DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 1
Dr Ali El-Agamey 1
LEARNING OUTCOMES LECTURES 1-2
Understand the meaning of phase, regioselectivity, regiospecificity, stereoselectivity, stereospecificity.
various types of pericyclic reactions.
Realize common features among pericyclic reactions.
Identify molecular orbital diagram of various systems.
2
1 Lecture 1-2: -Phase, Electron wave functions, Molecular orbitals, Regioselectivity, Regiospecificity, Stereoselectivity, Stereospecificity. - Types of Pericyclic Reactions, Various approaches to explain the pericyclic reactions, The Frontier Orbital Approach, Common Features among Pericyclic Reactions, Molecular Orbital Description of Various Systems. Lecture 3-4: -Electrocyclic reactions (Principle of microscopic reversibility, conrotatory and disrotatory motions; Torquoselectivity; Forbidden electrocyclic reactions). - Electrocyclic reactions of cations and anions (Pentadienyl cation; Pentadienyl anion; Allyl cations; oxyallyl cations; Allyl anion; Aziridines; 1,3-Dipoles). -Woodward-Hoffmann rules for electrocyclic reactions. Lecture 5: -Cycloaddition reactions (Energy consequences of the interaction between orbitals; [4 + 2] cycloaddition; [2 + 2] cycloaddition; suprafacial addition; antrafacial addition). -Factors affecting the rate of the Diels-Alder reaction (The diene; Electron-demand in Diels-Alder reactions; Lewis-acid catalysis). 3
Lecture 6-7: -Recognizing a Diels–Alder Product. -Diels-Alder Reaction (Regioselectivity; Stereospecificity; Stereoselectivity: endo vs exo; Stereoselectivity: Why endo). -Factors Affecting endo/exo Product Ratio (Steric Factors; Reversibility; Temperature; Lewis-Acid Catalysis; Pressure; Solvent used (Hydrophobic Effects)). -Cycloreversions. -[4 + 2] Cycloadditions of Cations and Anions (Oxyallyl-Diene; Allyl Cation-Diene; Allyl Anion-Alkene). -Woodward-Hoffmann Rules for [i + j] Cycloadditions. -[2 + 2] Cycloaddition (Promoted by Light; Alkene and a Ketene; Alkene and Ph3P=CH2 or R2Ti=CH2). Lecture 8: -Cycloadditions Involving more than Six Electrons. -Not all Cycloadditions are Pericyclic. -1,3-Dipolar Cycloadditions (Regioselectivity) -Examples of 1,3-Dipoles (Nitrones; Azomethine Ylids; Nitrile Oxides; Ozone).
-[π2s + π2s + π2s] Cycloadditions. 4
2 Lecture 9-10: -Sigmatropic Reactions (Migration of Hydrogen; Migration of Carbon). -The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements. Lecture 11: -Ene reaction. Lecture 12: -Problems
Reading J Morrison et al, Organic Chemistry, Oxford University Press, 2001. J Clayden et al, Organic Chemistry, Oxford University Press, 2001. RB Grossman, The art of writing reasonable organic reaction mechanism, Springer, 2003. B Miller, Advanced organic chemistry: reactions and mechanisms, Prentice Hall, 1998. I Fleming, Pericyclic reactions, Oxford University Press, 1999. S Sankararaman, Pericyclic reactions, Wiley-VCH, 2005. PS Kalsi, Organic reactions, NEW AGE, 2010.
5
Wave functions: Phase
Standing waves. Plus and minus signs show relative phases.
6
3 Wave functions: Phase
The places where the amplitude is zero are called nodes and they lie in a plane called the nodal plane (perpendicular to the plane of the paper). Wave function gives the amplitude as a function of distance along the standing wave. 7
Two ways of combining waves: in-phase and out-of-phase
8
4 Electron wave functions
Electrons in atoms are best described as waves. Electron wave functions gives the amplitude as a function, not of a single coordinate, but of the three coordinates necessary to describe motion in three dimensions. It is these electron wave functions that we call orbitals. Like a standing wave, an electron wave can have nodes, where the amplitude is zero. On the opposite sides of a node the amplitude has opposite signs, that is, the wave is of opposite phases.
9
Electron wave functions
Between the two lobes of a p orbital lie a nodal plane, perpendicular to the axis of the orbital. The two lobes are of opposite phases. 10
5 Electron wave functions
Within the 2s orbital but not within the 1s orbital, there is a region where there is no electron density at all (radial node). 11
Electron wave functions
12
6 Molecular orbitals: LCAO method One way to construct molecular orbitals (MOs) is to combine the atomic orbitals of the atoms that make up the molecule. This approach is known as the Linear Combination of Atomic Orbitals (LCAO). Atomic orbitals can combine in the same way- in-phase or out-of- phase.
13
Molecular orbitals (s atomic orbitals)
14
7 Molecular orbitals: breaking bonds
The electron in the antibonding orbital cancels out the bonding of the electron in the bonding orbital. Therefore, since there is no overall bonding holding the two atoms together, they can drift apart as two separate atoms with their electrons in 1s atomic orbitals.
15
Molecular orbitals: breaking bonds
16
8 Molecular orbitals: Helium
Any bonding due to the electrons in the bonding orbital is cancelled out by the electrons in the antibonding orbital. 17 He2 does not exist.
Molecular orbitals (p atomic orbitals)
An antibonding orbital has a nodal plane perpendicular to
the bond axis, and cutting between the atomic nuclei. 18
9 Molecular orbitals (p atomic orbitals)
19
Regioselectivity
Regioselective: Term describing a reaction that can produce two (or more) constitutional isomers but gives one of them in greater amounts than the other. In other words, a regioselective reaction selects for a particular constitutional isomer.
a regioselective reaction
20
10 Regioselectivity
(1) Dehydration of alcohols:
(2) Dehydrohalogenation of alkyl halides:
(3) The addition of HX:
21
Regiospecificity
A regiospecific reaction: is a reaction that gives exclusively or nearly exclusively one of several possible isomeric products i.e. a reaction that is 100% regioselective is termed regiospecific.
22
11 Stereoselectivity
A stereoselective reaction: is one in which a single starting material can yield two or more stereoisomeric products, but gives one of them in greater amounts than any other i.e. a stereoselective reaction selects for a particular stereoisomer. a stereoselective reaction
e.g. Alcohol dehydrations: 23
Stereospecificity
A stereospecific reaction: is a reaction in which the reactant can exist as stereoisomers and each stereoisomeric reactant leads to a different stereoisomeric product or a different set of stereoisomeric products.1
a stereospecific reaction
In the preceding reaction, stereoisomer A forms stereoisomer B but does not form D, so the reaction is stereoselective in addition to being stereospecific.1
All stereospecific reactions, therefore, are also stereoselective.1
A stereoselective reaction is not necessarily stereospecific.1 24
12 Reactions of Organic Compounds
A pericyclic reaction, a reaction that has a cyclic transition structure in which all bond-forming and bond-breaking takes place in concert, without the formation of an intermediate.125
Pericyclic Reaction I
An intramolecular reaction in which a new σ bond is formed between the ends of a conjugated π system and leads to the formation of a cyclic compound 26
13 Electrocyclic Reactions Are Reversible
27
Pericyclic Reaction II
Two different π bond-containing molecules react to form a cyclic compound 28
14 Pericyclic Reaction III
A σ bond is broken in the reactant, a new σ bond is formed in the product, and the π bonds rearrange 29
30
15 Note • The electrocyclic reactions and sigmatropic rearrangements are intramolecular reactions
• The cycloaddition reactions are usually intermolecular reactions
• Common features among the three pericyclic reactions
• are concerted reactions
• are highly stereoselective
31
32
16 The scientific method has four major elements: observation, law, theory, and hypothesis.
33
Normally Experiments Theory
Theory Rarely Experiments (e.g. mathematics)
Predictions
34
17 • Three approaches have been employed to explain the pericyclic reactions and these are: 1- Frontier orbitals 2- Correlation diagrams 3- Aromatic transition states
35
The Frontier orbital Approach1
• It is common in chemistry for the chemical properties of atoms to be approximated by considering only the properties of the highest occupied orbitals (the valence orbitals). The lower orbitals can be ignored.
