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5.37 Introduction to Organic Synthesis Laboratory
Spring 2009
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Massachusetts Institute of Technology
Chemistry 5.37
Professor Timothy M. Swager
The Diels-Alder Reaction
Lecture 2: Theory and “Swager Centric” Applications
April 7, 2009!
First: A Little Review of Simple Bonding!
!*"
Molecular Hydrogen
Is Stable: Orbital Overlap
Leads to a Net Lowering of Energy
H
H
!"
H
H
!*"
Molecular Helium
Is Unstable: Orbital Overlap
Leads to a Net Increase In Energy
(The !* is higher than shown due to
e-e repulsion)
He
He
!"
He
He
Dimerization of Ethylene�
2+2
+
Thermally Forbidden
Photochemically Allowed
�
�
Higher e-e Repulsion
�
�
Dimerization of Ethylene�
2+2
+
�
Thermally Forbidden
Photochemically Allowed
�
�
�
�
�
Higher e-e Repulsion
h
�
�
Example of a Thermally Allowed 2+2�
CN
CN
2+2
+
H2 C
C
CH2
Example of a Thermally Allowed 2+2�
CN
CN
2+2
+
H2 C
C
CH2
H H
CN
Bonding in the
Tranisition State
Allene HOMO
Acrylnitrile LUMO
H
H
Orbitals of Butadiene and Ethylene�
a�
a�
s�
a�
Relative Symmetry
of Orbitals�
s�
s�
Orbitals of the Same Symmetry Can Interact�
Butadiene HOMO
Ethylene LUMO
a�
a�
s�
Interactions of Filled�
and Empty Orbitals is Stabilizing�
a�
s�
s�
Butadiene LUMO
Ethylene HOMO
Purturbation Theory: �
Orbitals Closer in Energy, Interact Stronger�
EWG
D
EWG
e-e Repulsion Raises the Occupied Orbitals
D
D
D
EWG
EWGs Lower the LUMO
D
EWG
D
Purturbation Theory: �
Orbitals Closer in Energy, Interact Stronger�
D
EWG
EWG
e-e Repulsion Raises the Occupied Orbitals
D
D
EWG
D
EWGs Lower the LUMO
Strong Bonding
D
Alder Endo Rule: �
Secondary Orbital Interactions�
Secondary
Orbital
Interactions
+
O
O
O
O
O O
Alder Endo Rule: �
Secondary Orbital Interactions�
Secondary
Orbital
Interactions
+
O
+
O
O
O
O O
DA Reaction in Materials Chemistry�
Features:
Often a Very Clean Reaction
It can be a Reversible Reaction
Forms 2 New Bonds at Once
Produces Structurally Rigid Stuctures
Self Healing Polymers�
O
C
O
O
O
O
O
N
4
+
Heat
O
O
N
N
Crosslinked Network
3
O
Wudl and coworkers�
Science 2002, 295, 1698�
+
Heat
Retro-DA to Form an Organic Metal�
DA Rxn
CF3
F3C
CF3
CF3
LxM=CHR
Ring Opening Metathesis
Polymerization (ROMP)
R
R
Retro
DA Rxn
n
Wittig like
Endcapping
n
CF3
R'
R'
Polyacetlylene
a Conducting Polymer
CF3
CF3
R
n
CF3
O
R'
LxM
CF3
Soluble Polymer
CF3
James Feast (Durham U.) Cira 1983
�
Through Space -Interactions
Eox > 2.4 V
Eox = 1.28 V
Decreasing oxidation potential
Grimme, Gleiter et al. Angew Chem. Int. Ed. Engl. 1991, 30, 205-207.
What About Double DA Adducts?
Synthetic Access to New Monomers
2
+ X
X
X
X
Monomer and Polymer Synthesis�
O
O
O
O
O
O
TIPS
O
TIPS
O
O
TIPS
anthracene (40 equiv)
o-xylene
180 oC
(76% yield)
O
TIPS
O
O
Syn–Syn
O
O
TIPS
TIPS
O
Anti–Anti
O
Bu
O
Et
N
O
(Not Observed!)
