Formation$&$Quenching$

$

$

206.1:$Dichlorocarbene$

$

$

206.2:$Simmons2Smith$Reagent:$Carbenoid$

$

$

$

207.1:$Making$Alcohols$leave$with$Acid$(conc$HBr$or$conc$HI)$

$ See#201#for#1o#alcohols#and#203#for#3o#alcohols#

207.2:$Making$Alcohols$good$LGs$w/$Tosylates$

$

$$

207.3:$Making$Alcohols$good$LGs$w/$SOCl2$

$

$

$

207.4:$Making$Alcohols$good$LGs$w/$PBr3

Br Mg MgBr MgBr HH2O

Grignard Formation Grignard Quenching

H C

Cl

Cl

Cl

tBuO: C

Cl

Cl

Cl

ClC

Cl

R R' R R'

Cl Cl

(+/-)

CH2

I

I

R

R'

R R'(+/-)

Zn-Cu

CH2

ZnI

I

OHCl S

O

O

CH3

HOS

O

O

RN

OTs

OHHO

SN

Cl

O

SCl Cl

O

Cl OS

O

Cl

Cl

O S O+

+ Cl

OHHO

PBr2BrBr

P

BrBr

Br

H P

O

Br

Br

+


$ $ 5/28$

301:$Alcohol$$Alkoxide$

$ $

302:$Thiol$$Thiolate$$

$

305.1:$Thiol$$Disulfide$

$

$

$

$

305.2:$Thiol$$Sulfide$

$

305.4:$Neighboring$Participation$

$

$

$

307.1:$Alcohol$$Ether$(1o21o/2o)$

$

$

307.2:$Alkene$$Ether$(2o22o)$

$

$

$

307.3:$Alkene$(3o)$$Ether$(3o2other)$

$

OH

H O

SH

SOH

SH

S

OH

I IS

I

S

SS

SH

SOH

BrS

O Br O

OH

OHg(OAc)2

NaBH4

HR

OHO

Hsol O

SOH

Br H

SOH2

S

BrS

Br


$ $ 6/28$

308.1:$Ether$(1o)$$Dihalide$

$

$

$

$

308.2:$Ether$(3o)$$Alcohol$(1o)$+$Halide$(3o)$

$

$

$

$

309.1:$Alkene$$Epoxide$(1$step)$

$

$

309.2:$Alkene$$Epoxide$(2$steps)$

$

$

$

$

310.1:$Opening$of$Epoxide$in$Acid$

$

$$

310.2:$Opening$of$Epoxide$in$Base$

$

$

O H Br

HO

Br

HOBr

H Br

H2OBr

Br

BrBr

O

H ClCl

HO

Cl

HO+

Cl

HO+

O

O

H O

R

O

O

H O

R+

Br Br

Br

H2O

Br

HO

OH2H

Br

OH

Br

OH

OH

Br

O

O

Rac

O

H

OH

H3C OH

OH

OCH3

Hsol

OH

OCH3

O

O CH3

O

OCH3

H OCH3 OH

OCH3


$ $ 7/28$

311:$Epoxide$$C2C$bond$via$Grignard$

$

$

312.1:$Epoxide$$Vicinal$Diol$(anti)$

$

$

312.2:$Alkene$$Vicinal$Diol$(syn)$

$

$

313:$Vicinal$Diol$$Ketone$&$Aldehyde$

$

$

314.122:$Alkyne$$Alkene$Halide$$Geminal$Dihalide$

$

$

314.324:$Alkyne$$Trans$Vicinal$Dihalo$Alkene$$Tetrahalo$Alkane$

$

$

314.5:$Alkyne$$Enol$$Aldehyde$

$

$

$

$

$

O

BrMgCH3

OHO H

OH

O H OH

H2O

O

OH

H

H

OH2

OH

OH

+O

Os

O

O

O O

Os

O O

O

H2O

OH

OH

OH

OHHIO4

O

I

O O

O

O

O

CH3

H

=H

CH3

O

O

C CH

H BrBr

C CH2

Br

Br

H Br

Br

Br

Br Br

C CH

Br Br

Br

HBr

Br

Br

Br BrBr

Br

Br

Br

Br

Br

BrBr

C CH

H BR2BR2H BR2

2. H2O2, NaOH

O

OHH

O

HH

O


$ $ 8/28$

314.6:$Alkyne$$Enol$$Ketone$

$

$

$

$

$