• A similar approach can be employed with molecules. Ignore lower-energy orbitals, and consider only the properties of the frontier orbitals.
• Frontier MOs: the Highest Occupied Molecular Orbitals (HOMO) and Lowest Unoccupied Molecular Orbitals (LUMO).2
36
18 A Molecular Orbital Description of Ethene
37
Four p atomic orbitals interact to give the four π MOs of 1,3-butadiene
LUMO
HOMO LUMO
HOMO
38
19 Note
The normal electronic state of a molecule is known as its ground state
The ground state electron can be promoted from its HOMO to its LUMO by absorption of light (excited state)
In a thermal reaction the reactant is in its ground state; in a photochemical reaction, the reactant is in its excited state
A photochemical reaction takes place when a reactant absorbs light
A thermal reaction takes place without the absorption of light
39
Questions
Define the type of pericyclic reactions for the following reactions and determine if they are 4n + 2 or 4n systems.
40
20 Questions
41
DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 2
Dr Ali El-Agamey 42
21 • Three approaches have been employed to explain the pericyclic reactions and these are: 1- Frontier orbitals 2- Correlation diagrams 3- Aromatic transition states
43
A Molecular Orbital Description of Ethene
44
22 Four p atomic orbitals interact to give the four π MOs of 1,3-butadiene
LUMO
HOMO LUMO
HOMO
45
Drawing HOMO and LUMO of various (neutral) polyenes1
Draw the HOMO and LUMO of 1,3,5-hexatriene??
Can we draw the whole molecular orbital diagram of 1,3,5-hexatriene??
46
23 A Molecular Orbital Description of 1,3,5-hexatriene
47
The Allyl cation
48
24 The Allyl radical
49
The Allyl anion
50
25 The pentadienyl system
• The pentadienyl system has five MOs.
• In pentadienyl cation, ψ2 (asymmetric) is the HOMO and
ψ3 (symmetric) is the LUMO.
• In pentadienyl free radical and anion, ψ3 (symmetric) is the HOMO and ψ4 (asymmetric) is the LUMO.
51
Electronic Structure of the Atom
• An atom has a dense, positively charged nucleus surrounded by a cloud of electrons. • The electron density is highest at the nucleus and drops off exponentially with increasing distance from the nucleus in any direction.
Chapter 1 52
26 Rule
• For systems containing 4n + 2 electrons, the HOMO is symmetric.
• For systems containing 4n electrons, the HOMO is asymmetric.
53
Questions
Draw the HOMO and LUMO of 1,3,5,7-octatetraene?
54
27 An electrocyclic reaction is completely stereoselective and completely stereospecific1
55
56
28 57
1 Photochemical means it is driven by light energy58
29 To form the new σ bond in the electrocyclic reaction, the π orbitals at the end of the conjugated system must overlap head-to-head
59
Only the symmetry of the HOMO is important in determining the course of the reaction Bonding interaction
Antibonding interaction
Bonding interaction
60
30 Only the symmetry of the HOMO is important in determining the course of the reaction
61
(ψ2) Heat
Heat
62
31 (ψ3)
Heat
The symmetry of the HOMO of the compound undergoing ring closure controls the stereochemical Heat outcome of an electrocyclic reaction
63
64
32 • In reactions under photochemical conditions every thing is reversed.1 • The ground state and excited state HOMO’s have opposite symmetries. If 1 the ground state HOMO is symmetric, the excited state HOMO is asymmetric65 .
The configuration of the product formed depends on:
• the configuration of the reactant
• the number of conjugated double bonds or pairs of electrons in the reacting system
• whether the reaction is a thermal or a photochemical reaction A photochemical reaction takes place when a reactant absorbs light
A thermal reaction takes place without the absorption of light 66
33 Robert Woodward (1917-1979) received the Nobel Prize in 1965 for his work on the synthesis of natural products. Had he lived, he would undoubtedly have shared a second Nobel Prize in 1981. Roald Hoffmann shared the Nobel Prize in chemistry in 1981 with K. Fukui of Japan for their work on molecular orbital theory and pericyclic reactions.
67
Woodward-Hoffmann rules for electrocyclic reactions
No. of Mode of Motion electrons activation 4n thermal conrotatory 4n photochemical disrotatory 4n + 2 thermal disrotatory 4n + 2 photochemical conrotatory
68
34 According to the principle of microscopic reversibility, the reverse process of thermal ring opening takes exactly the same path.1
The sigma bond will open (via a conrotatory motion) so as to give the resulting p orbitals which will have the symmetry of 1 69 ψ2 (HOMO).
70
35 The direction taken by an electrocyclic reaction is dependent on the relative stabilities of the ring and open-chain reactants.1
The strained ring of the cyclobutene makes this reaction take place in the ring-opening sense, while hexatriene and octatetraene reactions are ring closures.2 71
The diene must assume a s-cis-conformation in order to make the terminal carbons p orbitals overlap.1
The “s” in the terms “s-cis” and “s-trans” refers to a sigma bond and indicates that these are conformations about a single bond and not configurations about a double bond.2 72
36 Now we can easily depict conrotations and disrotations directly Without drawing molecular orbitals.1
73
Questions
Write the structures of the products for the thermal electrocyclic reactions for the following compounds? For (a) and (c), show terminal orbitals during the course of reaction and omit it for (b). In addition, specify the type of rotation and write the names of reactants and products and specify which of them is thermodynamically favored?
(a) (b) (c)
74
37 Questions Write the structures of the products for the photochemical electrocyclic reactions for the following compounds? For (a) and (c), show terminal orbitals during the course of reaction and omit it for (b).
In addition, specify the type of rotation and write the names of reactants and products and specify which of them is thermodynamically favored?
trans-3,4-Dimethylcyclobutene
(a) (b) (c)
75
There are always two conrotatory modes clockwise and anticlockwise and both are equally probable. Similarly, there are two disrotatory modes.1
76
38 The ring opening of 3-susbtituted cyclobutene can result in a mixture of isomers (cis and trans-butadiene) due to the motion of the substituent either inward or outward during the breaking of the sigma bond.1
Thermolysis of 3-methylcyclobutene yields exclusively trans-penta-1,3-diene. This would involve the motion of the methyl group outward, which is preferred because of the minimum steric effect involved in the T.S.1 77
However, the ring openeing of 3-alkyl-3-methylcyclobutenes gave a mixture of isomers.1
78
39 Torquoselectivity: the stereoselectivity due to the inward/ outward motion of the substituents in the electrocyclic ring opening reactions.1
Torquoselectivity is controlled by (1) Steric effect (2) Electronic effect.
79
(1) Steric effect
In the elctrocyclic ring opening of trans-3,4-dimethylcyclobutene, two products might be obtained from conrotatory ring openings but in fact only the trans, trans product is obtained because there are severe steric interactions in the TS leading to the cis, cis product.2
80
40 (2) Electronic effect The preference for the outward rotation of the substituent increases with the increasing of pi-donar nature of the substituent, whereas with increasing the pi-acceptor nature of the substituent, the inward motion is preferred.1
Methoxy is better pi-donar than methyl.
cis-Penta-2,4-dienal is formed exclusively
81
Questions (a) Why Dewar-benzene (extraordinarily high-energy molecule) is not easily converted to benzene or compound 2 at room temperature, although isomerization of Dewar-benzene to benzene has been estimated to be exothermic by about 79 kcal/mol. (b) In your opinion, what are the reasons responsible for the high exothermicity of this reaction?
2
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41 DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 3
Dr Ali El-Agamey 83
Rule
• For systems containing 4n + 2 electrons, the HOMO is symmetric.
• For systems containing 4n electrons, the HOMO is asymmetric.
