Third Year Organic Chemistry CourseCHM3A2

Frontier Molecular Orbitals and Pericyclic Reactions

Part 4:

Advanced Cycloaddition Reactions

Facial SelectivitiesTandem ReactionIonic Reactions

1,3-Dipolar CycloadditionsSecondary Orbital Interactions

O

O

O

KINETIC CONTROL

THERMODYNAMIC CONTROL

LOW TSHORT t

HIGH TLONG t

O

O

O

H

H

ENDO ADDUCT

O

O

H

O

H

EXO ADDUCT

– Learning Objectives Part 4 –

Advanced Cycloaddition Reactions

CHM3A2– Frontier Molecular Orbitals and Pericyclic Reactions –

After completing PART 4 of this course you should have an understanding of, and be able to demonstrate, the following

terms, ideas and methods.

(vi) 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 (CHM2I3).

(vii) Tandem cycloaddition reactions are useful synthetic reactions for the construction of fused cyclic systems,

however, one has to consider the implications of kinetic and thermodynamic control, in many cases.

(viii) 1,3-Dipolar cycloadditions are an important class of cycloaddition reactions, as they are a versatile route to

highly functionalised heterocycles. They involve the reaction of a 1,3-dipole with a dipolarophile.

(viii) Cycloaddition reactions can be initiated by photoexcitation. This allows many reactions that are not

thermally allowed to occur. However, it is not clear in some cases whether the mechanism is truly concerted

in nature, or has some component of radical generation and a step-wise reaction.

Facial

Selectivities

anti- and syn-Diels-Alder Adducts

MeMe

MeMe

Me

XO

O

O

X Me

O

O

O

Me X

O

O

O

Exo-Diels-Alder Adducts (Thermodynamic Product)

anti-Adduct syn-Adduct

X % anti-Adduct % syn-Adduct

H 20 80SMe 90 10S(O)Me >95 <5

S(O)2ME >95 <5

iPr >95 <5Et >95 <5CHO >95 <5

CH2OH >95 <5

OH <5 >95

Sterically Favoured

Me O

OO

O

H

?

[4s + 2s]‡

Other Dienophiles and -Facial Diastereoselectivity:

OO

Singlet

O

O

OO

27%

73%

[4s + 2s]‡

N

O

O

Ph

N

O

O

Ph

NO

O

Ph>90%

<10%

[4s + 2s]‡

Tandem

Diels-Alder

Reactions

Tandem Diels-Alder Reactions

O

O

Z

Z

Z

Z

Z

Z

Z

ZLow T High T

KINETIC PRODUCT

THERMODYNAMIC PRODUCT

LUMO of Dienophile Closest to Butadiene

HOMO

Z groups least sterically hindered

O

O[4s + 2s]‡Retro

[4s + 2s]‡

NN

CF3

CF3

N

N

CF3

CF3

N

N

CF3

CF3

N NCF3

CF3

25°C

100%

N NCF3

CF3

100°C

100%

KINETIC PRODUCT

THERMODYNAMICPRODUCT

100°C 100%Thermal [4s + 2s]‡

Ionic

Cyclo-additions

Cationic Cycloadditions (Allyl Cation)

R2 electron system

R' R'

R

LUMO 2

R' R'

HOMO 2

R

I

Thermal [2s + 4s]‡

R

R' R'

R

R' R'

Ph

Ph Ph

Anionic Cycloadditions (Allyl Anion)

Ph

Ph Ph

Ph

HOMO 2

Ph Ph

LUMO 2

4e -system

Ph

H

B:H

Ph

Ph PhThermal [4s + 2s]‡

1,3-Dipolar

Cyclo-additions

Sub

Sub

1,3-Dipolar Cycloadditions

YX Z

X Y Z ZY

X

Sub

ZY

X

Sub

ZY

X

Sub

ZY

X

Sub

REGIOISOMERS

4s

+

2s

4s

+

2s

[4s + 2s]‡

[4s + 2s]‡

Linear 1,3-Dipoles

X Y Z X Y ZGeneral

HC N CH2 H2C N CH2Nitrile ylids

NHNHCNHNHCNitrile Imines

HC N O HC N ONitrile oxides

CH2NNCH2NNDiazoalkanes

NHNNNHNNAzide

ONNONNNitrous oxide

General YX Z

YX Z

Azomethine ylids

NH2C CH2

NH2C CH2

Azomethineimines

NH2C NH

NH2C NH

Nitrones NH2C O

NH2C O

Carbonyl ylids

OH2C CH2

OH2C CH2

Carbonylimines

OH2C NH

OH2C NH

CarbonylOxides

OH2C O

OH2C O

Bent 1,3-Dipoles

H2CC

CH2 H2CN

NH

H2CC

CH2 H2C

NNH

Heteroatoms desymmetrise the

coefficients.This has effect on regiochemistry of

cycloaddition reaction

K.N. Houk, J. Sims, R.E. Duke, R.W. Strozier, J.K. GeorgeJ. Am. Chem. Soc., 1973, 95, 7287