316:$Alkyne$$trans2Alkene$

$

$

$

$

317:$Alkyne$(terminal)$$Acetylide$$C2C$bond$

$

$

318.1:$Benzylic$Hydrogen$$Bromine$

$

$$

318.2:$Allylic/Benzylic$Hydrogen$$Bromine$

$

$

$

319:$Benzylic$Hydrogen$$Carboxylic$Acid$

$

$

C CH

Hg2+

C CH

Hg2+

H2OOH2

Hg

OH

Hg

OH2

H

OH

Hg

OH

H

OH OH2

O

C C

H NH2

H NH2

C CH

NH2

C C Br

Br Br

H H Br Br Br Br

Br+

+

O

O

Br

(NBS)

+

Cl

Cl ClCl

Br

H H

H H

KMnO4

O

O

OH

OH

Week$4$Mechanisms$$ CHEM$S220ab$ Alex$Engler$

$ $ 9/28$

400.1:$CrO3$mech:$2o$Alcohol$$Ketone$

$

$

$

400.2:$CrO3$mech:$1o$Alcohol$$Aldehyde$$Carboxylic$Acid$

$

$

$

$

$

$

$

$

401.1:$Phenyl$Hydrogen$$Chlorine$

$

$

$

401.2:$Phenyl$Hydrogen$$Bromine$

$

$

$

401.3:$Phenyl$Hydrogen$$Nitro$

$

$

Cl

ClCl

AlCl Cl

Cl

AlCl

Cl

ClCl

H ClH

solv

AlCl4-+

Cl

Br

BrBr

FeBr Br

Br

FeBr

Br

BrBr

H BrH

solv

FeBr4-+

Br

HNO2

Hsolv

NO2ON

OH

O

H OSO3H

ON

OH2

O

ON

O

OH

Cr

O

O O

OH

CrO

OO

pyr

H-pyr

proton

transfer

H

O

CrO

OOH

pyr

O

OHO

CrOO

OH

CrO

OO

H+

transfer

O

CrO

OOH

HH2OH

O

H

O

H2O

H3O+

H

OH HO OH2

H

OH2 HO OH

H

O

CrOO

OH

H

HO CrO

OO

H+

transferO

H

HO CrO

OOH

H2O O

OH

+ H3O+ + H2CrO3


$ $ 10/28$

401.4:$Phenyl$Hydrogen$$Sulfonic$Acid$

$

$

$

401.5:$Friedel2Crafts$Alkylation$

$

$

$

401.6:$Friedel2Crafts$Acylation$

$

$

$

402.1:$Addition2Elimination$w/$Aryl$Halides$

$

$

$

402.2:$Elimination2Addition$via$Benzyne$

$

$

$

$

$

403.01:$Aldehyde/Ketone$$Cyanohydrin$

$

$

HSO3H

Hsolv

SO3HOS

O

O

H OSO3H

OS

OH

O

Cl

AlCl Cl

Cl

AlCl Cl

Cl

H H

solv

Cl

Cl

AlCl Cl

Cl

AlCl Cl

Cl

HH

solvO

R Cl O

R

O

R

OO R

R

N

O2N Cl

O

OOH

N

O2NCl

O

O

OH

N

O2N OH

O

O

Br

HNH2

BrNH2

NH2

NH2

NH3

NH2

NH3

NH2 NH2

H

O

H

O CNHCN

H

HO CN

CN


$ $ 11/28$

403.02:$Ketone$$Alcohol$&$C2C$via$Grignard$

$

$

403.03:$Aldehyde/Ketone$$Geminal$Diol$or$Hydrate$

$

$

$

403.04:$Aldehyde$or$Ketyone$in$Base$$Hemiacetal$

$

$

$

$

$

403.05$&$403.06:$Protecting$Ketones$and$Aldehydes$using$Acetals$

$

$

$

$

$

$

$

$

$

$

MgBrO H+ w/u

OH

H

O H+

H

OH

H2O

H

HO OH2

H2O

H

HO OH

O

H

OMe

O

H

OMesolv-H HO

H

OMe

HOH

O

OH

OH

O OO

HO-H

OOH

O

H

H+ OH

H

OH

HO

HO

H

OH

OH

H+

transfer

H2O

H

O

OH

H

OHO

solv

H

OO

H+

H

OHO

H

O

OH

H

O

OH

OH2

H2O

H

O

OH

H+

transfer

HO

H

OH

OH

OH

H

OH2

S.M.