84
42 Woodward-Hoffmann rules for electrocyclic reactions
No. of Mode of Motion electrons activation 4n thermal conrotatory 4n photochemical disrotatory 4n + 2 thermal disrotatory 4n + 2 photochemical conrotatory
85
Questions (a) Why Dewar-benzene (extraordinarily high-energy molecule) is not easily converted to benzene or compound 2 at room temperature, although isomerization of Dewar-benzene to benzene has been estimated to be exothermic by about 79 kcal/mol. (b) In your opinion, what are the reasons responsible for the high exothermicity of this reaction?
2
86
43 Forbidden electrocyclic reactions1
It is not clear whether the isomerization of Dewar-benzene and other forbidden electrocyclic reactions, actually violate the Woodward-Hoffmann rules. We have assumed that both terminal carbons of a polyene must rotate simultaneously.
There is another possibility: initially, one end of a polyene might rotate breaking a pi bond to form a diradical. Rotation of the other end of the chain could then result in formation of the ring isomer. Such two-step mechanisms would not be expected to be stereospecific but should give rise to mixtures of stereoisomers.
87
Electrocyclic reactions of cations and anions1
Electrocyclic opening and closing of some linearly conjugated ions.
88
44 Electrocyclic reactions of cations and anions
Five-atom electrocyclizations
89
Electrocyclic reactions of cations and anions
Pentadienyl cation Nazarov cyclization: electrocyclic ring closure of divinyl ketone, upon treatment with acid, to give a cyclopentenone.1,2
90
45 Electrocyclic reactions of cations and anions
Pentadienyl cation Nazarov cyclization:
91
Electrocyclic reactions of cations and anions
Pentadienyl cation Nazarov cyclization:
In electrocyclic ring closure of the pentadienyl cation to the cyclopentenyl cation, the decrease in cation stabilization is compensated by the gain of a C-C sigma bond.2 92
46 Electrocyclic reactions of cations and anions
Pentadienyl anion Thermal electrocyclic ring closure of pentadienyl anions occurs in a disrotatory fashion.1
Irradiation of the anion 4.96 gives the trans isomer of 4.97.1
93
Electrocyclic reactions of cations and anions
Thermal electrocyclic ring closure of cyclooctadienyl anion occurs in a disrotatory fashion.1
94
47 Questions
Why is cyclooctadienyl anion stable for at least a week at -78 oC in broad daylight?1
95
Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons) • Allyl cations are conjugated systems containing 2 pi electrons.1
• Therefore, thermal electrocyclic ring closure occurs via a 1 disrotatory manner. 96
48 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons) • The product would be cyclopropyl cation. In fact, it is the cyclopropyl cations that undergo this reaction very readily because of the relief of ring strain and the charge delocalization in the allyl cation.1,2
97
Three-atom electrocyclizations (2 electrons)
• Reactions that would be expected to yield cyclopropyl cations proceed with simultaneous ring opening to from allylic cations i.e. case 2.1,3 • Cyclopropyl cations are very unstable (they are virtually unobservable) i.e. case 2.1,3 • In case 2, the cleavages of C-C bond and C-X bond take place in a concerted manner.2 98
49 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons) • Solvolysis of 1-chloro-2,3-dimethylcyclopropane diastereomers (5a-5c).2
99
scheme Miller p39
100
50 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons) • Solvolysis of 1-chloro-2,3-dimethylcyclopropane diastereomers (5a-5c) clearly established the disrotatory ring opening.2
• Each of the isomers underwent only one of the two possible modes of disrotatory ring opening (torquoselectivity).2
101
Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons)
102
51 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons)
• The observed stereospecificity and torquoselectivity suggest that the C-C bond (HOMO) and the C-X bond (LUMO) cleavages take place in a concerted manner and the electron density of the C-C bond breaking assists the cleavage of the C-X bond.2
• This is possible only if the disrotatory mode occurs in one direction so as to enable the electron density of the C-C bond to participate from the back side of the C-X bond (structure A 2 and B) in a manner similar to the familiar SN2 mechanism.
103
Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons)
• Molecular orbital calculations show that of the two possible modes of disrotatory ring openings of cyclopropyl derivatives, the preferred path will be that in which the substituents trans to the leaving group rotate apart.3
104
52 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons) • During the inward motion of the two methyl groups there will be severe steric interaction in the TS of 5a reaction, therefore its reaction is much slower than that of 5c.1,2
5c
105 5a
Questions • Explain the following experimental rates observed during the solvolysis reactions of cyclopropyl tosylates?
106
53 Questions • Explain the following experimental results?
107
Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (2 electrons) • Cyclopropanones are in electrocyclic equilibrium with oxyallyl cations. The cyclopropanone is generally lower in energy, but the oxyallyl cation is not so much higher in energy that it is kinetically inaccessible. Oxyallyl cations can undergo cycloadditions as will be discussed later.1
2 • The ring closure involves the disrotatory pathway. 108
54 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (4 electrons) Allyl anion-cyclopropyl anion is a 4 electron-system Therefore, thermal electrocyclic ring closure (or ring openeing) occurs via a conrotatory manner.3
109
Questions
Why is the opening of cylopropyl ring in anion 7 about 104 times as fast as the ring openings of anions 8?3
110
55 Electrocyclic reactions of 1,3-dipoles
Three-atom electrocyclizations (4 electrons)
111
Electrocyclic reactions of 1,3-dipoles
Three-atom electrocyclizations (4 electrons) Generally, the 1,3-dipole, is a compound for which a relatively stable resonance structure can be drawn in which one terminus has a formal positive charge (and is electron-deficient) and the other terminus has a formal negative charge.2
All the common 1,3-dipoles, have a heteroatom (N or O) in the central position in order to stabilize the electron-deficient terminus.2 1,3-Dipoles, are isoelectronic with allyl anion and they have 4 pi electons.1 The HOMO and LUMO of a 1,3-dipole are similar in symmetry to that in a diene.1 112
56 Electronic Structure of the Atom
• An atom has a dense, positively charged nucleus surrounded by a cloud of electrons. • The electron density is highest at the nucleus and drops off exponentially with increasing distance from the nucleus in any direction.
Chapter 1 113
Electrocyclic reactions of 1,3-dipoles
Three-atom electrocyclizations (4 electrons) Aziridines (three-membered ring amines) are isoelectronic with cyclopropyl anions. Aziridines will open on heating to form azomethine ylids (1,3-dipoles).3,4
114
57 Electrocyclic reactions of 1,3-dipoles
Three-atom electrocyclizations (4 electrons)
Azomethine ylids can be trapped by [3 + 2] cycloaddition reactions with dipolarophiles.4
115
Electrocyclic reactions of 1,3-dipoles
Three-atom electrocyclizations (4 electrons)
Since cycloaddition is stereospecific (suprafacial on both components), the stereochemistry of the products can tell us the stereochemistry of the intermediate ylid (4 pi electron system), and confirms that the ring opening is conrotatory.4
116
58 Electrocyclic reactions of 1,3-dipoles
Three-atom electrocyclizations (4 electrons) Heating of oxiranes (epoxides) give the corresponding carbonyl ylids, which can be trapped by cycloaddition reactions.1,2
These ring openings proceed stereospecifically by conrotatory paths.1,2 117
Questions
5a 5b 5c
1- Provide an arrow pushing mechanism for the formation of 5a, 5b and 5c and show whether the reactions proceed via conrotatory or disrotatory.
2- Provide a molecular orbital representation for the transition state for the rearrangement of 5b to 5c. HINT: your answer requires you to identify the HOMO of the pi system, and indicate how the symmetry of this HOMO is reflected in the transition state.
118
59 Woodward-Hoffmann rules for electrocyclic reactions1,2 Electrocyclic reactions No. of electrons Thermal Photochemical allyl cation-cyclopropyl cation 2e (4n + 2) disrotatory conrotatory allyl anion-cyclopropyl anion butadiene-cyclobutene
pentadienyl cation- cyclopentenyl cation pentadienyl anion- cyclopentenyl anion hexatriene-cyclohexadiene heptatrienyl cation- cycloheptadienyl cation heptatrienyl anion- cycloheptadienyl anion octatetraene-cyclooctatriene
nonatetraenyl cation- 119 cyclononatrienyl cation
Questions
Define the type of pericyclic reactions for the following reactions and determine if they are 4n + 2 or 4n systems.