Desymmetrising Coefficients and Regiochemistry

2 HOMO 2 HOMO

Driving force: -bond conjugation

1,3-Dipolar Cycloaddition Reaction Examples

NHN

C-OMeOproton

transfer

N

N

1,3-Dipole

C-OMeO

Dipolarophile

NN

C-OMe

H

O

NN

C-OMeO

H

Regioisomers

[4s + 2s]‡

Major Product

Minor Product

NN

C-RO

H

NN

C-ROH

NN

C-R

Oproton transfer

H

NHN

C-R

O

Most Acidic: -ve Charge Delocalised into C=O group

as well as into aromatic ring

NHN

C-RO

MinorProduct

MajorProduct

NN

O

1,3-Dipole Dipolarophile

R

[4s + 2s]‡

Secondary Orbital

Interactions

Secondary Orbital Interactions. 1

ENDO ADDUCT

KINETIC PRODUCT

EXO ADDUCT

THERMODYNAMIC PRODUCT

LUMO

HOMO

1

2

3

4

1

LUMO

2

3

4

5

6

HOMO

O

OO

H

HLow T

Short t

High T

Long t

O

O

H

O

H

O

O

O

Thermal [4s + 2s]‡

Secondary Orbital Interaction Control

O

HOMO of Cyclopenatadiene

LUMO of Maleic Anhydride

Primary Orbital

Interactions

Secondary Orbital

Interactions

Note that all of the -conjugated system of maleic anhdride needs to be considered, and not just the monoene unit, in order that the secondary orbital interactions can be taken into account

The ENDO Transition State

[4s + 2s]‡

The EXO Transition State

This orientation of reactants in the transition state does not facilitate any secondary orbital interactions.

Thermal [4s + 2s]‡

OOO

Energy

Reaction Coordinate

Endo Isomer:KineticProduct

G2‡< G1

‡

O

O

OO

OO

H

H

O

O

H

O

H

G1°

G2‡

G1‡

G2°

Exo Isomer:Thermodynamic

ProductG1

°>G2°

Kinetic & Thermodynamic Product

O

[4s + 2s]‡

OOO

Secondary Orbital Interactions. 2

O

O

O

O

O

Antibonding Secondary Orbital Interactions

Thermal [4s + 6s]‡

Thermal 10 (4n+2, n=2) e D-A

– Summary Sheet Part 4 –

Apied Cycloaddition Reactions

CHM3A2–Frontier Molecular Orbitals and Pericyclic Reactions –

Attack of a monoene on appropriately substituted dienes can take place in a suprafacial/suprafacial process on either face of the diene, leading two diastereoisomers. It is often found that there is some p-facial diastereoselectivity, which can usually be explained by considering the ease of accessibility of the monoene to the two different faces.

In many cycloaddition reactions with the correct substitution on the two partners, the two components are able to react to afford regioisomers. In practice it is found that one regioisomer is formed in preference to the other. The reason for this is attributed to the matching of the coefficients of the HOMO and LUMO in the transition state. Calculation predicts that the smallest coefficient of one partner (HOMO) will interact with the smallest coefficient of the second partner (LUMO), and vice versa for the large coefficients, because this results in the smallest energy gap and the lowest energy transition state. In many, instances the use of a Bronsted (H+) or a Lewis acid, increases the propensity for one regioisomer. The reason for this is that the coefficients at the termini of p-system are made increasingly larger and smaller, respectively, and as a result, the overlap with the second reacting partner becomes even more efficient.

Cycloaddition reactions can also be utilised to construct multiple ring systems, via what are referred to as tandem cycloaddition reactions. These are important reactions in synthetic chemistry as complex fused ring systems with high degrees of stereo and regio control can be formed in one-pot reactions. The nature of tandem cycloaddition reactions generally means that the second cycloaddition has two choices, one of which is controlled by thermodynamics (the product stability) and the other by kinetics (the ease of attainment of the transition state). Thus, it is important to bear this in mind in experimental design: should the reaction be carried out a low temperatures (favouring the kinetic product) or high temperatures (favouring the thermodynamic product), for example.