$ $ 12/28$

403.07:$Aldehyde$or$Ketone$$Imine$

$

$

$

$

$

403.08:$Aldehyde$or$Ketone$$Enamine$

$

$

$

403.09$&$403.10:$Wittig$Alkene$Synthesis$

$

$

$

$

$

$

403.14:$Baeyer2Villiger$Oxidation$

$

$

$

$

404:$Grignard$+$CO2$$Carboxylic$Acid$

$

$

O

H

H+ OH

H

NH2Me

HO H

NH2Me H+

transfer

H2O H

NHMe

H

HNMe

solvNMe

O

HN

+as above

w/ LPPN

Hsolv:

N

Br

Ph3P:

PPh3

Hn-Bu:

PPh3

Ph H

O

O PPh3

Ph H

O PPh3PPh3

PhH

H

Ph

H

+

O

PPh3

MgBrC

O

OO

O

H+ O

OH

R R'

ORCO3H

R R'

OHO

O

O

RR

OHR

OR'

H+

O O

RR

OHR

OR'O OH

RR

R O

OH

R'

:solv

R O

O

R'

H


$ $ 13/28$

405.1:$Fischer$Esterification$

$

$

405.2:$Diazomethane$Esterification$

$

$

$

405.3:$Esterification$with$halide$in$presence$of$K2CO3$

$

$$

405.4:$Acid2cat$tert2butyl$ester$formation$

$

$

405.5:$Carboxylic$Acid$$Acid$Chloride$

$

$

$$

405.6:$LAH$Reduction$of$Cbx$Acid$

$

$

$

$

$

OH

OH+

OH

OH

ROH

OHOHR

OH H+

transferOH2

OR

OH

OR

OH:solv

OR

O

OH

O

H2C N N

O

OH3C N N

O

OCH3

+ N2 (g)

OH

O O

O

O

OCH3O O

O

H3C I

OH

O

Br

OH

O

O

O

:solv

OH

O

O

SCl Cl

OH

OS

O

Cl

ClOH

OS

O

Cl

ClCl

OH

O S O + Cl

:solv

Cl

O

OH

O

H

Al

H

H HH2 (g)