120
60 DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 4
Dr Ali El-Agamey 121
Homework: Complete the Following Table Electrocyclic reactions No. of electrons Thermal Photochemical allyl cation-cyclopropyl cation 2e (4n + 2) disrotatory conrotatory allyl anion-cyclopropyl anion butadiene-cyclobutene
pentadienyl cation- cyclopentenyl cation pentadienyl anion- cyclopentenyl anion hexatriene-cyclohexadiene heptatrienyl cation- cycloheptadienyl cation heptatrienyl anion- cycloheptadienyl anion octatetraene-cyclooctatriene
nonatetraenyl cation- 122 cyclononatrienyl cation
61 Pericyclic Reaction II
Two different π bond-containing molecules react to form a cyclic compound 123
Number of atoms or number of electrons1
Two conventions for naming cycloadditions are used in the literature.
The older convention is that m and n denote the number of atoms in each component.
Woodward and Hoffmann altered the convention to make m and n denote the number of electrons in each component. The number of electrons and the number of atoms are the same for reactions involving neutral species such as the Diels–Alder reaction, but they are not the same for reactions involving charged or dipolar species.
For example, the 1,3-dipolar cycloaddition is a [3 + 2] cycloaddition according to the older convention and a [4 + 2] cycloaddition according to the newer one.
Always be careful to note which convention is being used.
124
62 Cycloaddition reactions
Cycloadditions are classified according to the number of π electrons that interact in the reaction
125
Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (4 electrons)
Azomethine ylids can be trapped by [3 + 2] cycloaddition reactions with dipolarophiles.4
126
63 Why?????
127
Questions
Define the type of pericyclic reactions for the following reactions and determine if they are 4n + 2 or 4n systems.
128
64 Energy consequences of the interaction between orbitals There are 3 types: (1) occupied-occupied (2) unoccupied- unoccupied (3) occupied-unoccupied.
129
Energy consequences of the interaction between orbitals
130
65 Energy consequences of the interaction between orbitals For occupied-unoccupied interactions, interactions between orbitals are greater if the individual energies are similar, and less if they are significantly different (Fig d and e). Thus, the largest (favorable) energy interactions occur when there is the least energy difference between the interacting orbitals.
131
Energy consequences of the interaction between orbitals
Figure 7.4 132
66 Energy consequences of the interaction between orbitals These occupied-unoccupied interactions, correspond to interactions between the HOMO of one molecule and the LUMO of the other (Fig 7.4). If the two reacting molecules have similar energy levels, the HOMO-LUMO interactions in each direction will both contribute significantly (Fig 7.4a). Whereas if the levels are different in energy, the dominant interaction will be the one where there is the lesser difference in energies (Fig 7.4b).
133
Energy consequences of the interaction between orbitals
In the TS of cycloaddition, stabilization comes chiefly from overlap between the HOMO of one reactant and the LUMO of the other.
134
67 There are two possible ways to form bonds to the atoms of a pi bond.1 Woodward and Hofmann designated addition to lobes on the same side of a pi system as suprafacial addition on that pi system and called addition to lobes on opposite sides of a pi system antrafacial addition.1 These modes of addition are identified by the symbols s and a, respectively.
135
Cycloaddition of a four-electron unit reacting antrafacially with a two-electron unit reacting suprafacially would be classified 1 as a [π4a + π2s] reaction.
136
68 Frontier Orbital Analysis of a [4 + 2] Cycloaddition Reaction
Supra, supra Supra, supra 137
Frontier Orbital Analysis of a [4 + 2] Cycloaddition Reaction In the course of a pericyclic cycloaddition, the p-orbitals at the ends of the conjugated system of each component form sigma bonds to the p-orbitals at the ends of the conjugated system of the other component.1,2
The p-orbitals must therefore approach each other head on, (see Fig. 2.84, the diene actually comes down on the top of the dienophile) with the new sigma-bonds forming between C-1 and C-1' and between C-4 and C-2'. At the same time, a new pi-bond forms between C-2 and C-3 of the diene.1,2
138
69 A [2 + 2] Cycloaddition Reaction
139
Frontier MO Analysis of the [2 + 2] Cycloaddition Reaction
Thermal
Fig 33.23 [2 + 2] thermal cycloaddition. Supra, supra: geometrically possible, but symmetry-forbidden. Supra, antara: symmetry-allowed, but geometrically difficult. 140
70 Frontier MO Analysis of the [2 + 2] Cycloaddition Reaction
Photochemical
Fig 33.22 symmetry-allowed photochemical [2 + 2] cycloaddition: two molecules of ethylene, one excited and one in the ground state. Interaction is bonding. 141
Antrafacial overlap
Almost all pericyclic cycloadditions are suprafacial on both components.
Straightforward antarafacial attack in cycloadditions is therefore very rare.
Antrafacial overlap on one component in a cycloaddition would need a most unusually long and flexible conjugated system.
142
71 Woodward-Hoffmann rules for [i + j] cycloadditions1
No. of Thermal Photochemical electrons (i + j) 4n supra, antara supra, supra antara, supra antara, antara 4n + 2 supra, supra supra, antara antara, antara antara, supra
143
Antrafacial overlap
1,2 The [π14 + π2] reaction shown proceeds antrafacially.
144
72 Antrafacial overlap
1,2 The [π14 + π2] reaction shown proceeds antrafacially.
145
The Diels-Alder reaction is a [4 + 2] cycloaddition.
146
73 The Diels-Alder reaction is a [4 + 2] cycloaddition.
Otto Diels and his research student Kurt Alder worked at the University of Kiel and discovered this reaction in 1928. They won the Nobel Prize in 1950.
147
Factors affecting the rate of the Diels-Alder reaction (1) The diene
(a) Conformation of the diene
The dienes must have the s-cis conformation.2
The most reactive dienes are those in which the diene unit is forced to maintain an s-cis conformation e.g. cyclopentadiene undergoes Diels-Alder dimerization at RT.1,2 Dienes in which one or both substituents at C1 and C4 are cis to the other double bond react very slowly.1 Fixed transoid dienes are unreactive.2a,2
148
74 (b) Aromaticity1
149
(2) Electron-demand in Diels-Alder reactions
Very slow1
Fast1
Most Diels–Alder reactions occur with what is called normal electron-demand, in which an electron-rich (bears electron-donating group) diene reacts with an electron-poor (bearing electron-withdrawing group 2 e.g. carbonyl, CN, sulfonyl, NO2) dienophile.
150
75 Electron-demand in Diels-Alder reactions1
Frontier MO theory can be used to understand the dependence of the rate of the Diels–Alder reaction on the electronic nature of the substrates. As in any reaction, the rate of the Diels–Alder reaction is determined by the energy of its TS. In the TS of most (normal electron-demand) Diels–Alder reactions, the HOMO of the diene interacts with the LUMO of the dienophile.
151
Electron-demand in Diels-Alder reactions
Very electron-poor dienes can undergo Diels–Alder reactions with electron-rich dienophiles in the inverse electron-demand Diels–Alder reaction. The dominant interaction in the TS of inverse electron-demand Diels–Alder 1 reactions is between the LUMOdiene and the HOMOdienophile.
152
76 Electron-demand in Diels-Alder reactions1
153
Electron-demand in Diels-Alder reactions
154
77 LEARNING OUTCOMES LECTURE 5
Lewis-acid catalysis of the Diels-Alder reactions.
Recognizing a Diels–Alder product.
Regioselectivity. Influence of Lewis-acid catalysis on regioselectivity of the Diels-Alder reactions. Stereospecificity.
Stereoselectivity: endo vs exo.
