pericyclic reactions
TRANSCRIPT
© Macquarie University, 2012
CBMS304/CBMS804; Advanced Organic and Biological Chemistry B, Topic 2
Pericyclic Reactions No intermediates No electrophile or nucleophile Rate not dependant on solvent Two or more bonds are broken simultaneously Catalysed by light or heat Are reversible
© Macquarie University, 2012
Pericyclic ReactionsPericyclic Reactions
no electrophile?no nucleophile?no intermediate?
high stereoselectivity
electrocyclicreactions
1 new σ-bondσ1 leσσ π-bondσ
ring cloσing:HOMO of π
ring oπening:HOMO of σ, LUMO of π
diσrotatoryconrotatory
thermal πhotochemical
sigmatropicrearrangements
0 new σ-bondσ0 leσσ π-bondσ
bondσ σhifted
H-σhiftC-σhift
HOMO of σ, LUMO of π
σuπrafacial antarafacial
thermal πhotochemical
MAP FOR 331CONCEPT
cycloadditions2 new σ-bondσ2 leσσ π-bondσ
[4n + 2]π electronσ
[4n]π electronσ
σecondary orbital overlaπ= exo or endo TS
πhotochemicalthermal
HOMO + LUMO
regioσelectivity baσedon electronegativity
© Macquarie University, 2012
Bonding in carbon compounds
Valence bond model Equates covalent bonds with the sharing of two electrons
Thus H should form 1 bond and O 2 etc.
1s
2s
2p { Lewis rule of eight Lewis rule of eight Aufbau principleAufbau principlePauli exclusion principlePauli exclusion principle
© Macquarie University, 2012
Valence Bond Theory
Thus Oxygen should form two bondsAnd Nitrogen three bondsBut why does carbon form four bonds?
O N
H
HHHH
© Macquarie University, 2012
Hybridisation
Carbon should form two bonds but it usually forms four
sp3
CCH
H
H
H
© Macquarie University, 2012
Pauling theory of hybridisation
Mathematical combination of s and p orbitals gives sp3 hybrids
This explains four equivalent bonds and tetrahedral geometry
+ 3 4
sp sp3
© Macquarie University, 2012
Does H2+ exist? Correlation Diagrams
H:H H.H+ ?• Rule #1: Conservation of Orbital Number
H.H+H HH:H
© Macquarie University, 2012
Why is O2 paramagnetic?
Rule #2: Sigma (σ) Orbitals are Always the Lowest Energy [and Sigma* (σ*) the Highest]
Rule #3: pi (π) Orbitals are Higher in Energy than σ but pi* (π*) are Lower than σ*
O O
O
2p2p
O
O O••
© Macquarie University, 2012
Ethylene (or is it ethene)?
Rule #2: Sigma (σ) Orbitals are Always the Lowest Energy [and Sigma* (σ*) the Highest]
Rule #3: pi (π) Orbitals are Higher in Energy than σ but pi* (π*) are Lower than σ*
C
sp2sp2
C
π
σ
σ
π
C CH
H
H
H
LUMO
HOMO
© Macquarie University, 2012
Frontier Molecular Orbitals
Highest Occupied Molecular Orbital (HOMO) andLowest Unoccupied Molecular Orbital (LUMO)
are the orbitals that can either donate or receive electrons from another molecule and thus are the most important
The HOMO of one reactant interacts with the LUMO of the otherie a filled orbital of one and an empty orbital of another are the closest in energy
© Macquarie University, 2012
NH3 + H-Cl NH4Cl
Is something as simple as the reaction of ammonia with hydrochloric acid describable with a correlation diagram?
NH3 HCl
σ*n
NH4+
sp3
HOMO
LUMO
© Macquarie University, 2012
Reaction of ethylene and bromineThe HOMO of ethylene is the π-bondThe LUMO of Bromine in the σ* orbital
π
σ
σ
π
LUMO
HOMO
σ
σLUMO
HOMO
© Macquarie University, 2012
Guidelines to Constructing Molecular Orbitals in Conjugated Systems
With n p-orbitals you get n -orbitals (Rule #1) The energy of the -orbital increases with the number of nodes
(Rule #5) Nodes MUST be symmetrically placed Bonding (π) orbitals have energies less than an isolated p-orbital Non-bonding (n) orbitals have the same energy as an isolated p-
orbital Antibonding (π*) orbitals have greater energy than an isolated p-
orbital Rotation (or reflection) about the centre of the conjugated system
produces an image with phases reversed (A) or the same (S)
© Macquarie University, 2012
The Allyl system
A
S
A0
2
1
nodes
QuickTime™ and aGIF decompressorare needed to see this picture.
QuickTime™ and aGIF decompressorare needed to see this picture.