O

O

H

AlH H

O

O

AlH H

H

O

OAlH2H

O

H

H

Al

H

H H

O

HH

H+

w/uOH


$ $ 14/28$

406.1:$Transesterification$

$$

406.2:$Acidic$Hydrolysis$of$Esters$

$

$

406.3:$Basic$hydrolysis$(preferred$to$acidic)$

$

$

406.4:$Dry$Hydrolysis$of$tert2butyl$ester$

$

$

406.5:$LAH$reduction$to$primary$alcohol$

$

$

406.6:$Reduction$with$DIBAL$at$278oC$$aldehyde$

$

$

$

$

406.7:$Grignard$Addition$to$Ester$

$

$

$

$

OR

O H+

OR

OH

H2O

OH

OROH2

H+

transfer

OH

OHROH OH

OH :solv

OH

O

OR

O

OH

O

-OH

O

OHOR OH

O-OH

O

O H+

workup

O

O

H+ OH

O

O

OH

+

O

OR

H

Al

H

HH

O

ORH

O

H

H

Al

H

HH

O

HH

OH

O

OR

Al

H

HOR

OAl H3O+ O

H

Ph

O

OR

BrMg Et

Ph OR

O

Ph

O

BrMg Et

Ph

O

H+

workup Ph

OH

H+

workup


$ $ 15/28$

407.1:$Acid$Chloride$with$water$

$

$$

407.2:$Acid$Chloride$with$Alcohols$

$

$$

407.3:$Acid$Chloride$with$Amines$

$

$$

407.4:$Acid$Chlorides$with$organozinc$reagents$

$

$$

408.1:$Acidic$hydrolysis$of$amides$

$ same#mech#as#406.2#

408.2$Basic$hydrolysis$of$amide$


408.3$Alcoholysis$of$amide$(not$very$effective)$


408.4:$LAH$reduction$of$amide$

$

$

$

$

O

Cl

OH2

O

ClOH2

H+

transfer

OH

ClOH

OH

OH

OH2 O

OH

O

Cl

OHR

O

ClOHR

H+

transfer

OH

ClOR

OH

OR

OH2 O

OR

O

ClBrZn

O

Cl

O

O

NH

R

H

AlH H

H

O

NH

R

H

AlH H

O

N

AlH

HH

H

R

N

R

OAlH2

HH

NR

H

H

AlH H

HH

NR

H

H+

workupN

R

H

O

Cl

O

NH2RCl

H2NR

H+

transfer

OH

NHRCl

OH

NHR

pyr O

NHR


$ $ 16/28$

409.1:$Weinreb$amide$w/$Grignard$addition$

$

$

$$

409.2:$Weinreb$amide$w/$LAH$reduction$

$

$

$$

409.3:$Formation$of$Weinreb$amides$

$

$

$

$

410.1:$Acidic$Hydrolysis$of$Nitrile$

$

$

$

$

410.2:$Basic$Hydrolysis$of$Nitrile$


410.3:$Nitrile$to$Amine$via$LAH$

$

$

O

N

CH3

OCH3

BrMg R

O

N

CH3

OCH3

MgBr

R

O

N

O

Mg

R

Br

CH3

CH3

H3O+

R

O

O

N

CH3

OCH3

O

N

CH3

OCH3

H

O

N

O

Al

H

H

CH3

CH3

H3O+

H

O

AlH4

H

O

N

CH3

OCH3Cl

O

HN

CH3

OCH3

+ pyr

Me C N

H+

Me C NH

H2O Me NH

OH2 H+

transferMe NH2

OH OH

Me NH2

OH2

O

NH2

same mech as beforeO

OH

Me C Nadd "H:-"

