Pericyclic Reactions

1
Pericyclic Reactions
????????????????????????????????????? ???
2. ????????????????????, ?????????????????????????
????(radical initiator) ???? ?????????
??????????????????????????????????
3. ???????????????????????????????????????????????
??????? ??????????? ????????????
2
?????????????? transition state ????????????????
???????????????????????????? ??? bonding electron
pairs??????????? ? ??? ????????????
SINGLE STEP
3
4 classes of pericyclic reactions

1. Cycloaddition Reactions
2. Electrocyclic Reactions
3. Sigmatropic Reactions
4. Ene Reactions

4

1. Cycloaddition Reactions

?????? 2 ??????????????? ? ???????????????????????
????? ?????????????? ???????? 2 ?????
??????????????? 2 ?????
cycloaddition
cycloreversion
42 cycloaddition Diels-Alder reaction
5
NOBEL PRIZE 1950
Otto Paul Hermann Diels (1876-1954)
He was the son of a professor of
philology  at the University of Berlin, where he
himself earned his doctorate in chemistry in the
group of Emil Fischer.
Kurt Alder (1902-1958)
He studied chemistry at the University of
Berlin  from 1922, and later at the University of
Kiel where his PhD was awarded in 1926 for work
supervised by Diels.
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DielsAlder Reaction
4?2? cycloaddition

1. ???????????????????????????? (a thermal reaction)
2. ????????????????
3. ????? 3 ? bonds, ????? 2 ? bonds 1 ? bond
4. Concerted ?????????????? ???????????????????????
   ???????????????? (single step)

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More examples of the Diels-Alder reaction
More examples of the Diels-Alder reaction
1,3-Diene
Dienophile
Diels-Alder product
3 new bonds
8
????????????????????????????????? Diels-Alder
reaction
????????????????????????????????? Diels-Alder
reaction
??????? 1
??????????????? 1,3-diene ???????????? s-cis
conformation ???? ?????? dienophile ??????????
????????????????? diene ???? ??????????????
dienophile
????????????????????????
rotate
dienophile
1,3-diene s-trans
s-cis
????????????????????????
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??????? 2
??? ? bonds ???? 3 ???????????????????????????
?????????? ??????????
Diels-Alder product
diene
dienophile
??????????????????????????? Diels-Alder ????????
a)
b)
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??????????????????? Diels-Alder

• Diene reactivity diene ?????????????????????????
  ????????
• conformation ??? s-cis ????????

Acyclic diene ????? s-trans ?????????? ?-bond
??????????????????? s-cis ????????
?????????????????????????
rotate
s-trans
s-cis
reacting conformer
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?????? cyclic diene ..
Conformation ????????????????? ????? ...

• ????? diene ????????? s-cis ???????????????????
• ????? diene ????????? s-trans ?????????????????

s-cis diene
s-trans diene
very reactive
unreactive
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2. Dienophile reactivity ??????????????????
(e-withdrawing group) ?? dienophile
?????????????????????????
???????????? conjugated diene ?????????
nucleophile ???????? dienophile ?????????
electrophile ??????? ??????????????????
(Z) ???????????? dienophile ???? electrophile
????????????? (reactive ????) ????????????????????
??????????????
Z electron withdrawing group
13
??
??
Some common dienophiles
benzoquinone
acrolein
methyl acrylate
maleic anhydride
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3. Stereospecificity ????? dienophile
????????????????? stereochemistry ???????????

• cis dienophile ??????? cis-substituted
  cyclohexene.

• trans dienophile ??????? trans-substituted
  cyclohexene.

cis dienophile
cis product
or
maleic acid
achiral meso compound
trans dienophile
trans product

fumaric acid
enantiomers
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Cyclic dienophile ????????????????? bicyclic
????????????? ??? C-C bond ??????? ???????? fused
ring system
cis Hs in the product
cis Hs in the dienophile

cyclic dienophile
bicyclic product
cis-fused bicyclic compound
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4. The Rule of Endo Addition ???????????? endo
???????????????????? exo
????????? 1,3-diene ????????????????????????????
?????????????????? ??????????????????????
?????????????????? bridged ring system
???? ?????(bridge)?????? C-atom
??????????????????????????????????

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Fused bicyclic system
Bridged bicyclic system
??? C-C bond ???????
??? C-atoms ???????

• carbon atoms ????????????? ?????????????

• 2 ?????????????????????
• carbon atoms ????????????? ??????????