QuickTime™ and aGIF decompressorare needed to see this picture.π
π*
n
Bonds
–2
0
+2
© Macquarie University, 2012
The Butadiene systemC2
S
A
S
A
mirror
A
S
A
S
© Macquarie University, 2012
The Cyclobutadiene SystemBonds
–3
–1
+1
+3
Bonds
–4
0
+4
Nodes
3
2
1
0
Nodes
4
2
0
© Macquarie University, 2012
The Cyclohexatriene SystemBonds
–5
–3
–1
+1
+3
+5
Nodes5
4
3
2
1
0
Nodes Bonds6 –6
4 –2
2 2
0 6
A
S
A
S
A
S
A
S A
S A
S
© Macquarie University, 2012
Pericyclic reactions
Concerted reactions proceed with no intermediate E.g. SN2 reactions
C Br
H
H H
HO–
C Br
H
H H
HO CHO
H
HHBr–
Pericyclic reactions are concerted reactions with a cyclic transition state
© Macquarie University, 2012
Examples Cycloadditions
1,-3-dipolar additions
Electrocyclic reactions
Sigmatropic rearrangements
OO
O
O
O
O
O
O
+Δ
O
O
O
OH
H
hn
Ph N N NΔ
NN
N
Ph
O OHΔ
© Macquarie University, 2012
Cycloadditions
cycloadditions2 new σ-bondσ2 leσσ π-bondσ
[4n + 2]π electronσ
[2n + 2]π electronσ
σecondary orbital overlaπ= exo or endo TS
HOMO + LUMO
regioσelectivity baσedon electronegativity
thermal πhotochemical
© Macquarie University, 2012
Cycloaddition Reactions: Mechanism
The simplest example is the photolysis of ethylene: A [2π+2π]-cycloaddition
1. Arrow pushing
Electrons can go either way
© Macquarie University, 2012
Cycloaddition Reactions: Mechanism
Consider two ethylenes approaching each other and the π-orbitals slowly become σ-orbitals
© Macquarie University, 2012
Cycloaddition Reactions: Mechanism
2. Correlations Diagrams 2 π-bonds are converted to two σ-bonds
π
π
σ
σS S
A A
S A
A S
© Macquarie University, 2012
Cycloaddition Reactions: Mechanism
2. Correlations Diagrams Photochemically allowed: Excited state goes to excited state
π
π
σ
σ
© Macquarie University, 2012
Cycloadditions: Mechanism
3. Frontier Molecular Orbital (FMO) approach
π
π HOMO
LUMO
X
HOMOLUMO
© Macquarie University, 2012
Cycloadditions: [4π+2π]-Cycloaddition
Also known as the Diels-Alder reaction Involves a 4-electron system (diene) andA 2-electron system (dienophile)3 π-bonds become 2 σ-bonds and one new π-bondNeed to consider only the orbitals that change.
© Macquarie University, 2012
Cycloadditions: [4π+2π]-Cycloaddition
Also known as the Diels-Alder reaction
π1
π2
π2
π1
m1
A
S
A
S
A
S
S A
A
S
S A
© Macquarie University, 2012
Cycloadditions: [4π+2π]-Cycloaddition
FMO model
π1
π2
π2
π1
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
HOMO
LUMO
© Macquarie University, 2012
Cycloadditions: [4π+2π]-Cycloaddition
Aromatic TS Rule Add up the number of electrons involved in the transition
state (TS) If the TS is aromatic then the reaction is thermally allowed (4n+2) electrons is the magic number because it allows
electron delocalisation and REDUCTION in overall energy
© Macquarie University, 2012
Secondary Effects: Secondary Orbital Overlap
Notice that in the Diels-Alder reaction the dienophile approaches the diene from one face: Suprafacial.
QuickTime™ and aGIF decompressorare needed to see this picture.
© Macquarie University, 2012
Secondary Effects: Secondary Orbital Overlap
What happens if the dienophile is more than just an alkene? For the dimerisation of cyclopentadiene, you can have endo
or exo attack
exo endo
© Macquarie University, 2012
Secondary Effects: Secondary Orbital Overlap
The two orientations end up with different stereochemistries
exo
endo
H
H
H
H
© Macquarie University, 2012
Secondary Effects: Secondary Orbital Overlap
Frontier molecular orbital analysis
π1
π2
π2
π1
LUMO
HOMO
exo
endo
© Macquarie University, 2012
DNA damage; an example of [2π+2π]-cycloaddition
Two thymidine bases can react when one is excited photochemically.