twice

H+

workup Me NH2

H H


$ $ 17/28$

501:$Carbohydrate$$Saccharide$OR$Hemiacetal$$Acetal$

$

$

$

$

$

502:$Strecker$Synthesis$of$Amino$Acids$

$

$

$

$

$

$

$

503:$Forming$Peptide$bonds$with$the$Coupling$Agent$DCC$

$

$

$

$

$

$$

504.1:$Protecting$an$Amine$with$Boc2O$

$

$

O

HO

HO

HO

OH

OH

H+

O

HO

HO

HO

OH

OH2

O

HO

HO

HO

OHO

HO

HO

HO

OH

OH

O

HO

HO

HO

OH

OO

OH

HO

OH

OH

& deprotonate

Ph

OH H-NH3

Ph

OHH

H3N

Ph

OHH

NH3

H+

transferPh

OH2H

NH2

Ph

NH2H

:sol

Ph

NHH

Ph

NHH

NC

Ph

CHN

H3N-H

Ph

CH2NNN

H2O-H

Ph

CH2NNH

OH2

Ph

H2N

OH2

NH H+

transfer

Ph

H2N

OH

NH2

Ph

H2N

OH

NH2OH2

Ph

H2NNH2

OHH2O

H+

transfer

Ph

H2NNH3

OHHO

Ph

H2N

OH

OH

:sol

Ph

H2N

O

OH

O

OH

CN

N

H+

CNH

NR R

O

OH

NR

NH

R

sol:O

O

NR

NH

R

H2N

O

O

NR

NH

R

NH2 H+

transfer

HO

O

NR

NH

R

NH

OH

NH

O

NHN

R RO

NH

+

O

NH

NH

H2N

O

OH

Me

O O O

O O

(Boc) Boc2O

HN

O

OH

Me

O

O


$ $ 18/28$

504.2:$Deprotecting$an$Amine$with$TFA$

$

$$

504.324:$Protecting/Deprotecting$Cbx$Acid$with$acidic$alcohol$/$NaOH$

$

$

$

505:$Solid$Phase$Synthesis$

$

$

$

$

$

$

$

$

506.1:$Keytone$to$Enol$via$Enolate$in$base$

$

$

$

506.2:$Keytone$to$Enol$in$acid$

$

$

$

H2N

O

OH

Me

HN

O

OH

Me

O

O

F3C

O

OH

H2N

O

OH

Me

MeOH, H+ H2N

O

OMe

Me

NaOH (aq) H2N

O

OH

Me

NH

O

OHBocNH

O

OBocCs2CO3 Cl

ONH

O

BocTFA O

H2N

OCmpd A

BocNH

OH

O

Cmpd A, DCC ONH

O

O

HN

Boc HF

OHNH

O

O

H2N

O

H OH

O

enolate

H-OH OH

enol

OH O

H-OH

O

O OH OH OH OH+

Hsol: H-sol

:sol


$ $ 19/28$

506.3:$Ketone$in$acid$to$Alpha2halocarbonyl$via$enol$

$

$

$

506.4:$Ketone$in$base$to$saturated$Alpha2Halocarbonyl$via$enol$

$

$

506.5:$Bromoform$from$Methyl$Ketone$

$

$

507.1:$Aldol$Reaction$in$base$

$

$

$

$

$

507.2:$Aldol$Reaction$in$acid$

$

$

$

$

$

$

$

O H+ OH

H

OH2 OH

BrBr

OH

Br

OH2 O

Br

Ph

O

H

Ph

O

HOH HBr Br

Ph

O

H BrOHPh

O

BrBr Br

Ph

O

Br Br

Ph

O

Ph

O

CBr3

HOPh CBr3

O OH

Ph

O

OH

CBr3

Ph

O

O

+ HCBr3

O

H

H OH

O

H

O

HH

O OHO-H

H

OH O

H

OH O

H OHH

OH O

H

O

aldol additionintermediate

aldol condensationproduct

H

O

O

H+

H

OH

OH :sol

H

OH

OH+

H

OH

OH

OH

HO

H

O

HOAldol addition intermediate

sol:OH

HO H+

OH

H2O

OH :solO

Aldol condensationproduct


$ $ 20/28$

508.1:$Claisen$Condensation$

$

$

$

$

$

508.2:$Hydrolysis$&$Decarboxylation$of$β-keto$esters$

$

$

$

$

$

$

509.1:$Alkylation$of$β2dicarbonyl Enolate$Ions$

$

$$

509.2:$Alkylation$and$Decarboxylation$

$

$

$

$

$

$

$

O

OMe

O

OH

O

OMe

O OH O

OH

O

OH

O

O

O

H+ workup

O

O

OH

OHO

C

O

+

H+OH OHO

EtO OEt

H

O O

OEt

EtO OEt

O O

BrEtO OEt

O O

O

H

OHO

EtO OEt

O O O

OEtOEt

O O

OEtH

OH

O O

OEt

H3C I

O O

OEt

MeHydrolysis &Decarboxylation

O

Me

H

O

OEt

OEt

OEt

O O

OEt

O OEt O

OEt

O O

OEt

O O

OEt

O O

OEtH OEtstable enolate

H+

workup


$ $ 21/28$

510.1:$Slight$excess$of$LDA:$Kinetic$Lithium$Enolate$

$

$

510.2:$Slight$deficit$of$LDA:$Thermodynamic$Lithium$Enolate$

$

$

511.1:$Alkylation$at$alpha$position$with$LDA$(Ester$or$Nitrile)$

$

$$

511.2:$Opening$Epoxides$with$LDA$

$

$

512.1:$α,β2unsataturated$carbonyls$with$Grignards$

$

$512.1:$R2Li$or$LiAlH4$addition:$1,2$addn$ONLY$

$

$

$

512.3:$1,4$Conjugate$Addition$with$R22CuLi$

$

$

$

O

R2N:

H1.1 eq

OLiLi

-78oC

O

LDA

-78oC

O Li

Me-I

O

+ LiI

O

Ph-MgBr

OPh

H+

workup

OHPh

kinetic product

O

Ph-MgBr

O

H+

workup

O

thermodynamic productPh Ph

O

R-Li

OR

H+

workup

OHR

O O

H+

workup

O

R RR

CuR

Li

O

OEt

H

O

OEt

OO

OEtO H+

workup

O

OEtHO

:NR2

H

O

Li

R2N:0.9 eq

-78oC

O O+

0.1 eq 0.9 eqH

OLi O+

0.1 eq0.9 eq


$ $ 22/28$

512.4:$Conjugate$additions$with$NaOH,$NaCN$(in$alcohol$solvent),$$$ $$Thiolate$(NaSR),$or$primary$and$secondary$amines$

