A Molecular Orbital Description

A Molecular Orbital Description of Ethene

(LUMO)

(HOMO)
 A Molecular Orbital Description of 1,3-butadiene
Four p atomic orbitals interact to give the four p MOs of 1,3-butadiene

(LUMO)

(LUMO) (HOMO)

(HOMO)

y1 and y3 are symmetric Mos; y2 and y4 are asymmetric MOs

The ground state HOMO and the excited HOMO have opposite symmetry
A Molecular Orbital Description of 1,3,5-hexatriene

(LUMO)

(LUMO) (HOMO)

(HOMO)
 An electrocyclic reaction:
is completely stereoselective & Stereospecific

Only the symmetry of the HOMO is important in determining the

course of the reaction
 An electrocyclic reaction:
is completely stereoselective & Stereospecific
A symmetry-allowed pathway is one in which in-phase orbitals overlap
If a reaction is symmetry-forbidden, it cannot take place by a concerted
pathway
The symmetry of the HOMO of the compound undergoing ring closure
controls the stereochemical outcome of an electrocyclic reaction
An electrocyclic reaction:
is completely stereoselective & Stereospecific
An electrocyclic reaction: is completely stereoselective & Stereospecific
An electrocyclic reaction: is completely stereoselective & Stereospecific
 Electrocyclizations

n=1,2,3,4 thermal photochemical

4n con dis

4n+2 dis con

 Cycloadditions
Cycloadditions are classified according to the number of p electrons
that interact in the reaction
 Cycloaddition:
Diels-Alder Reaction An Allowed [4+2] Cycloaddition

diene dienophile

*4 A
2-antibonding
LUMO

A
LUMO S
*3

HOMO A
2 S

1-bonding
HOMO
1 S

ethylene
butadiene
Frontier Orbital Analysis of a [4 + 2] Cycloaddition Reaction
 Diels-Alder Reaction:
The Effect of Electron Withdrawing Groups

+
EWG EWG

diene dienophile

*4 A

2-antibonding
LUMO
LUMO S
*3
A
EWG

HOMO A
2 S
EWG
1-bonding
HOMO
1 S

butadiene deactivated ethylene

Diels-Alder Reaction: The Endo Effect

Secondary Effect

O
 More details of the Diels-Alder reaction.
1) Diene must be in the s-cis conformation: This will react: But not this:

(ends are too

s-cis s-trans far apart)

2) Dienophiles with electron-withdrawing groups (EWG) react faster:

Me Me
slow

O
This is because the electron-
CO2Me
OMe withdrawing group reduces
the LUMO energy and
improves the overlap with the
O orbitals in the diene more
CO2Me information later in course.
OMe
fast
OMe
CO2Me

O
3) The reaction is stereospecfic:
MeO2C
CO2Me MeO2C CO2Me
CO2Me
CO2Me

CO2Me CO2Me
5) Endo-product often favoured: Two isomers can be formed:
O O O
H
O
H
+ O O O
O H
ENDO EXO
MAJOR MINOR H
O
O
O O

In a kinetically controlled (product is fastest to form, irreversible) the ENDO is favoured but for reversible
reactions (thermodynamic control) the EXO may dominate e.g. with furan.

All these observations can be explained by considering the orbitals involved in the
reactions:
In this Diels-Alder reaction the reagents approach each other in a face to face
manner, i.e. so that the p- orbitals of the -system can combine with each other.
The relevant orbitals are shown below:

H H
H H
H LUMO H H LUMO
H
H H
Alkene Butadiene
H H
H H
H H HOMO H H HOMO
H H
[2 + 2] Cycloaddition Reaction

2-antibonding
LUMO 2-antibonding
LUMO (HOMO*)

A A
light (hn)

S S

1-bonding 1-bonding
HOMO HOMO
 Sigmatropic Rearrangements
Migration of a s-bond across a conjugated -system
[m,n] shift when the s-bond migrates across m atoms of one
system and n of another
2 2
3 1 [1,3]-shift 3 1

1'
R 1' R

2 2
1 3
1 3 [3,3]-shift
3'
3'
R 1' R 1'
2'
2'
 [1,3] Sigmatropic Rearrangements: H migration
+
H H H

R R' R R' R R'

[1,3] Sigmatropic Rearrangements: C migration

+
CH3 H3C CH3

R R' R R' R R'

[1,5] Sigmatropic Rearrangements

X + X
X
R R' R R' R R'
 [2,3] Sigmatropic Rearrangements
R R' R R'
* R R' *
X X Y Y
Y X

X, Y = C, N, O, S, Se, P

BuLi [2,3]
O O +
Li LiO Ph
Ph Ph
X=O, Y=C Wittig Rearrangement

X=S, Y=C
BuLi [2,3]
+ + Sulfonium Ylide
S S
Li
+ S S Rearrangement
S S
Sigmatropic Rearrangements
 [3,3] Sigmatropic Rearrangements
X X
Claisen Rearrangement O O X = C,H, O, N

X = C, H, O, N

Thermodynamic driving force: (C-O) -bond and (C-C) s-bond formation

X=Heteroatom leads to higher exothermicity and reaction rate

H OR
~30
O O ~20
H
OR
~20 kcal/mol O
~30 kcal/mol
O
Sigmatropic [3,3]-reactions proceed and are of great synthetic utility:

O OTMS OH
LDA
O O O
TMSCl
Sigmatropic [3,3]-reactions CLAISEN rearrangement applications
Claisen rearrangement are generally irreversible and synthetically useful:

re-
O O aromatises OH
O

A [3,3]-sigmatropic reaction is
pivotal to the Fischer indole synthesis:
H
H H steps H
N N NH N
NH NH NH
-NH3

H
[3,3] Sigmatropic Rearrangements

Claisen Variants: Johnson Orthoester Claisen

EtO OEt OEt OEt

OH MeC(OEt)3
O O O
+
H

Claisen Variants: Eschenmoser Claisen

MeO NEt2 MeO NEt2 NEt2 NEt2

OH
MeO O O O
Xylene
150C
 Cope Rearrangement: Boat vs. Chair Transition State
H H
Me trans-trans
Me Me
H Me
H
Me Me
H cis-cis
H H
H Me
Me
Me H
Me H H trans-cis
H Me Me

Me Me

Me trans-cis
H Me
H
H H
Me Me
Me H Me trans-trans
H H H
[3,3] Sigmatropic Rearrangements

Cope Rearrangement: Use of ring strain

H
5-20C

H
Relief of ring strain upon rearrangement

Oxy-Cope Rearrangement
H
220C keq ~ 105

OH OH O

Tautomerism shifts equilibrium to right

 Asymmetric epoxidation of alkenes (1980s)
4 R3 R4 R3
R RCO3H
O Mechanism? Could you modify this in
an asymmetric manner?
R1 R2 R1 R2

Sharpless discovered that a combination of diethyl tartrate, titanium isopropoxide

and a peroxide. But it requires an allylic alcohol as substrate. The oxidant is used
stoichiometrically (i.e. you need one equivalent), but the titanium and tartrate are
used in catalytic amounts (ca. 5 mol%).

The (-)-diethyl tartrate gives

the opposite enantiomer.
How the Sharpless epoxidation (of allylic alcohols) works (catalytic cycle):

The tartrate and metal form a complex:

OiPr O
OiPr Ti
EtO2C O
OH O O CO2Et
Ti
O Ti
EtO2C O O CO2Et OH
Ti O O O CO2Et
PrOi O CO2Et The substrate
OiPr and oxidant
replace two The oxygen atom is
OiPr ligands. directed to the alkene.
The alkene is above the peroxide.
O OH 2 x iPrO ligands
replace the departing product Ti
hence the catalyst is regenerated.
product O O CO2Et
O Ti

O O CO2Et
OH O

side-product
Asymmetric epoxidation of alkenes using Mn/Salen complexes
(Jacobsen epoxidation):
The iodine reagent transfers its oxygen atom to Mn, then the Mn tranfers
in to the alkene in a second step. The chirality of the catalyst controls the
absolute configuration.
Advantage? You are not limited to allylic alcohols.

catalyst -
5 mol%
H H
N N
Mn
But O O tBu
O
tBu But

I
O
(hypervalnet iodine
reagent)
Source of oxygen.
 Asymmetric catalysis Ketone reduction

The reduction of a ketone to a secondary alcohol is a perfect reaction for

asymmetric catalysis:

HO H
O
i) Borane (BH3),
oxazaborolidine catalyst

ii) hydrolysis (work up)

Oxazaborolidine Ph Concave molecule

catalyst: hydride directed to one face.
Ph O
H Ph How it works: N B Me
H Ph O
O B
N H H
B H
Me
 Asymmetric catalysis Organocatalysis (no metals)

Some time ago, it was found that proline catalyses the asymmetric cyclisation of a
diketone (known as the Robinson annelation reaction).

this is not a Now this IS a chiral centre-

L-proline S configuration
chiral centre
O O CO2H O
10 mol%: N
H
Major product

O O

The enantiomeric
Mechanism is via: O compound is:
O

N
O
O
HO2C
 Asymmetric catalysis Organocatalysis (no metals)
This is now the basis for many other reactions e.g.:

Aldols: L-proline
90% yield
O O CO2H O OH
10 mol%: N 4:1 anti:syn
H
H H H
Me anti product e.e.: 99%
Me Me DMF Me

and even more complex ones:

OtBu
20 mol%
O OH
O O
H2N CO2H
H O O
O TBSO OTBS O
TBSO OTBS 3 mol% water, rt 2 days.

68%, major product: D-fructose

precursor
(it turns out that most amines act as catalysts!)
Asymmetric catalysis Organocatalysis Other applications
Other applications include:

Diels-Alder reactions:

O catalyst catalysed by:

+
H R
O L-proline
R
H
CO2H
Asymmetric reductiions: N
O H
O H H
or pyrrolidines:
EtO
+ 2C CO2Et catalyst

N Ph Ph Ph
N Ph N
Ph H H H
(Hantzsch ester- H
hydride source)

or other N-heterocycles:
and oxidations:
O O
O catalyst NMe
+ R O
H H Ph CO2H
H O O N
H
R
R
67
Can you work out the mechanisms?
Asymmetric catalysis Addition to an aldehyde
(C-C bond forming reaction)
HO Et
O

Et2Zn, toluene (solvent) H

H See table for results
(-)-DAIB (see below)

Results:
NMe2
mol% DAIB used Yield E.e.
(relative to aldehyde)
OH
(-)-DAIB 0 (i.e. none) 0% -

(two pictures 2 (0.02 eq.) 97% 98

of the same
molecule)
100 (1.0 eq.) 0% -
NMe2
OH How come a little bit of amino alcohol
catalyses the reaction, but a lot of it doesn't?