HN
N N
NH
O O
O O
HN
N N
NH
O O
O OH H
280 nm
240 nm
© Macquarie University, 2012
Not all cycloadditions are endo
[6π+4π]-cycloadditions
O O
O O
Exo
EndoX
© Macquarie University, 2012
Secondary effects: Regioselectivity
If the diene and dienophile are substituted many products are possible
OCH3
OHCOCH3
OCH3
CHOOCH3
CHO
OCH3
CHOCHO
© Macquarie University, 2012
Secondary effects: Regioselectivity
[4π+2π]-cycloaddition, therefore thermally allowedAldehyde has a double bond that is conjugated with
the dienophile so it is really a diene tooSubstituents on the diene and dienophile can
polarise the pi-system to favour one orientation over another
© Macquarie University, 2012
Secondary effects: Regioselectivity
Resonance effects can explain the regioselectivity
OCH3
H
O
OCH3
H
O
OCH3
H
O
OCH3
H
O
© Macquarie University, 2012
Secondary effects: Regioselectivity
Secondary orbital overlap explains the stereoselectivity
OH
OHH3CO H3CO
HOMO
LUMO
© Macquarie University, 2012
Secondary effects: Regioselectivity
Only one product is formed
OHC
OCH3
OCH3
CHO
OCH3
CHO
OCH3
CHO
OCH3
CHO
OHC
OCH3
OCH3
CHO
OCH3
CHO
OCH3
CHO
OCH3
CHO
OHC
OCH3
OCH3
CHO
OCH3
CHO
OCH3
CHO
OCH3
CHO
© Macquarie University, 2012
1,3-dipolar addition
Another example of [4π+2π]-cycloaddition
© Macquarie University, 2012
1,3-dipolar addition
Correlation diagram is constructed as usual
π
π
σ σ1
n
σ σ1
S
A
A
S
S
S A
S
S A
© Macquarie University, 2012
1,3-dipolar addition
FMO analysisTake the HOMO and LUMO of two reactantsSee if the orbitals overlap constructively or not
anion
HOMO
LUMO
cation
HOMO
LUMO
© Macquarie University, 2012
1,3-dipolar addition
Ozonolysis of an alkene is an example of 1,3-dipolar addition
The malozonide is the product of the addition which quickly rearranges to the ozonide
OO
OO
O O O
OOOO O
malozonide
© Macquarie University, 2012
Larger rings
Explain the following reaction: 1. Draw arrows to explain the mechanism 2. Use frontier molecular orbitals to determine if the
reaction is allowed or forbidden 3. Identify the HOMO and LUMO of each reactant 4. Does the HOMO of one overlap with the LUMO of the
other in a constructive fashion?
Δ
© Macquarie University, 2012
Larger rings
LUMO of the hexatriene has 3 nodesHOMO of alkene has none
Δ LUMO
HOMO
© Macquarie University, 2012
Larger rings
For larger rings, the ends can be flexible
Δ
suprafacial antarafacial
© Macquarie University, 2012
SummaryCycloadditions involve the conversion of two π-
bonds to two σ-bondsThey can be allowed (thermal) or forbidden (requires
electronic excitation of one reactant)Allowed reactions involve [4n+2] electronsPhotochemical reactions require [4n] electronsExo and Endo products are determined by
secondary orbital overlapRegiochemistry is determined by electronic effectsReactions are typically suprafacial but larger rings
can react in an antarafacial way
© Macquarie University, 2012
Summary
Adding two more electrons reverse the rules Catalysing with UV-light reverses the rules Going from suprafacial to antarafacial reverses the rules
© Macquarie University, 2012
Summary
Pericyclic ReactionsPericyclic Reactions
no electrophile?no nucleophile?no intermediate?
high stereoselectivity
cycloadditions2 new σ-bondσ2 leσσ π-bondσ
[4n + 2]π electronσ
[2n + 2]π electronσ
σecondary orbital overlaπ= exo or endo TS
HOMO + LUMO
regioσelectivity baσedon electronegativity
thermal πhotochemical
electrocyclicreactions
1 new σ-bondσ1 leσσ π-bondσ
ring cloσing:HOMO of π
ring oπening:HOMO of σ, LUMO of π
diσrotatoryconrotatory
thermal πhotochemical
sigmatropicrearrangements
0 new σ-bondσ0 leσσ π-bondσ
bondσ σhifted
H-σhiftC-σhift
HOMO of σ, LUMO of π
σuπrafacial antarafacial
thermal πhotochemical
© Macquarie University, 2012
Electrocyclic Reactions
Pericyclic ReactionsPericyclic Reactions
no electrophile?no nucleophile?no intermediate?
