Reaction Mechanisms-Alex Engler
28
Week 1 Mechanisms CHEM S20ab Alex Engler 1/28 101: Alkene + HX 102: Alkene + H3O + 103: Alkene + ROH, H+ 104: Alkene + X2 105 & 106: Alkene + X2 + *OH (* = H or R) 107: Alkene + H2, Pd/C 108 & 109: (Alk)Oxymercuration/reduction of Alkenes H Br Br Br H OH 2 OH 2 O H H OH 2 OH H OHMe OHMe OMe O H OHMe Br Br Br Br Br Br Br Br Br OH 2 Br OH 2 OH 2 Br OH H H Pd C Pd C H H H 2 C CH 2 Pd C H 3 C CH 3 AcO Hg OAc Hg OAc OH 2 OH 2 HgOAc OH 2 + NaBH 4 OH
Transcript of Reaction Mechanisms-Alex Engler
Week 1 Mechanisms CHEM S-‐20ab Alex Engler
1/28
101: Alkene + H-‐X
102: Alkene + H3O+
103: Alkene + ROH, H+
104: Alkene + X2
105 & 106: Alkene + X2 + *-‐OH (* = 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 S-‐20ab 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 S-‐20ab 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
Week 2 Mechanisms CHEM S-‐20ab Alex Engler
4/28
205.1-‐2: Grignard Formation & Quenching
206.1: Dichlorocarbene
206.2: Simmons-‐Smith 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
+
Week 3 Mechanisms CHEM S-‐20ab Alex Engler
5/28
301: Alcohol Alkoxide
302: Thiol Thiolate
305.1: Thiol Disulfide
305.2: Thiol Sulfide
305.4: Neighboring Participation
307.1: Alcohol Ether (1o-‐1o/2o)
307.2: Alkene Ether (2o-‐2o)
307.3: Alkene (3o) Ether (3o-‐other)
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
Week 3 Mechanisms CHEM S-‐20ab Alex Engler
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
Week 3 Mechanisms CHEM S-‐20ab Alex Engler
7/28
311: Epoxide C-‐C bond via Grignard
312.1: Epoxide Vicinal Diol (anti)
312.2: Alkene Vicinal Diol (syn)
313: Vicinal Diol Ketone & Aldehyde
314.1-‐2: Alkyne Alkene Halide Geminal Dihalide
314.3-‐4: 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
Week 3 Mechanisms CHEM S-‐20ab Alex Engler
8/28
314.6: Alkyne Enol Ketone
316: Alkyne trans-‐Alkene
317: Alkyne (terminal) Acetylide C-‐C 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 S-‐20ab 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
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
10/28
401.4: Phenyl Hydrogen Sulfonic Acid
401.5: Friedel-‐Crafts Alkylation
401.6: Friedel-‐Crafts Acylation
402.1: Addition-‐Elimination w/ Aryl Halides
402.2: Elimination-‐Addition 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
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
11/28
403.02: Ketone Alcohol & C-‐C 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.
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
12/28
403.07: Aldehyde or Ketone Imine
403.08: Aldehyde or Ketone Enamine
403.09 & 403.10: Wittig Alkene Synthesis
403.14: Baeyer-‐Villiger 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
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
13/28
405.1: Fischer Esterification
405.2: Diazomethane Esterification
405.3: Esterification with halide in presence of K2CO3
405.4: Acid-‐cat tert-‐butyl 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
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
14/28
406.1: Transesterification
406.2: Acidic Hydrolysis of Esters
406.3: Basic hydrolysis (preferred to acidic)
406.4: Dry Hydrolysis of tert-‐butyl ester
406.5: LAH reduction to primary alcohol
406.6: Reduction with DIBAL at -‐78oC 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
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
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
same mech as 406.3
408.3 Alcoholysis of amide (not very effective)
same mech as 405.1
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
Week 4 Mechanisms CHEM S-‐20ab Alex Engler
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
same mech as 406.3
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
Week 5 Mechanisms CHEM S-‐20ab Alex Engler
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
Week 5 Mechanisms CHEM S-‐20ab Alex Engler
18/28
504.2: Deprotecting an Amine with TFA
504.3-‐4: 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
Week 5 Mechanisms CHEM S-‐20ab Alex Engler
19/28
506.3: Ketone in acid to Alpha-‐halocarbonyl via enol
506.4: Ketone in base to saturated Alpha-‐Halocarbonyl 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
Week 5 Mechanisms CHEM S-‐20ab Alex Engler
20/28
508.1: Claisen Condensation
508.2: Hydrolysis & Decarboxylation of β-keto esters
509.1: Alkylation of β-‐dicarbonyl 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
Week 5 Mechanisms CHEM S-‐20ab Alex Engler
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,β-‐unsataturated carbonyls with Grignards
512.1: R-‐Li or LiAlH4 addition: 1,2 addn ONLY
512.3: 1,4 Conjugate Addition with R2-‐CuLi
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
Week 5 Mechanisms CHEM S-‐20ab Alex Engler
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
Week 6 Mechanisms CHEM S-‐20ab Alex Engler
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 β-‐amino 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
Week 6 Mechanisms CHEM S-‐20ab Alex Engler
24/28
603.1: Beckmann Rearrangement (1,2-‐Alkyl Migration to Nitrogen)
603.2: Curtius Rearrangement (1,2-‐Alkyl Migration to Nitrogen)
603.3: Hofmann Rearrangement (1,2-‐Alkyl 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
Week 6 Mechanisms CHEM S-‐20ab Alex Engler
25/28
604.1: Synthesis of Aryl Diazonium Salts
604.2-‐4: Reactions of Aryl Diazonium Salts
605.1: Diels-‐Alder 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
Week 6 Mechanisms CHEM S-‐20ab Alex Engler
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
Week 6 Mechanisms CHEM S-‐20ab Alex Engler
27/28
607.3: The Claisen Rearrangement: [3,3] Sigmatropic Rearrangements
608.1: The Thiamine Cofactor (TPP): Turning an α-‐decarboxylation into a β-‐decarboxyliation
608.2: NADH Cofactor – a source of H-‐
608.3: HSCoA Cofactor: Transesterification or Retro-‐Claisen
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
Week 6 Mechanisms CHEM S-‐20ab Alex Engler
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
