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. LUMO –  2 Suprafacial HOMO –  2 Suprafacial

– Learning Objectives Part 2(ii) – Cycloaddition Reactions CHM3A2 – Introduction to FMOs – 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 stereospecific (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 controlled by the HOMO/LUMO interactions of the two  -systems in the transition state. (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 165°C 900 atm 17 hours 78% 150°C 10 days 85% 0%

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

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

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

Analysing Cycloaddition Reactions The interaction is between the HOMO of one  -system with the LUMO of the second  -system, such that the energy difference is least. Interaction of the termini of the two  -systems Interaction of the termini of the two  -systems

SUPRAFACIALANTARAFACIAL Terminology n New bonds to the same side of the  -system n New bonds to the opposite side of the  -system

4n+2  Electron Cycloaddition Transition States

Suprafacial-Suprafacial Interaction: 4n+2  Electron Transition States Suprafacial  Xs +  Ys Suprafacial Number of  -electrons in each component LUMO HOMO suprafacial In-phase

Diels-Alder Cycloaddition Reaction: 6  -Electron Transition State Suprafacial  4s +  2s  2 HOMO  2 LUMO

4n  Electron Cycloaddition Transition States

Suprafacial  Xs +  Ya Suprafacial-Antarafacial Interaction: 4n  Electron Transition States LUMO HOMO antarafacial Antarafacial

Why Ethene Does Not Dimerise: 4  -Electron Transition State Suprafacial  2s +  2s  2 LUMO  1 HOMO

Why Ethene Does Not Thermally Dimerise: 4  -Electron Transition State In-phase Out-of-phase Can not react via suprafacial/suprafacial Interaction Suprafacial  2s +  2s  2 LUMO  1 HOMO

How About a Suprafacial/Antarafacial Interaction? Suprafacial Antarafacial  2s +  2a  2 LUMO  1 HOMO

How About a Suprafacial/Antarafacial Interaction? In principle, suprafacial/antarafacial is possible by FMO theory, however, it is geometrically impossible Suprafacial Antarafacial  2s +  2a  2 LUMO  1 HOMO

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 Dieneophile HOMO –  2 LUMO –  2 Suprafacial  4s +  2s MESO EWGEWG EWG EWG

Diene Dieneophile HOMO –  2 LUMO –  2 Suprafacial  4s +  2s i.e. enantiomers EWG EWG EWG EWG EWGEWG One of two equally likely transition states See Next 2 Slides…

A pair of Enantiomers Enantiomer Formation Bottom Top Bottom Top

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

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

Raising and Lowering the Energy of HOMO and LUMOS

Diene HOMO/Dienophile LUMO: Normal Electron Demand

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

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

Substituents and Desymmetrisation of Orbitals O O OMe OMe

Small/Small Large/Large Coefficient interaction Large/Small Small/Large Low Energy Transition State Z X Z X High Energy Transition State Despite more pronounced steric interactions

Number of  -ElectronsThermal Photochemical ___________________________________________________________________ 4n sa ss 4n + 2 ss sa (aa) ___________________________________________________________________ s = suprafacial a = antarafacial Rules for Cycloadditions Photochemical cycloaddition reactions are dealt with in CHM3A2 in year 3

– Summary Sheet Part 2(ii) – Cycloaddition Reactions CHM3A2 – Introduction to FMOs – 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 – either to the same face of the  -bond, i.e. in a suprafacial way, or to opposite faces, i.e. in an antarafacial way. The same definitions apply to longer  systems. Suprafacial, suprafacial (ss) approach of two polyenes is normally sterically suitable for efficient-orbital overlap. The vast majority of concerted additions involves the ss approach. 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.

Answer 1: 4n+2  Cycloadditions Factor 2: Butadiene does not exist preferentially in the reactive cis conformation, thus the concentration of reactive conformations of butadiene is always low. Explain the difference in the rates of reaction of the two reaction shown right. 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.  E 2 <<  E 1 ). Reactive Conformation Locked Reactive Conformation LUMO HOMO MeO 2 C CO 2 Me HOMO  E 1 HOMO  E 2 Energy In contrast, the bridging methylene unit in cyclopentadiene forces the diene moiety to exist exclusively in the reactive conformation.

Exercise 2: 4n+2  Cycloadditions Utilise FMOs to predict stereochemical outcome of the Diels-Alder reaction shown right

Answer: 4n+2  Cycloadditions 2 Utilise FMOs to predict stereochemical outcome of the Diels-Alder reaction shown right CO 2 MeMeO 2 C Ph Ph MeO 2 CCO 2 Me PhPh PhPh MeO 2 CCO 2 Me H H HOMO  2 of Butadiene moiety LUMO  2 of Ene moiety MESO

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.

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 N CO 2 Me CO 2 Me CO 2 Me CO 2 Me O 4°C, 3d 20°C, 3d  e's   N N CO 2 Me CO 2 Me CO 2 Me CO 2 Me O  e's  e's  8s +  2s  8s +  2s  4s +  6s ± Meso

Exercise 4: 4n+2  Cycloadditions Utilse FMOs to rationalise the stereochemical outcome of the cycloaddition reaction shown right

Answer 4: 4n+2  Cycloadditions Utilse FMOs to rationalise the stereochemical outcome of the cycloaddition reaction shown right Enantiomers  Octatetraene (3 nodes, 9/4) HOMO  2 Ene LUMO MeO 2 C CO 2 Me H MeO 2 C CO 2 Me H s/s

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.

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. The reaction requires forcing conditions because the HOMO/LUMO gap is large "Diene" Dieneophile O O H O O H Enantiotopic hydrogen O  2 HOMO O H  2 LUMO O  2 HOMO O H  2 LUMO Enantiotopic Hydrogen will go down Enantiotopic Hydrogen will go up

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.

Answer 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 N N CO 2 Me CO 2 Me A retro-Diels-Alder A Diels-Alder N 2 gas liberation: Strong driving force Rearomatisation: Strong driving force