Third Year Organic Chemistry Course

CHM3A2

Frontier Molecular Orbitals and Pericyclic Reactions

Part 2(ii): Cycloaddition Reactions

Cycloaddition reactions

are intermolecular pericyclic processes involving the formation of a ring from two independent conjugated systems through the formation of two new



-bonds at the termini of the



-systems.

The reverse process is called

cycloreversion

or is referred to as a

retro-reaction.

Suprafacial HOMO –

y

2 Suprafacial Sub Sub LUMO –

y

2

CHM3A2

– Introduction to FMOs – – Learning Objectives Part 2(ii) –

Cycloaddition Reactions

After completing PART 2(ii) of this course you should have an understanding of, and be able to demonstrate, the following terms, ideas and methods.

(i) A cycloaddition reaction involves the formation of two  bonds between the termini of two independent  systems, resulting in ring formation - or the reverse process.

(ii) Cycloaddition reactions are

stereospecifi

c (

e.g.

cis/trans isomers). The stereospecificity being afforded by the

suprafacial

or

antarafacial

nature of the approach of the two  -units in the transition state.

(iii) The

suprafacial

or

antarafacial

process involved in the  bond making process is

HOMO

/

LUMO

interactions of the two 

-systems

in the

transition state.

controlled

by the (v) Cycloaddition reactions can be

regioselective

. The regioselectivity cannot be predicted from the simple treatment given to frontier molecular orbitals in this course. However, generalisations can be made from looking at classes of substituents (C, Z, X) which are in conjugation with the  -systems, which allow us to predict the regioselectivity in an empirical manner.

The Questions FMO Theory Can Answer 150 °C 10 days 165 °C 900 atm 17 hours 85% 0% 78%

FMO Theory Explains Difference in Rates of Cycloadditions CHO 150 °C 0.5 hours O O 90% CHO 20 °C 68 hours O O 92% MeO 2 C CO 2 Me 25 °C 4 hours MeO O OMe O MeO O OMe O 80%

FMO Theory Explains Stereospecificity of Cycloadditions CO 2 Me CO 2 Me 25 °C OMe O O OMe OMe O O OMe MeO 2 C CO 2 Me 25 °C OMe O O OMe OMe O O OMe

FMO Theory Explains Regiochemistry of Cycloadditions OMe O ( ±) OMe O 19 CO 2 Me 20 °C 1 year 64% O OMe ( ±) O OMe 1

Analysing Cycloaddition Reactions Interaction of the termini of the two



-systems Interaction of the termini of the two



-systems The interaction is between the HOMO of one



-system with the LUMO of the second



-system, such that the energy difference is least.

Terminology SUPRAFACIAL New bonds to the same side of the



-system ANTARAFACIAL New bonds to the opposite side of the



-system n n

4n+2



Electron Cycloaddition Transition States

Suprafacial-Suprafacial Interaction: 4n+2



Electron Transition States Suprafacial

n

HOMO Number of



-electrons in each component



Xs +



Ys suprafacial In-phase Suprafacial LUMO

n

Diels-Alder Cycloaddition Reaction: 6



-Electron Transition State Suprafacial

y

2 HOMO



4s +



2s Suprafacial

y

2 LUMO

4n



Electron Cycloaddition Transition States

Suprafacial-Antarafacial Interaction: 4n



Electron Transition States Suprafacial Antarafacial LUMO

n

HOMO

n 

Xs +



Ya antarafacial

Why Ethene Does Not Dimerise: 4



-Electron Transition State Suprafacial

y

1 HOMO



2s +



2s

y

2 LUMO Suprafacial

Why Ethene Does Not Thermally Dimerise: 4



-Electron Transition State Suprafacial

y

1 HOMO



2s +



2s In-phase

y

2 LUMO Suprafacial Out-of-phase Can not react via suprafacial/suprafacial Interaction

How About a Suprafacial/Antarafacial Interaction?

Suprafacial

y

1 HOMO



2s +



2a

y

2 LUMO Antarafacial

How About a Suprafacial/Antarafacial Interaction?

Suprafacial

y

1 HOMO



2s +



2a

y

2 LUMO Antarafacial In principle, suprafacial/antarafacial is possible by FMO theory, however, it is geometrically impossible

The Diels-Alder Reaction: In Detail The Diels-Alder reaction is an extremely well studied cycloaddition reaction, The reason for this is that careful design of the diene component and the ene component (the dienophile) has led to a great insight into the reaction mechanism.