155
(3) Lewis-acid catalysis of the Diels-Alder reactions
Lewis acids (e.g. BF3, AlCl3, TiCl4, SnCl4,..) are known to catalyse Diels–Alder reactions. They coordinate to a Lewis base site, normally a heteroatom such as a carbonyl oxygen of the dieneophile. The coordination of a Lewis acid makes the dienophile more electron-deficient.1
156
78 (3) Lewis-acid catalysis of the Diels-Alder reactions
The energy of the HOMO and LUMO of the dieneophile is decreased compared to the uncomplexed dienophile and hence the
HOMOdiene- LUMOdienophile gap is further reduced. Consequently, the rate of the Diels–Alder reactions is further enhanced.1
157
Lewis-acid catalysis of the Diels-Alder reactions
158
79 Recognizing a Diels–Alder product1
We can easily recognize a Diels–Alder product as follows:
159
Recognizing a Diels–Alder product1
The simplest way to find the starting materials is to draw the reverse Diels–Alder reaction.
160
80 Regioselectivity
The Diels-Alder reaction between an unsymmetrical diene and an unsymmetrical dienophile can lead to the formation of a mixture of regioisomers depending upon the relative orientation of the diene and the dienophile in the TS.1
Generally, the more powerful the electron-donating and electron-withdrawing substituents, the more regioselective is the reaction.2 161
Regioselectivity
How can we determine the regioselectivity of the reaction?
(1) Draw an “ionic” stepwise mechanism.
(2) Orbital coefficient arguments.
162
81 Regioselectivity
(1) Draw an “ionic” stepwise mechanism.
The simplest way to predict which product will be formed is to draw an “ionic” stepwise mechanism for the reaction to establish which end of the diene will react with which end of the dienophile.
Of course this stepwise mechanism is not completely correct but it does lead to the correct orientation of the reagents.
163
Regioselectivity
164
82 Regioselectivity
165
Regioselectivity
166
83 Regioselectivity
167
Regioselectivity
The Diels-Alder reaction is generally highly regioselective and the formation of ortho and para adducts predominate over the meta adduct.2
168
84 Regioselectivity1
• Sometimes, looking at the resonance structures can not explain many cases.
• In such cases, orbital coefficient arguments should be used.1
169
DAMIETTA UNIVERSITY
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LECTURE 6
Dr Ali El-Agamey 170
85 Stereospecificity
The stereochemical relationships among substituents in a suprafacial component of a cycloaddition are preserved in the cycloadduct.1
Groups that are cis (or trans) to one another in the dienophile become cis (or trans) to one another in the product. The two out groups in the diene become cis to one another in the product, as do the two in groups.1
Because one diastereomeric starting material gives one diastereomeric product, cycloadditions are said to be stereospecific.1
171
Stereospecificity Dienophile Groups that are cis (or trans) to one another in the dienophile become cis (or trans) to one another in the product.
172
86 Stereospecificity Diene The two out groups in the diene become cis to one another in the product, as do the two in groups.1
173
Stereospecificity
The stereochemical relationships among substituents in a suprafacial component of a cycloaddition are preserved in the cycloadduct.1
Groups that are cis (or trans) to one another in the dienophile become cis (or trans) to one another in the product. The two out groups in the diene become cis to one another in the product, as do the two in groups.1
Because one diastereomeric starting material gives one diastereomeric product, cycloadditions are said to be stereospecific.1
174
87 Stereospecificity 1,3-dipolar cycloadditions
175
Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (4 electrons)
Since cycloaddition is stereospecific (suprafacial on both components), the stereochemistry of the products can tell us the stereochemistry of the intermediate ylid (4 pi electron system), and confirms that the ring opening is conrotatory.4
176
88 Electrocyclic reactions of cations and anions
Three-atom electrocyclizations (4 electrons) Heating of oxiranes (epoxides) give the corresponding carbonyl ylids, which can be trapped by cycloaddition reactions.1,2
These ring openings proceed stereospecifically by conrotatory paths.1,2 177
Questions
Write the structure of the product of the following reaction and predict its stereochemistry.
178
89 Questions
Predict the stereochemistry of the product of the following reaction.
179
Stereoselectivity: endo vs exo
There are two possible stereoisomeric products that are consistent with the Woodward–Hoffmann rules. The two green hydrogen must be cis in the product but there are two possible products in which these Hs are cis. They are called exo and endo.1,2
The Woodward–Hoffmann rules allow you to predict the stereochemical relationship between substituents derived from the same component. They do not allow you to predict the relationship between substituents derived from different components. Guidelines for predicting the latter kind of relationship will be discussed shortly.1,2 180
90 Stereoselectivity: endo vs exo
The product is, in fact, the endo compound. This is impressive not only because only one diastereoisomer is formed but also because it is the less stable one.
These names arise from the relationship in space between the carbonyl groups on the dienophile and the newly formed double bond in the middle of the old diene. If these are on the same side they are called endo (inside) and if they are on opposite sides they are called exo (outside).
181
Stereoselectivity: endo vs exo
182
91 Stereoselectivity: endo vs exo
183
Stereoselectivity: endo vs exo
The TS leading to the product in which the substituents are trans is clearly less sterically hindered than the other TS, and so one would predict that the trans product is predominantly obtained. However, the major product is the one in which the groups are cis.1
184
92 Stereoselectivity: endo vs exo How can we draw the product of Diels-Alder reaction?
(The out-endo-cis rule): The out-endo-cis rule is a device for drawing the products of Diels–Alder reactions with stereochemistry consistent with the endo rule.
185
Stereoselectivity: endo vs exo Predict the stereochemistry of the major product of the following Diels–Alder reaction?
Orient the two starting materials so that the strongest EDG on the diene is in a 1,2- or 1,4-relationship with the strongest EWG on the dienophile. The out-endo-cis rule tells you that the OAc and CHO groups are cis in the product. In the diene, OAc and R groups (out) are cis in the product. In the dienophile, the CHO and Me groups are trans in the product. Draw the OAc up (or down, it doesn’t matter), and the rest of the stereochemistry follows. 186
93 Stereoselectivity: endo vs exo
Consider the Diels–Alder reaction between 1-methoxybutadiene and ethyl acrylate.1
The major product has the MeO and CO2Et groups on adjacent C atoms (“ortho product”).1 A reaction that is stereospecific with respect to each component could give either the cis or the trans product.1 187
Stereoselectivity: endo vs exo
The endo rule applies equally to inverse electron-demand Diels–Alder reactions. In these reactions, the most electron-donating group on the dienophile is preferentially endo. The out-endo-cis rule applies, too.
188
94 Stereoselectivity: endo vs exo
1,3-Dipolar cycloadditions give predominantly endo-products, too. Again, the out-endo-cis rule applies.
189
Problem
Predict the stereochemistry of the major product of the following Diels–Alder reaction?
190
95 Stereoselectivity: endo vs exo
191
Problems
Draw the transition state for the following process?
Intramolecular Diels-Alder reactions are very powerful methods for constructing target molecules. Draw the product of the following intramolecular Diels-Alder reactions and show its stereochemistry?
192
96 193
194
97 Stereoselectivity: why endo!!!!! Frontier MO explanation for the endo rule Why is the more sterically hindered TS lower in energy?1
Diene Diene
Dienophile Dienophile Primary orbital overlap leads directly to the formation of new chemical bonds2
195
Stereoselectivity: why endo!!!!!
The most widely accepted explanation cites secondary orbital interactions.1
In the more crowded approach, the orbitals of the carbonyl group of the dienophile can interact with the orbital on C2 of the diene.1
These secondary orbital interactions lower the energy of the TS for endo cycloaddition compared to the TS for exo addition. So the kinetic product is the more crowded, less thermodynamically stable endo product.1,2
Diene
Dienophile
196
98 Stereoselectivity: why endo!!!!!
197
198
99 Stereoselectivity: why endo!!!!! Other explanation for the endo rule In the following figure, the dipoles associated with the in C–H bond of the diene and the electron-withdrawing group of the dienophile interact most favorably when the electron-withdrawing group is endo.1
Lewis acids increase the endo selectivity by polarizing the electron-withdrawing group and thus increasing the magnitude of the dipole.1 199
Stereoselectivity: why endo!!!!! Other explanation for the endo rule
200
100 DAMIETTA UNIVERSITY
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LECTURE 7
Dr Ali El-Agamey 201
LEARNING OUTCOMES LECTURE 7
Factors affecting endo/exo product ratio (1) Steric factors; (2) Reversibility; (3) Temperature; (4) Lewis-acid catalysis; (5) Pressure and (6) Solvent. Hydrophobic effects. Cycloreversions.