high stereoselectivity
electrocyclicreactions
1 new σ-bondσ1 leσσ π-bondσ
ring cloσing:HOMO of π
ring oπening:HOMO of σ, LUMO of π
diσrotatoryconrotatory
thermal πhotochemical
sigmatropicrearrangements
0 new σ-bondσ0 leσσ π-bondσ
bondσ σhifted
H-σhiftC-σhift
HOMO of σ, LUMO of π
σuπrafacial antarafacial
thermal πhotochemical
© Macquarie University, 2012
Electrocyclic Reactions
Involve the conversion of two π-bonds into a σ-bond and a new π-bond
What happens if the butadiene is substituted? If this is like the other pericyclic reactions the reaction should go with stereospecificity
© Macquarie University, 2012
Cycloaddition Reactions
The reverse reaction (ring opening) is possible because it is an equilibrium system
RR
H
H
R
R
H
H
trans
cis
Conrotatory
RR
H
H
H
R
H
R
cis
cis
Disrotatory
© Macquarie University, 2012
Disrotatory vs Conrotatory
Look at the reaction in more detail
Disrotation
Conrotation
mirror
axisof
rotation
Disrotatory Conrotatory
© Macquarie University, 2012
Conrotatory and Disrotatory
QuickTime™ and aGIF decompressor
are needed to see this picture.
QuickTime™ and aGIF decompressor
are needed to see this picture.
© Macquarie University, 2012
Disrotatory Correlation Diagram
RR
H
H
RR
H
H
RR
H
H
RR
H
H
R
H
R
H
R
H
R
H
R
H
R
H
R
HH
energy
S
S
A
A
S
A
S
A
R
Thermally forbidden
© Macquarie University, 2012
Conrotatory Correlation Diagram
Thermally allowed
RR
H
H
RR
H
H
RR
H
H
RR
H
H
R
R
H
H
R
R
H
H
R
R
H
H
R
RH
energy
S
A
S
A
A
S
A
S
H
© Macquarie University, 2012
R
R
H
H
FMO approachR
R
H
H
R
R
H
H
R
R
H
H
R
RH
H
HOMO
HOMO
LUMO RR
H
H
© Macquarie University, 2012
Biosynthesis of vitamin D
An example of a biological electrocyclic reaction
HO
HO
H H
H
HO
H H
ergosterol lumisterol
previtamin D3
hn
hn
© Macquarie University, 2012
Biosynthesis of vitamin D
Looking at just the reacting ring
H
H HHHOMO
LUMO
H
© Macquarie University, 2012
Biosynthesis of vitamin D
Provitamin D2 is converted spontaneously to vitamin D
HO
H
provitamin D2
HO
H
vitamin D2
© Macquarie University, 2012
Sigmatropic Rearrangements
Pericyclic ReactionsPericyclic Reactions
no electrophile?no nucleophile?no intermediate?
high stereoselectivity
cycloadditions2 new σ-bondσ2 leσσ π-bondσ
[4n + 2]π electronσ
[2n + 2]π electronσ
σecondary orbital overlaπ= exo or endo TS
HOMO + LUMO
regioσelectivity baσedon electronegativity
thermal πhotochemical
electrocyclicreactions
1 new σ-bondσ1 leσσ π-bondσ
ring cloσing:HOMO of π
ring oπening:HOMO of σ, LUMO of π
diσrotatoryconrotatory
thermal πhotochemical
sigmatropicrearrangements
0 new σ-bondσ0 leσσ π-bondσ
bondσ σhifted
H-σhiftC-σhift
HOMO of σ, LUMO of π
σuπrafacial antarafacial
thermal πhotochemical
© Macquarie University, 2012
Sigmatropic Rearrangements
Nomenclature
1
2
3
1'2'
3'
12
3
1'2'
3'
One sigma bond is destroyed and a new one made
© Macquarie University, 2012
1
2
3
1'2'
3'
12
3
1'2'
3'
Sigmatropic Rearrangements
Nomenclature, [3, 3]-sigmatropic shift
© Macquarie University, 2012
Cope Rearrangement
HOMO of σ and LUMO of π-bonds
HOMOLUMO
LUMO
© Macquarie University, 2012
Name this reaction
HOMO
LUMO
123
4
5
1'
6
new π-bond
new σ-bond
© Macquarie University, 2012
Charged species
Name this sigmatropic rearrangement
O
Ph
O
Ph
base
O
Ph
1
2
3
1'2'
© Macquarie University, 2012
Biosynthesis of vitamin D
Provitamin D2 is converted spontaneously to vitamin D
HO
H
provitamin D2
HO
H
vitamin D2
H
© Macquarie University, 2012
[1,7]-migrations should be forbidden
So why does it proceed spontaneously in the biosynthesis of vitamin D?
suprafacial antarafacial
HOMO
LUMO
© Macquarie University, 2012
Last silde
How many peaks does this compound have in its 1H NMR spectrum?
Macquarie University
Where is Macquarie University???
Sydney, Australia