$

$

512.5:$Tandem$1,4$Addition$and$Alkylation$

$

$

$

513:$The$Michael$Reaction$

$

$

$

$

$$

514.$The$Robinson$Annulation$

$

$

$

$

$

$

$

$

O OO

CuLi2

Br

(+/-)

OEt

H

O O

OEt

+

O

OEt

O O

+

O O

OEt

O

O

EtO-H

O

OEt

O

O

12

34

5

5

O

Nu:

O

Nu

sol-HO

Nu

O

O

H

Me

OEtO

O

Me

O

β-dicarbonylMichael Acceptor:α,β− unsaturatedcarbonyl

OMe

O

O OMe

O

O

H-OEtHEtO

OMe

O

OOMe

OO H-OEt

OMe

OHO

OMe

O

AldolCondensation

Polycyclic system wherenew ring has α,β− unsat.carbonyl; 1,5 dicarbonyl


$ $ 23/28$

601.1:$1o$Amine$Synthesis$via$Azide$Reduction$

$$

601.2:$1o$Amine$Synthesis$via$Nitrile$Reduction$

$$

601.3:$Aryl$Amine$Synthesis$via$Nitro$Reduction$

$

$$

601.4:$2o/3o$Amine$Synthesis$via$Amide$Reduction$

# See#408.4$

601.5:$2o/3o$Amine$Synthesis$via$Reductive$Amination$

$

$

$

$

602:$The$Mannich$Reaction:$Making$β2amino$carbonyls$

$

$

$

$

$

$

$

$

N N N Br NN

N

NN

N

H2, Pd

NH2

BrC N

CN 1. LiAlH4

2. H+ w/uNH2

HNO3H2SO4

O2N

SnHCl

H2N

O H+ OH

H2N

HOH2N

H+

transfer

H2OHN HN

H B

H

C

H

N

HN

O H+ OH

H:sol

OH

O

H

Ketone/Aldehyde

Aldehyde

H+OH

H

H2N

1o or 2o amine

enol intermediate

H

HOH2N

H

H2OHN

HN

H

iminium intermediate

OH HN

:sol

O HN


$ $ 24/28$

603.1:$Beckmann$Rearrangement$(1,22Alkyl$Migration$to$Nitrogen)$$

$

$

$

$

$

$

$

$

603.2:$Curtius$Rearrangement$(1,22Alkyl$Migration$to$Nitrogen)$

$

$

$

$

$

603.3:$Hofmann$Rearrangement$(1,22Alkyl$Migration$to$Nitrogen)$

$

$

$

$

$

$

$

$

O H+ OHH2N

OH

HO H2N OH

H+

transfer

H2O HN OH HNOHsol:

NOH

oxime intermediateend step 1

H+

NOH2

rearrangement step

N

NN

OH2

N

OH2 :sol

N

OH

tautomer of amide"enol form"

H+

HN

OH :sol

HN

O

ketone(cyclic or acyclic)

amide

Ph

O

Cl

NN

N

Ph N

O Cl

NN

Ph N

O

NN

Ph N

O

NN

rearrangement stepPh

CN

O

PhN

CO

MeOH

PhN OHMe

O

H+

transferPh

N OMe

OHamide tautomer

H+

Ph

HN OMe

OH

Ph

HN OMe

O :sol

O

NH

HOH

O

NH

Br Br

O

NBr

HOH

O

NBr

rearrangement step

C

O

N

NC

OHO

ON

OH

OHN

OH

HO-H

"amide enolate"

OH

OHN

O

NH

HO-H

NH2

1o amine

1o amide


$ $ 25/28$

604.1:$Synthesis$of$Aryl$Diazonium$Salts$

$

$

$

$

604.224:$Reactions$of$Aryl$Diazonium$Salts$

$

$

$

$

605.1:$Diels2Alder$Reaction$

$

$

$$

605.2:$Suprafacial$cycloaddition$

$

$

$

$

$

605.3:$Antarafacial$cycloaddition$

$

$

$

ON

O H+ ON

OH H+ ON

OH2 O NNH2

H2N

NO

H+ t/f

HN

NOHH

NN

OH H+

transferN

NOH2N

N

Cl

N2CuIX

(X = Cl, Br, I, CN)