202
101 Factors affecting endo/exo product ratio
(1) Steric factors: Steric effects can favour the exo-product.
203
Factors affecting endo/exo product ratio (2) Reversibility: In cases where the reaction readily reverses (e.g. reactions with furan), the thermodynamically preferred exo-adducts are usually obtained.1
The unusually low energy of furan (an aromatic compound) allows the retro-Diels–Alder reaction of the endo-product to proceed at a reasonable rate.2
Even though the rate of formation of the endo-product is faster than the rate of formation of the exo-product, establishment of an equilibrium between starting materials and products leads to a thermodynamic ratio that favors the 2 exo-product. 204
102 Factors affecting endo/exo product ratio
(3) Temperature: since Diels-Alder reactions is reversible at elevated temperatures, the exo/endo ratio depends on the reaction temperature.2
205
Factors affecting endo/exo product ratio
(3) Temperature:
206
103 Factors affecting endo/exo product ratio
Therefore, the use of high temperature and extended periods of time can result in the formation of the thermodynamically more favorable exo-product.1
207
Factors affecting endo/exo product ratio
(4) Lewis-acid catalysis: Lewis acid catalysis improves endo diastereoselection.2
Lewis acids increase the endo selectivity by polarizing the electron- withdrawing group and thus increasing the magnitude of the dipole.1
208
104 209
Factors affecting endo/exo product ratio
(5) Pressure:
TS is smaller than starting materials
210
105 Factors affecting endo/exo product ratio
(6) Solvent used:
Since Diels–Alder reaction has no ionic intermediates, it is expected that the influence of solvent is weak. However, in the 1980s an extraordinary discovery was made. Water has a large accelerating effect on the Diels–Alder reaction!!!!!
And that is not all. The endo selectivity of these reactions is often superior to those in no solvent or in a hydrocarbon solvent. Here is a simple example.
211
Factors affecting endo/exo product ratio
(6) Solvent used:
The suggestion is that the reagents, which are not soluble in water, are clumped together in oily drops by the water and forced into close proximity i.e. water is not exactly a solvent.
212
106 Hydrophobic effects1-3
It has been shown that some intermolecular Diels–Alder reactions are accelerated under hydrophobic effects in aqueous media.1
β-Cyclodextrin has a hydrophobic cavity and if the system of a particular Diels–Alder combination can fit within the cavity a significant rate enhancement is observed.1
For example, in aqueous medium with β-cyclodextrin as an additive, the rate of Diels–Alder of methyl vinyl ketone and cyclopentadiene is significantly enhanced (1800 times as compared to the same reaction in hydrocarbon solvent, see previous table).1-3
213
Hydrophobic effects1-3
214
107 cycloreversions.
The reverse of cycloadditions are retrocycloadditions, or cycloreversions.1
Diels-Alder reactions are reversible.2
The direction in which any pericyclic reaction takes place is determined by thermodynamics.2
Diels-Alder reaction takes place to form a ring because two sigma-bonds are produced at the expense of two pi-bonds i.e. exothermic reaction.2,3
215
cycloreversions.
Retro-Diels-Alder reaction is facile when one of the products is 1-3 N2, CO2, or an aromatic ring.
216
108 DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 8
Dr Ali El-Agamey 217
LEARNING OUTCOMES LECTURE 8
Cycloadditions involving more than six electrons.
[π2s + π2s + π2s] cycloadditions Sigmatropic Reactions
218
109 Cycloadditions involving more than six electrons
[8 + 2] cycloaddition
219
Homework
Complete the following equations and (1) define the type of cycloaddition? (2) Will the pericyclic reaction proceed under thermal or photochemical conditions?
220
110 Homework
221
[π2s + π2s + π2s] cycloadditions
Although thermal [π2s + π2s + π2s] cycloadditions are theoretically allowed, the simultaneous combination of three molecules would suffer from a large, negative, entropy effect. This would be particularly unfavorable at the high temperatures necessary for many cycloaddition reactions. Thus there appear to be no examples of concerted thermal cycloadditions of three molecules.1 Several examples of thermal cycloaddition reactions of unconjugated dienes with alkenes are known e.g. the reaction of norbornadiene with acrylonitrile.1
Because the two pi bonds in the norbornadiene are not conjugated, each is designated separately in the description of the reaction so this is a 222 2 [π2s + π2s + π2s] cycloadditions.
111 Pericyclic Reaction III A σ bond is broken in the reactant, a new σ bond is formed in the product, and the π bonds rearrange
A sigmatropic rearrangement produces a new sigma bond at the expense of a sigma bond, so this reaction is the most inherently reversible of all pericyclic reactions. The position of the equilibrium depends on the relative thermodynamic and kinetic stabilities of the starting material and products.1 223
224
112 Sigmatropic Reactions
Sigmatropic reactions: A concerted reaction in which a group migrates with its sigma bond within a pi framework, an ene or a polyene, and the migration is accompanied by a shift in pi bonds.1
Since in these reactions a change in the position of one sigma bond takes place, Woodward and Hofmann coined the term “sigmatropic shifts” to describe them.2-4
In a sigmatropic reaction, a sigma bond that breaks is bonded to an allylic carbon.2-3
225
Sigmatropic Reactions1
To identify the type of a particular sigmatropic reaction, the two atoms forming the bond being broken are both numbered as atom 1.
Then the atoms in each direction from the bond being broken, up to and including the atoms that form the new sigma bond in the product, are numbered consecutively as atoms 2,3, and so on.
The numbers assigned to the atoms forming the new bond, separated by commas, are placed within brackets to designate the reaction type.
226
113 Sigmatropic Rearrangements
In the designations [1,3] and [1,5] the “3” and “5” refer to the number of the carbon to which migrating group is moved to (the migration terminus). The “1” does not refer to the migration source; instead it specifies that in both reactant and product bonding is to the same atom (number 1) in the migrating 227group. 1
Homework
Indicate the order of each of the sigmatropic shifts shown in the equations below.
228
114 DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 9
Dr Ali El-Agamey 229
LEARNING OUTCOMES LECTURE 9
(1) Sigmatropic Reactions
(2) Migration of Hydrogen [1,3] hydrogen shift
[1,5] hydrogen shift [1,7] hydrogen shift Degenerate rearrangements
(3) Migration of Carbon 230
115 Sigmatropic Rearrangements
It is important to note the number of electrons involved in sigmatropic rearrangements.1
The [3,3] and [1,5] rearrangements are six-electron reactions, the cationic [1,2] rearrangement is a two-electron reaction, and [1,3] rearrangement is a four-electron reaction.1
231
Sigmatropic Rearrangements
In the TS of sigmatropic reaction, the migrating group is bonded to both the migration source and the migration terminus.
232
116 Sigmatropic Rearrangements
Sigmatropic rearrangements have cyclic transition states.3
For all sigmatropic rearrangements, the size of the cyclic transition state is given by the sum of the two numbers in the square brackets. For example; [3,3] and [1,5]-sigmatropic rearrangements have six-membered cyclic transition states. Also, [2,3]-sigmatropic rearrangements have five-membered cyclic transition states.1
233
Sigmatropic Rearrangements
We consider the bonding in the TS for sigmatropic reactions to arise from overlap between an orbital of an atom or free radical (G) and an orbital of an allylic free radical (the pi framework).