Diels-Alder Reaction Transition State Geometry Diene Suprafacial HOMO –

y

2 EWG EWG Dieneophile EWG EWG LUMO –

y

2 Suprafacial EWG EWG MESO



4s +



2s

Diene Suprafacial HOMO –

y

2

One of two equally likely transition states See Next 2 Slides…

EWG EWG Dieneophile EWG EWG LUMO –

y

2 Suprafacial



4s +



2s EWG EWG EWG EWG

i.e.

enantiomers

Enantiomer Formation EWG Top EWG Top Bottom Bottom EWG EWG A pair of Enantiomers EWG EWG

Enantiomer Formation EWG EWG Top EWG Top EWG Bottom EWG Bottom EWG EWG EWG A pair of Enantiomers EWG EWG

Normal Electron Demand in Diels-Alder Cycloaddition Reactions EWG EWG EDG

Diene Dieneophile

EWG EDG

Diene Dieneophile

EWG

Raising and Lowering the Energy of HOMO and LUMOS Energy LUMO Z = EWG X = EDG LUMO LUMO HOMO X HOMO HOMO Z

Diene HOMO/Dienophile LUMO: Normal Electron Demand 165°C 900 atm 17 hours 78% CHO 150°C 0.5 hours 90% O LUMO LUMO LUMO HOMO HOMO HOMO Z

Regiochemistry Issues in the Diels-Alder Reaction Except C/Z/X X C/Z/X X

C = Extending Conjugation Z = Electron Withdrawing Group X = Electron Donating Group

C/Z/X C/Z/X X X

X/Z/C X Except C/Z/X X

C = Extending Conjugation Z = Electron Withdrawing Group X = Electron Donating Group

X/Z/C X C/Z/X X

Substituents and Desymmetrisation of Orbitals O Z Z O X OMe OMe X

Low Energy Transition State High Energy Transition State Large/Large Coefficient interaction X Small/Small Z X

Despite more pronounced steric interactions

Z Large/Small Z X X Small/Large Z

Rules for Cycloadditions Number of



-Electrons Thermal Photochemical ___________________________________________________________________ 4n sa ss 4n + 2 ss sa (aa) ___________________________________________________________________ s = suprafacial a = antarafacial Photochemical cycloaddition reactions are dealt with in CHM3A2 in year 3

CHM3A2

– Introduction to FMOs – – Summary Sheet Part 2(ii) –

Cycloaddition Reactions Cycloaddition reactions

are intermolecular pericyclic processes involving the formation of a ring from two independent conjugated systems through the formation of two new



-bonds at the termini of the



-systems.

The reverse process is called

cycloreversion

or is referred to as a

retro-reaction.

By far the best known example of a cycloaddition is a

Diels-Alder

reaction. The reverse process is known as a

retro-Diels Alder reaction.

Perhaps the simplest approach for assessing the feasibility of a particular cycloaddition uses frontier molecular orbital theory.

In the concerted cycloaddition of two polyenes, bond formation at each terminus must be developed to some extent in the transition state.

Thus, orbital overlap must occur simultaneously at both termini.

For a low energy concerted process - an allowed reaction - to be possible, such simultaneous overlap must be geometrically feasible and must also be potential bonding.

There are two stereochemically different ways in which new bonds can be formed

i.e

. in a

suprafacial

way, or to opposite faces,

i.e

. in an

antarafacial

– either to the same face of the way. The same definitions apply to longer

 

-bond, systems.

Suprafacial, suprafacial (ss) approach of two polyenes is normally sterically suitable for efficient-orbital overlap.

majority of concerted additions involves the ss approach.

The vast However, this type of overlap will only be energetically favourable when the HOMO of one component and the LUMO of the other component can interact in a bonding fashion at both termini.

Thus, these orbitals must be of the correct phase of symmetry.

In the Diels-Alder reaction of a diene with a monoene, the HOMO and LUMO of each reactant are of the appropriate symmetry so that mixing of these orbitals will result in simultaneous potential bonding character between the terminal atoms.

In contrast, a similar ss approach of two olefins does not lead to a stabilising interaction since the HOMO and LUMO are of incompatible phase for simultaneous bonding interaction to occur at both termini.

Thus, the initial approach of reactants for a concerted ss addition is favourable for a Diels-Alder reaction - which is therefore an allowed process - but not for olefin dimerisation, which is therefore disallowed.

Exercise 1: 4n+2



Cycloadditions Explain the difference in the rates of reaction of the two reaction shown right.

MeO 2 C relative rate = 1 MeO 2 C CO 2 Me relative rate >> 1 CO 2 Me CO 2 Me CO 2 Me CO 2 Me CO 2 Me

relative rate = 1 Answer 1: 4n+2



Cycloadditions MeO 2 C CO 2 Me CO 2 Me CO 2 Me Explain the difference in the rates of reaction of the two reaction shown right.

MeO 2 C relative rate >> 1 CO 2 Me CO 2 Me CO 2 Me The difference in rates is a result of at least 2 factors.