X

N2H2O

OH

N2H P OH

O

H

OMe

OMe

CN

NC

OMe

OMe

CN

CN

OMe OMeO

H

O

H

(+/-) (+/-)

CN "trans" w/ CN, like SMOMe "cis" w/ OMe, like SM

"Endo" diastereomer"ortho" isomer, not "meta"

∆

∆

ψ1 −> π∗π∗ −> π∗

hν

NOTE: the UV light excites an electron in the π orbital of one cyclopentene into the π∗ orbital, allowing suprafacial cycloaddition.

hν

6 π e-4 π e-

CH2CO

CH2CO∆

CH2CO

CH2CO

CH2

C

O

CH2

C

O

∆ O

O

CH2


$ $ 26/28$

606.1:$Disrotatory$Electrocyclic$Opening/Closing$

$

$

$

$

$

606.2:$Conrotary$Electrocyclic$Opening/Closing$

$

$

$

$

$

607.1:$[1,n]$Sigmatropic$Rearrangement$

$

$

$

$

$

$

$607.2:$The$Cope$Rearrangement:$[3,3]$Sigmatropic$Rearrangements$

$

$

$

$

H3C CH3

CH3 CH3∆

HOMO: ψ26 π e-

CH3

CH3

∆

CH3

CH3

CH3

H

H

CH3

hν

CH3

CH3(+/-)

CH3CH3

HOMO*: ψ24 π e-

hν

CH3

CH3

CH3

H

H

CH3

∆

CH3

CH3

CH3CH3

HOMO: ψ14 π e- CH3 CH3

∆

CH3

CH3

H3C CH3

∆CH3

CH3

HOMO: ψ38 π e-

∆

CH3

CH3

(+/-)

H3C H

∆

CH3

H

+

CH3

H

H+∆ H

H3CH3C

5 p orbitals, 6 π e-

HOMO: ψ2Suprafacial

CH3D

∆CH3D

D+

∆

7 p orbitals, 8 π e-

HOMO: ψ3Antarafacial D

LUMO of "cation": ψ1

HOMO of "anion": ψ1

32

1

32

1

12

3

65

4

12

3

65

4

12

3

65

4

12

3

65

4

∆ 6 π e-

Suprafacial


$ $ 27/28$

607.3:$The$Claisen$Rearrangement:$[3,3]$Sigmatropic$Rearrangements$

$

$$

608.1:$The$Thiamine$Cofactor$(TPP):$Turning$an$α2decarboxylation$into$$$ a$β2decarboxyliation$

$

$

$

$

608.2:$NADH$Cofactor$–$a$source$of$H2$

$

$608.3:$HSCoA$Cofactor:$Transesterification$or$Retro2Claisen$

$

$$

608.4:$Lipoamide$Cofactor:$Addition$of$a$Leaving$Group$

$

$

$

$

$

$

$

O ∆ O

CO2

OH

O CO2

∆

6 π e-; Suprafacial 6 π e-; Suprafacial O2C

OH

CO2

O

O

O

O

SRN

α-ketoacid

H-enz

OH

RN

S

OO

OH

RN

S

H-enzO

RN

S

H

enz:

H

O

DecarboxylationProduct: Aldehyde

TPP: Thiamine

O

H

aldehyde

RN

H H

H3N

O

NADH

H-enzRN

H

H2N

O

NAD+

+ +

OH

ethanol

O

NH3

O O

H-SCoAenz:

enz-H

O

NH3

HO OSCoAenz:

H-enz

O

NH3O

OHCoAS

+

:enzAcetyl CoA

H-enz

H3NO

OGlycine

O

O

O

enz-H

O

O

OHRN

S

RN

S

OH

RN

S

SS

R

enz-H

OHRN

S

S

R

SH

:enzO

S

R

SH

H-SCoAenz:

H-enz

HO S

R

SH

SCoA:enz

H-enz

SCoA

O SH SH

R

+

TPP

lipoamide

Acetyl CoA


$ $ 28/28$

608.5:$ATP$Cofactor:$$

$

$

$

P P P A

O

O R

Me OH :enz O

O R

Me O P O

O R

Me

R

Reaction Mechanisms-Alex Engler

Documents

Transcript of Reaction Mechanisms-Alex Engler