In the TS, there is overlap between the HOMO of one component and the HOMO of the other. Each HOMO is singly occupied, and together they provide a pair of electrons.1
The HOMO of an allylic radical depends on the number of carbons in the pi framework. The migrating group is passed from one end of the allylic radical to the other, and so it is the end carbons that we are concerned with.1
234
117 Sigmatropic Rearrangements Migration of Hydrogen
235
Sigmatropic Rearrangements Migration of Hydrogen In the TS, a three-center bond is required, and this must involve overlap between the s orbital of the hydrogen and the lobes of p orbitals of the two terminal carbons.1 For [1,5] hydrogen shift:
236
118 Sigmatropic Rearrangements Migration of Hydrogen
For [1,3] hydrogen shift:
237
Sigmatropic Rearrangements Migration of Hydrogen
The phase relationships between the HOMOs of the two “radicals” then determine whether the reaction is suprafacial or antarafacial.2
Whether a sigmatropic reaction actually take places, depends not only on the symmetry requirements but also on the geometry of the system.1
[1,3] and [1,5] antara shifts should be extremely difficult, since they would require the pi framework to be twisted far from the planarity that it requires for delocalization of electrons.1
For larger pi frameworks, both supra and antara shifts should be possible on geometric grounds.1
238
119 Sigmatropic Rearrangements Migration of Hydrogen1
Ψ3
Ψ2
Ψ1
Ψ5
Ψ4
Ψ3
Ψ2
Ψ1
239
Sigmatropic Rearrangements
Migration of Hydrogen
[1,3] sigmatropic shifts of hydrogen are not known, whereas [1,5] shifts are well known. For example:1
240
120 Sigmatropic Rearrangements Migration of Hydrogen1 As a general rule: for [1,x] hydrogen shift, where x = 2, 3, 4, 5, 6, 7,….
When the total number of electrons = 4n + 2 Suprafacial
When the total number of electrons = 4n Antarafacial
241
Sigmatropic Rearrangements Migration of Hydrogen
The preference for [1,5]-H shifts over [1,3]-H shifts has been demonstrated many times. For example:1
242
121 Sigmatropic Rearrangements Migration of Hydrogen
Migration of H would yield only III
243
Sigmatropic Rearrangements Migration of Hydrogen
244
122 Sigmatropic Rearrangements Migration of Hydrogen
In these rearrangements, a mechanism requiring disruption of an aromatic ring is preferred over a mechanism that leaves the aromatic ring intact throughout the reaction. This is strong evidence of the barriers to rearrangements proceeding by “forbidden” mechanisms.2
245
Sigmatropic Rearrangements Migration of Hydrogen1
A thermal, concerted [1,7]-H shift is sometimes observed in acyclic systems because the 1,3,5-triene system is floppy enough to allow the H to migrate from the top face to the bottom face (making the triene the antarafacial component).
246
123 247
Sigmatropic Rearrangements Migration of Hydrogen1
A very important [1,7] sigmatropic rearrangement occurs in the human body.
Precalciferol (provitamin D2) is converted to ergocalciferol (vitamin D2) by a thermal [1,7] sigmatropic H shift. This shift must be antarafacial.1,2
In cyclic compounds like cycloheptatriene, geometric constraints prevent the H from migrating from the top to the bottom face of the seven-carbon pi system, and the shift does not occur.1 248
124 Sigmatropic Rearrangements
249
Sigmatropic Rearrangements Degenerate rearrangements1
On heating, 1,3-pentadiene rearranges to itself via a [1,5]-H shift. Degenerate rearrangements: It is a process in which a reactant rearranges to itself.
250
125 Sigmatropic Rearrangements Degenerate rearrangements1
How can we establish the degenerate rearrangements?
This can be confirmed by using isotopically labeled molecules or suitably substituted molecules.
251
Sigmatropic Rearrangements Degenerate rearrangements1
252
126 Sigmatropic Rearrangements Migration of Hydrogen1
There are two suprafacial [1,5] pathways (top to top or bottom to bottom). 253
Sigmatropic Rearrangements Migration of Carbon1
As compared to a hydrogen atom, which has only one lobe (1s orbital), the carbon free radical has two lobes of opposite phases (p orbital). Thus carbon can simultaneously interact with the migration source and the migration terminus using either one of its lobes or both of them.1
254
127 Sigmatropic Rearrangements Migration of Carbon1
Bonding through the same lobe on carbon means attachment to the same face of the atom, that is to say, retention of configuration in the migrating group.1
255
Sigmatropic Rearrangements Migration of Carbon1
Bonding through different lobes of a p orbital- these lobes are on opposite faces of carbon- leads to an inversion of configuration in the migrating group.1
256
128 Sigmatropic Rearrangements
1 [1,3] alkyl shift: Migration of Carbon
Suprafacial migration with retention of configuration of the migrating group would again be forbidden. An antarafacial migration with retention, while theoretically allowed would be very unlikely to occur. A suprafacial migration forming a new bond to the "back" lobe of the migrating orbital would also be theoretically allowed. This process would result in inversion of the configuration of the migrating group. 257
Sigmatropic Rearrangements Migration of Carbon1 [1,3] alkyl shift:
It would obviously require grossly distorted bonds in the TS and would be an unlikely process, although perhaps not quite so unlikely as a migration to the opposite face of the pi system.1 Not surprisingly, there do not seem to be any examples of [1,3] alkyl shifts in open-chain alkenes. However, [1,3] shifts of alkyl groups can occur if the reactions involve expansions of strained three-membered or four-membered rings.1 258
129 Sigmatropic Rearrangements Migration of Carbon1
[1,3] alkyl shift ar or si
[1,5] alkyl shift ai or sr
[1,7] alkyl shift ar or si
Where s and a refer to suprafacial and antarafacial, and r and i to retention and inversion of configuration at the migrating center.2
259
Sigmatropic Rearrangements Migration of Carbon1 These prediction have been confirmed by experiments:
260
130 Sigmatropic Rearrangements Migration of Carbon1
This reaction proceeds by a [1,3] migration and with complete inversion of configuration in the migrating group.1
261
Sigmatropic Rearrangements Migration of Carbon1
Homework: Write a reasonable mechanism for the following reaction. Note: the reaction involves 1,5-alkyl and 1,5-H shifts.
This reaction is completely stereoselective and stereospecific.1
262
131 The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements1
If the migrating group is hydrogen, the pathways involving inversion must be263 ignored .
The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements1
(4n + 2) electrons e.g. 2 or 6 or 10 electrons
(4n) electrons e.g. 4 or 8 or 12 electrons
(4n + 2) electrons
suprafacial shift with retention (or antarafacial shift with inversion but impossible in practice)
132 The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements1
(4n) electrons are the opposite (4n) electrons
suprafacial shift with inversion (or antarafacial shift with retention)
Photochemical reactions follow the reverse of the thermal rule.
DAMIETTA UNIVERSITY
CHEM-405: PERICYCLIC REACTIONS
LECTURE 10
Dr Ali El-Agamey 266
133 LEARNING OUTCOMES LECTURE 10
(1) The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements -[1,2] cationic shift -[1,2] anionic shift (2) Photochemical Sigmatropic Rearrangements (3) [m,n] Sigmatropic Rearrangements
(a) [3,3] sigmatropic rearrangements:
-Cope rearrangement -oxy-Cope rearrangement -anionic oxy- Cope rearrangement -Claisen rearrangement (b) [5,5] sigmatropic rearrangements
267
Sigmatropic Rearrangements Migration of Carbon1 Retention or inversion???
The front C-C bond of the cyclopropane in 5.28 migrates to C-7 to give the C-C bond (starred) at the rear in the isomeric 5.29.
The two substituents on the migrating carbon remain with the cyano group exo in the bicyclic system and the methyl group endo. There is actually inversion of configuration in the migrating group.
How??????????? 268
134 The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements1
If the migrating group is hydrogen, the pathways involving inversion must be269 ignored .
The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements1
(4n + 2) electrons e.g. 2 or 6 or 10 electrons
(4n) electrons e.g. 4 or 8 or 12 electrons
(4n + 2) electrons
suprafacial shift with retention (or antarafacial shift with inversion but impossible in practice)
270
135 The Woodward-Hoffmann rules for [1,n] sigmatropic rearrangements1
(4n) electrons are the opposite (4n) electrons
suprafacial shift with inversion (or antarafacial shift with retention)
Photochemical reactions follow the reverse of the thermal rule.
271
Sigmatropic Rearrangements1
[1,2] cationic shift:
In the cationic [1,2] hydride shift (two-electron reaction), there are one-atom component, the H atom, and two-atom component.