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Endo vs. Exo .?
1C bridge (short)
2C bridge (long)
Z is endo (closer to 2C bridge)
Z is exo (closer to 1C bridge)
??????????????????
endo
endo is under
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Endo ??? exo ?????????????????? ?
???????


endo product major product
electron-withdrawing Z group ????????
electron-rich diene
Z ??????? ? bonds???????????


exo product minor product
Z ????????? ? bonds???????????
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Examples of endo addition
endo
major product
?????????????????????????????????????????
Diels-Alder ????????
a.
b.
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Retrosynthetic Analysis of a Diels-Alder Product
???????????????? ???????????????????? Diels-Alder
????? ??? diene ??? Dienophile ???????????????????
?? ??????????? ......

• ?????????????????? C C (cyclohexene)
• ?????????? 3 ??? ?????????????? cyclohexene
  ??????????? C C ???? ????? 1 ????????????????
  2 ?????????????????????????????,
  ???????????????? ? bond 1 ??? ??? ? bonds 2
  ??? ????????????? ? bonds 3 ???
• ????? stereochemistry ????????????????? C C
  ??? dienophile ?????? ??? ??????????
  stereochemistry ????????????????????????????
  cyclohexene

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Examples on Retrosynthetic Analysis
???? 6 ???????????? CC bond
?????????? 3 ??? ???????? ? bond
?????????????? cis
Diels-Alder product

cis dienophile
starting materials
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Examples on Retrosynthetic Analysis


starting materials
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????????? ???????????????????? diene ???
dienophile ???????????????????????
b.
a.
c.
d.
e.
f.
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?????????????????????? Diels-Alder
??????????????? steroids
Steroids lipids ???????????????????????? 3
??????????????????????? 1 ??
The steroid skeleton
estrone
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Estrone female sex hormone responsible for the
regulation of the menstrual cycle.
C ring ?????????????? Diels-Alder
steps
diene
dienophile
estrone
Diels-Alder product
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More examples of cycloaddition reactions
h?
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64
????????? 1. ? bond ????? 2 , ? bond ?? 2
2. ?????????? ½ ????? electrons
????????????????????
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Photochemical 22 cycloaddition
(E)-2-butene
1,2,3,4-tetramethylcyclobutane
DNA damage from strong sunlight skin cancer
DNA fragment ?? thymine residue 2 ???
Cyclobutane ??? photochemical cycloaddition
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????????? ???????? cycloaddition ??? ????? ?
electrons ??? transition state
Total Number of Electrons in the Transition State
Concerted Cycloaddition Reaction
4n 2 allowed in the ground state forbidden in
the excited state 4n allowed in the excited
state forbidden in the ground state
4n 2 thermal reaction (?)
4n photo reaction (h?)
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Cycloaddition problems
2. ???????????????????????????????????????????????
???????? cyclobutane ring ???????? ...
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2. Electrocyclic Reactions
??????????? concerted intramolecular??????????????
? conjugated ? ???????? ?????????????????????????
? ????????????????????
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Stereochemistry ??????????????????????????????????
?????
h?
h?
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Woodward-Hoffmann rules ?????????????
stereochemistry ???????????? ???????????
electrocyclic
Number of ? electrons Reaction Motion 4n therm
al conrotatory 4n photochemical disrotatory 4n
2 thermal disrotatory 4n2 photochemical conr
otatory
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A Review of ? Molecular Orbitals
?4
?3
LUMO
Energy
Frontier orbitals
?2
HOMO
?1
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Excited state of 1,3-butadiene
Ground state of 1,3-butadiene
?4
LUMO
Frontier orbital
HOMO
LUMO
?3
Energy
Frontier orbital
HOMO
?2
?1
1
2
3
4
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Conrotatory and Disrotatory Motion
excited state
ground state
HOMO
HOMO
in phase
out of phase
?2
?3
3
3
4
4
2
2
different directions
both clockwise
1
1
disrotatory
conrotatory
or
or
forming a new ? bond
but not
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ground state
excited state
?2 HOMO
?3 HOMO
conrotatory
disrotatory


cis
trans
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The reverse reaction electrocyclic ring-opening
280oC
LUMO of ? bond

conrotatory
HOMO of ? bond
?2 (HOMO) of a diene
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h?
diethyl ether
HOMO of ? bond (in the excited state)

disrotatory
LUMO of ? bond (in the ground state)
?2 (HOMO) of a diene
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Electrocyclic reaction of a 4n2 ? system
Excited state of 1,3,5-hexatriene
Ground state of 1,3,5-hexatriene
?6
?5
LUMO
Frontier orbital
?4
Energy
LUMO
HOMO
Frontier orbital
?3
HOMO
?2
?1
1
2
3
4
5
6
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ground state
excited state
?3 HOMO
?4 HOMO
conrotatory
disrotatory