Factor 1: The HOMO of cyclopentadiene is raised relative to the HOMO of butadiene as a result of the bridging methylene units +I inductive effect, thus the energy difference between the diene HOMO and dieneophile LUMO is the least with cyclopentadiene, and results in the greatest HOMO/LUMO interaction (i.e.

D

E 2 <<

D

E 1 ).

Factor 2: Butadiene does not exist preferentially in the reactive cis conformation, concentration thus of the reactive conformations always low.

of butadiene is MeO 2 C Reactive Conformation CO 2 Me LUMO HOMO

D

E 1 LUMO HOMO

D

E 2 LUMO HOMO 1% 99% In contrast, the bridging methylene unit in cyclopentadiene forces the diene moiety to exist exclusively in the reactive conformation.

Reactive Conformation Locked

Exercise 2: 4n+2



Cycloadditions Ph Utilise FMOs to predict stereochemical outcome of the Diels-Alder reaction shown right CO 2 Me Ph CO 2 Me Ph CO 2 Me Ph CO 2 Me

Answer: 4n+2



Cycloadditions 2 Ph Utilise FMOs to predict stereochemical outcome of the Diels-Alder reaction shown right CO 2 Me Ph CO 2 Me Ph MeO 2 C Ph CO 2 Me HOMO

y

2 of Butadiene moiety Ph CO 2 Me Ph CO 2 Me Ph MeO 2 C Ph CO 2 Me MESO Ph Ph H H MeO 2 C CO 2 Me LUMO

y

2 of Ene moiety

Exercise 3: 4n+2



Cycloadditions Predict the cycloaddition products formed from the following pairs of starting materials. State the number of



electrons involved and use the



ns/



na descriptor to describe each reaction.

20°C N CO 2 Me N CO 2 Me



e's CO 2 Me 4°C, 3d



e's CO 2 Me O 20°C, 3d



e's

Answer 3: 4n+2



Cycloadditions Predict the cycloaddition products formed from the following pairs of starting materials. State the number of



electrons involved and use the



ns/



na descriptor to describe each reaction.

20 °C N CO 2 Me N CO 2 Me

10 

e's



8s +



2s N CO 2 Me N CO 2 Me CO 2 Me CO 2 Me 4 °C, 3d

±

CO 2 Me CO 2 Me



8s +



2s 20 °C, 3d O O

Meso 

4s +



6s

Exercise 4: 4n+2



Cycloadditions CO 2 Me Utilse FMOs to rationalise the stereochemical outcome of the cycloaddition right reaction shown CO 2 Me 4°C, 3d CO 2 Me CO 2 Me

±

Answer 4: 4n+2



Cycloadditions CO 2 Me Utilse FMOs to rationalise the stereochemical outcome of the cycloaddition right reaction shown

y4

Octatetraene (3 nodes, 9/4) HOMO CO 2 Me 4°C, 3d s/s

y

2 Ene LUMO CO 2 Me MeO 2 C H CO 2 Me MeO 2 C CO 2 Me CO 2 Me

±

CO 2 Me CO 2 Me H Enantiomers CO 2 Me CO 2 Me CO 2 Me s/s H CO 2 Me H

Exercise 5: 4n+2



Cycloadditions Propose an arrow pushing mechanism for the reaction shown right Utilse FMOs to rationalise the stereochemical outcome.

Identify a regioisomer of the product.

O 210°C 24 hrs 90% O O ±

Answer 5: 4n+2



Cycloadditions Propose an arrow pushing mechanism for the reaction shown right Utilse FMOs to rationalise the stereochemical outcome.

Identify a regioisomer of the product.

Enantiotopic hydrogen O O H The reaction requires forcing conditions because the HOMO/LUMO gap is large O H O O "Diene" Dieneophile 210°C 24 hrs 90% O O O ± O Regioismer, not formed because coefficient overlap not maximised

y

2 HOMO

y

2 LUMO H O Enantiotopic Hydrogen will go up O

y

2 LUMO H O Enantiotopic Hydrogen will go down

y

2 HOMO O

Exercise 6: 4n+2



Cycloadditions Propose an arrow pushing mechanism, reagents and byproducts for the reaction shown right. Additionally, identify any driving forces which make the reaction proceed from starting material to product.

N N CO 2 Me CO 2 Me

Answer 6: 4n+2



Cycloadditions Propose an arrow pushing starting material to product.

mechanism, reagents and byproducts for the reaction shown right. Additionally, identify any driving forces which make the reaction proceed from N N CO 2 Me CO 2 Me N N A retro-Diels-Alder N 2 gas liberation: Strong driving force N N CO 2 Me CO 2 Me A Diels-Alder Rearomatisation: Strong driving force CO 2 Me CO 2 Me