No matter how the two electrons are distributed between the two components, the dominant HOMO–LUMO interaction in the TS is between the
1s orbital of the one-atom component and Ψ1 of the two-atom component.
Ψ2
Ψ1
136 Sigmatropic Rearrangements1
[1,2] cationic shift:
Likewise, in the cationic [1,2] alkyl shift, both components must be suprafacial. The migrating group retains its configuration because of the requirement for suprafaciality.
273
Sigmatropic Rearrangements1
[1,2] anionic shift:
By contrast, in the [1,2] anionic H shift, the dominant FMO interaction is
between the 1s orbital of the one-atom component and Ψ2 of the two-atom component. The H atom must have partial bonds to the top and bottom faces of the two-atom component simultaneously. Because this arrangement is geometrically impossible, [1,2] anionic H shifts are thermally disallowed reactions.
Ψ2
Ψ1
274
137 Sigmatropic Rearrangements1
[1,2] anionic shift:
In the case of the alkyl shift, the configuration is inverted. In fact, the geometric requirements for anionic [1,2] alkyl shifts are so stringent (severe, inflexible) that the reactions are extremely rare.
275
Photochemical Sigmatropic Rearrangements
Migration of Hydrogen
Photochemical sigmatropic rearrangements are extremely rare.3-4
For photochemical rearrangements, predictions are exactly reversed.1 In a photochemical [1,3] sigmatropic rearrangement, the stereochemical requirement changes because under these conditions, the HOMO of the 2 three-atom component is Ψ3 (symmetrical), not Ψ2 (antisymmetrical).
Ψ3
Ψ2
Ψ1 276
138 Mechanism???
277
Photochemical Sigmatropic Rearrangements Photochemical [1,3] alkyl shift:
This photochemical [1,3] sigmatropic rearrangement proceeds suprafacially with respect to both components, resulting in retention of configuration about the migrating one-atom component, a stereogenic alkyl group.1
The reaction fails to proceed at all under thermal conditions.1
278
139 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements:
The [3,3] sigmatropic rearrangements (Cope and Claisen rearrangements) are the most widely used sigmatropic rearrangements and are probably the most widely used pericyclic reactions after the Diels–Alder reaction. In the Cope rearrangement, a 1,5-diene isomerizes to another 1,5-diene.1
The Cope rearrangement is a [3,3]-sigmatropic rearrangement with only carbon atoms in the ring. In its simplest version it is not a reaction at all.2-3
279
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: The [3,3] sigmatropic rearrangement is a six-electron reaction. No matter how the six electrons are distributed between the two three-atom components,
the dominant FMO interaction in the TS is between Ψ2 of one component and Ψ2 of the other component. The reaction proceeds suprafacially with respect to both components.1
Ψ3 Ψ3
Ψ2 Ψ2
Ψ1 Ψ1
280
140 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements:
The Cope rearrangement of the simplest 1,5-diene, 1,5-hexadiene, is degenerate: the starting material is identical with the product, and the equilibrium constant for the rearrangement is 1.1
Substituents may shift the equilibrium to one side or the other. For example, the equilibrium between 3,4-dimethyl-1,5-hexadiene and 2,6-octadiene lies on the side of the more substituted pi bonds.1
281
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements:
Cope rearrangement occurs at exceptionally low temperatures when the single bond is part of a small strained ring and the two double bonds are cis to each other.1
282
141 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements:
The position of the Cope equilibrium can also be altered by removing the product 1,5-diene from the reaction mixture.1
In the oxy-Cope rearrangement, a 3-hydroxy-1,5-diene undergoes the Cope rearrangement to give an enol, which isomerizes quickly to a δ,ε-unsaturated carbonyl compound. The latter compound is a 1,6-diene, not a 1,5-diene, so it is incapable of undergoing the Cope rearrangement in the retro direction.1
283
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements:
Oxy-Cope rearrangements proceed at especially low temperatures when the alcohol is deprotonated. The anionic oxy-Cope rearrangement is accelerated compared with the neutral reaction because the negative charge is more delocalized in the TS than in the starting material. The driving force for the anionic oxy-Cope rearrangement is no longer removal of the product diene from the equilibrium but simply delocalization of the negative charge.1
284
142 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Base catalysis
That is to say sigmatropic rearrangements are catalyzed by bases. For example; the "oxy-Cope rearrangements" of the potassium salts of 3-hydroxy-1,5-hexadienes, such as 38, have been found to proceed as much as 1012 times as rapidly as the rearrangements of the parent alcohols.1
285
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements:
Claisen rearrangement: In the Claisen rearrangement, an allyl vinyl ether isomerizes to a γ,δ-unsaturated carbonyl compound.1
286
143 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement: Mechanism
287
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement:
How do we know that this is the mechanism?1
288
144 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement:
Studies using migrating groups labelled with 14C.2
These results indicate that Claisen rearrangement proceed by a 2 concerted mechanism. 289
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement: Which way will they go? Orbital symmetry tells us that [3,3]-sigmatropic rearrangements are allowed but says nothing about which way they will go. They are allowed in either direction. So why does the Claisen rearrangement always go in this direction?1
290
145 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement:
The combination of a carbonyl group and a C–C sigma bond made the keto form more stable than the enol form with its combination of a C=C pi bond and a C–O sigma bond. The same is true here. It is the formation of the carbonyl group that drives the reaction to the right. 1-2
The key to identifying Cope and Claisen rearrangements is the 1,5-diene in the starting material or in the product.
- A γ,δ-unsaturated carbonyl compound (a 1,5-heterodiene) can be made by a Claisen rearrangement, and
- a δ,ε-unsaturated carbonyl compound can be made by an oxy-Cope rearrangement.2 291
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement: Mechanism
One might expect that in this particular case, the equilibrium would lie on the side of the aromatic compound, not the carbonyl. However, the carbonyl quickly tautomerizes (by a nonconcerted mechanism!) to the aromatic 2-allylphenol, which can’t undergo the reaction in the reverse direction.1
292
146 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement: When both ortho positions on the aromatic ring are already substituted (and even, to small degree, when one or both are not substituted), the migrating allylic group will shift to the para position, resulting in a p-susbtituted phenol.1-2
293
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement:
The direct [1,5] shift mechanism seems unlikely, in view of the distance between the oxygen atoms and the para positions.1 In fact, para-Claisen rearrangements have been demonstrated to proceed by two successive [3,3] shifts (Eq 46). The allylic group first migrates to the ortho position and then undergoes a second [3,3] shift (a Cope migration step) to the para position.1
Finally, the para-cyclohexadienone formed in the second migration step tautomerizes to form a phenol-a process presumably catalyzed by acids or bases.1
The rearrangement is not a direct [3,5] shift.2
Homework: can you draw the [3,5] shift product?
147 [m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement:
295
[m,n] Sigmatropic Rearrangements
[3,3] sigmatropic rearrangements: Claisen rearrangement:
Several lines of evidence demonstrate that para-Claisen rearrangements proceed via two successive [3,3] shifts rather than a single [1,5] shift:
(1) The ortho-cyclohexadienone, 32, formed as the initial intermediate in the rearrangement of ether 31, has been trapped as its Diels-Alder adduct with maleic anhydride.1
296
148 [m,n] Sigmatropic Rearrangements
[5,5] sigmatropic rearrangements: Claisen rearrangement:
A longer conjugated system 5.65 allows a more direct delivery to the para position, giving the phenol 5.67 as the major product along with some of the product of a normal Claisen rearrangement.1
297
[m,n] Sigmatropic Rearrangements
[5,5] sigmatropic rearrangements: Claisen rearrangement: Similarily, the terminal methyl group in 5.65 shows that this is a [5,5] rearrangement (5.65 to 5.66) rather than two successive [3,3] rearrangements. The [5,5] rearrangement is allowed if it is all-suprafacial, a geometry 5.68 that is not difficult to achieve.1
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149 [m,n] Sigmatropic Rearrangements
Homework: In the previous reaction, what is (are) the structure(s) of the product(s) resulting from two successive [3,3] rearrangements?
299
Questions
Homework: Write the mechanism of the following reaction?
300
150