Another extremely important class of cycloaddition reactions are the 1,3-dipolar cycloadditions. This class of reactions allows the construction of heterocycles with high degrees of stereo and regioselectivity, and is thus very valuable in organic synthesis. The reactions involve a 1,3-dipole (X—Y+=Z, a 4 p-electron system) and a dipolarophile (generally an alkene, a 2 p -electron system), reacting in a concerted fashion via an ss transition state.

Cycloaddition reactions which were not permitted by thermal routes because the phase overlap of the FMOs was not appropriate, can be accomplished under photochemical conditions. For example, monoenes can be photodimerised. However, the product outcomes sometimes suggest that the reaction is not concerted (a stepwise radical mechanism may be involved). Furthermore, the issue is complicated by the fact that photoexcited singlet and triplet states can be formed, which results in different product outcomes.

In appropriate cases, the Diels-Alder reaction proceeds kinetically with endo selectivity. The so-called endo rule can be rationalised in terms of favourable secondary orbital interactions. Additionally, these so-called secondary orbital interaction can also explain the formation of only one diastereoisomer, by observing antibonding secondary orbital interactions (a point we shall return to when examining sigmatropic rearrangements).

Remember the following very wise phrase:

The man who says he can

and

The man who says he can’t

Are both right!Ali G!!

Good Luck with your exams…

…but remember they are nothing more than a stepping stone in life.

J.D. Walker

Tandem Diels-Alder Cycloadditions in Organic Synthesis

Chem. Rev., 1996, 96, 167.

W. Adams, M. Prein

-Facial Diastereoselectivity in the [4+2] Cycloaddition of Singlet Oxygen as a Mechanistic Probe

Acc. Chem. Res., 1996, 29, 275.

P.J. Parsons, C.S. Penkett, A.J. Shell

Tandem Reactions in Organic Synthesis: Novel Strategies for Natural Product Elaboration and the Development of New Synthetic Methodology

Chem. Rev., 1996, 96, 195.

Further Reading on Cycloaddition Reactions

Exercise 1: 4n+2 CycloadditionsIdentify the starting materials and propose arrow pushing mechanisms for the formation of the following products

OO

O

O

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

O O

80C

Benzene

80C

Benzene

64%

23%

45%

Answer 1: 4n+2 CycloadditionsIdentify the starting materials and propose arrow pushing mechanisms for the formation of the following products

80C

Benzene45%

OO

23%

Cl

Cl

Cl

Cl

O O

OO

O

O

Cl

Cl

Cl

Cl

O

O

Cl

Cl

Cl

Cl

80C

Benzene

64%O

O

Cl

Cl

Cl

Cl

Exercise 2: 4n+2 CycloadditionsIdentify the starting materials and propose arrow pushing mechanisms for the formation of the following products

O

CN

CN

20C

Ether92%

N

O20C

Ether66%

OO

BrBr80C

Benzene

Answer 2: 4n+2 CycloadditionsIdentify the starting materials and propose arrow pushing mechanisms for the formation of the following products

O

CN

CN

20C

Ether92%

O

NC CN

N

O20C

Ether66%

OO

BrBr80C

Benzene

O

N

O

Br

O

Br

Exercise 3: 4n+2 Cycloadditions and a bit more!

Rationalise the following reaction scheme utilising frontier molecular orbitals and identify reagent A.

CN

NC

CO2Me

CO2Me

NC CO2Me

CO2Me

Reagent A

Answer 3: 4n+2 Cycloadditions and a bit more!

Rationalise the following reaction scheme utilising frontier molecular orbitals and identify reagent A.

CN

NC

CO2Me

CO2Me

NC CO2Me

CO2Me

Reagent A

NC

CN

HOMO 3

H H

H

Attacking from least hindered side

4s +2s

DIS

CN

H

H

CN

H

H

NC

E

E

E

E

Exercise 4: 4n+2 CycloadditionsRationalise the following reaction scheme utilising secondary orbital interactions.

NN

N

Low Temp

HighTemp

Answer 4: 4n+2 CycloadditionsRationalise the following reaction scheme utilising secondary orbital interactions.

N

N

Low Temp

N

HighTemp

ThermodynamicProduct

KineticProduct

N

2 HOMO

3 LUMO

N

Primary Orbital Interactions

Secondary Orbital Interactions