42
Pericyclic Reactions and Vitamin D Synthesis
hv opening of the B ring
7-dehydrocholesterol
37oC rearrangement of a hydrogen atom
Vitamin D3 cholecalciferol
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hv conrotatory
precalciferol
ergosterol
hv conrotatory
lumisterol
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1,7sigmatropic rearrangement
precalciferol
Calciferol vitamin D2
?
Isopyrocalciferol pyrocalciferol
vitamin D2 s-trans conformation
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electrocyclic problems
1. ?????????????????????????????????? ....
2. ???????????????? stereochemistry
?????????????????? ???????? (2E,4Z,6E)-2,4,6-octat
riene ?????????? ??? ?????? uv
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3. Sigmatropic reactions
??????????? concerted intramolecular??????????????
? conjugated ? ???????????????? ?
???????????????????????????????????
???????? ??????????? ? ??????????
3.1 Hydrogen Shifts
Hydrogen atom ??? ????? ? ????????????????????????
?????? ??????? polyene
200 oC
1,5 H shift
(Z)-1,3-pentadiene
(Z)-1,3-pentadiene
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Molecular orbital picture of a 1,5 sigmatropic
rearrangement
phase ???????????
H atom ??????? ????????? C1 ?????????????? C5
s orbital ??? H atom
HOMO ??? ? bond
LUMO ??? diene
diene ???????
sp3 orbital ??? C atom
????? electrons ??????????????? transition state
6 4n 2
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1,5 hydrogen shift animation
?????????????????????????????????????????????? ?
suprafacial
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Molecular orbital picture of a 1,7 sigmatropic
rearrangement
1,7 H shift
H atom ??????? ????????? C1 ???????????????? C7
phase ???????????
HOMO ??? ? bond
LUMO ??? diene
diene ???????
????? electrons ??????????????? transition state
8 4n
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1,7 hydrogen shift animation
??????????????????????????????????????????? ?
antarafacial
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1,7sigmatropic rearrangement
precalciferol
Calciferol vitamin D2
antarafacial

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3.2 The Cope Rearrangement
300 oC
3-methyl-1,5-hexadiene
(E)-1,5-heptadiene
4n2 electrons
transition state
3,3-sigmatropic rearrangement
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???????? ? ????????????????????????? conjugate
??? aromatic ring ???? ???? carbonyl
?????????????????????????????????????????????????
??????????
185 oC
3-methyl-4-phenyl- 1,5-hexadiene
(1E,5E)-1-phenyl- 1,5-heptadiene 90
sigmatropic problems
1) ??????????? cyclobutane ???????????????????????
??? ??????????????????????? ?????????????
1,5-dimethyl-1,5-cyclooctadiene ???????????
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2) ??????????? hex-5-enal ?????????
hexa-1,5-dien-3-ol ???????????????????????????????
???? ????????????? intermediate
??????????????????????
3) ?????????????????? stereochemistry
??????????????????????
180oC
?
280oC
?
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3.3 The Claisen Rearrangement
???? 3,3 sigmatropic rearrangement ??? allyl
ether ????????????????? ? ????????? O atom
ethyl-2-allylacetoacetate 85
O-allyl ether
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Claisen Rearrangement of an Allyl Aryl Ether
K2CO3
acetone
phenol
o-allylphenol
allyl phenyl ether 86
Potassium phenolate
dienone unstable intermediate
57
4 h
2-butenyl phenyl ether
2-(1-methyl-2-propenyl) phenol 85
sigmatropic problems
????????????????????????????
175oC
225oC
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4. Ene reactions
????????????????? ????????????????????
????????????????????????? allylic hydrogen atom
???
150oC

• ?????????
• ????? electrons ????????????? 6 (4n2)
• cyclic transition state

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???????????????? electrocyclic reaction
????????????????????? ? 1 ????????????????? ?
????????? ???????????????????????????????????????
?(????????????????????? intramolecular)
xylene
intermolecular
intramolecular
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????????????????????????????????
??????????????????? electrons ?? transition state
???????????????? ?????????????????????????????????
????????????? pericyclic ?????????
Thermal Reactions Transition state class Configurational Preference
Thermal Reactions 4n 2 (aromatic) Suprafacial or Disrotatory
Thermal Reactions 4n (antiaromatic) Antarafacial or Conrotatory
Photochem Reactions Transition state class Configurational Preference
Photochem Reactions 4n 2 (aromatic) Antarafacial or Conrotatory
Photochem Reactions 4n (antiaromatic) Suprafacial or Disrotatory
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