O
O
TIPS
n
1. NH2CH2CH(Et)(Bu), -H2O
2. Deprotect TBAF
3. CuI, benzoquione
PdCl2(PPh3)2, Et2N
O O
O
TIPS
O
O
O
Bu
N
O O
Anti–Syn
Et
Mn= 17,000
A. McNeil
X-ray Crystallography�
O
O
O
TIPS
=
TIPS
O
O
O
(Not Observed!)
Photobleaching Studies: Thin Films�
Bu
H
n-Hex
n-Hex
O
H
H
N
O
Et
H
N
O
O
H
H
O
O N
H
P1�
Et
Bu
P2�
H
P3�
O
O
N
Et
Bu
UV Exposure at max
With 20nm Slit Width
Matched Optical
Densities
Seconds
Increased Stability by
Design:
1. No Reactive -Protons
2. Stabilized Cations by
Through Space ­
Interactions
3. Arene Faces Blocked
4. 3-D Non-Aggregating
Structure
A. McNeil
Synthesis of a
Poly(iptycene) Ladder
Polymer�
Zhihua Chen
PhD 200
Poly(iptycene)�
C8H17
O
OCH3
O
C8H17
C8H17
O
C8H17
O
*
OCHC
3 8H17
H3CO
*
C8H17
H3CO
(Branching agents)
Wudl, F. et al JACS, 2003, 125, 10190
Thomas S. M. et al JACS, 2005,127, 17976
A simple approach:
diene
dienophile
OR
O
OR
To improve solubility
Synthesis of Monomer�
O
c
b
a
82%
O
OH
O
OH
85%
OH
O
OH
OC6H13
d
45%
OC6H13
OC6H13
Br
Br
OC6H13
63%
OC6H13
e
O
76%
OC6H13
monomer
Reagents and conditions: (a) (1) NaBH4, MeOH, rt-reflux; (2) HCl, rt. (b) Na2S2O4, p-dioxane, H2O, rt; (c)
C6H13Br, K2CO3, KI,18-crown-6, DMF, 85 oC; (d) NBS, DMF, rt; (e) furan, THF, PhLi, 0 oC.
n
*
Synthesis of Monomer�
O
OH
O
OH
82%
O
c
b
a
85%
63%
OH
O
OH
OC6H13
OC6H13
Br
d
45%
Br
OC6H13
OC6H13
OC6H13
e
O
76%
OC6H13
DA
PhLi
OC6H13
OC6H13
Li
O
Br
OC6H13
OC6H13
High Energy "Alkene"
is the Dieneophile
Differential Scanning Calorimetry �
67 oC
Heat Flow (w/g)
6
5
4
Sample after DSC study:
Mn=2.8KDa, PDI =2.8
3
2
Second heating
First Heating
Exotherm: Down
1
0
111 KJ/mol
215 oC
35 KJ/mol
-1
50
100
150
200
250
300
o
Temperature C)
(
Thermal Neat Polymerization: OC6H13
neat, 170 oC
O
OR
O
72 h
OC6H13
Low MW!
n
RO
R = n-C6H13
Mn = 5~6 KDa
Differential Scanning Calorimetry �
67 oC
Heat Flow (w/g)
6
5
4
Sample after DSC study:
Mn=2.8KDa, PDI =2.8
3
2
Second heating
First Heating
Exotherm: Down
1
0
111 KJ/mol
215 oC
35 KJ/mol
-1
50
100
150
200
250
300
TemperatureoC)
(
Thermal Neat Polymerization: OC6H13
neat, 170 oC
O
Diels-Alder reactions can be
accelerated by the application
of high pressure, because the
transition state of D-A reaction
has a net contraction in
volume.
OR
O
72 h
V‡ = -RT(�lnk/�P)T
n
RO
OC6H13
R = n-C6H13
Low MW!
Mn = 5~6 KDa
Synthesis of Poly(iptycene) Dehydration Reaction�
pyridinium
p-toluenesulfonate
OR
O
n
RO
OR
acetic anhydride,
140 oC
n
RO
R = n-C6H13
R = n-C6H13
P1
P2
Summary of the synthesis of P1 and P2
[M]a
(M)
Temperature
(oC)
Time
(h)
Pressure
(psi)
1
0.50
145
5
2
0.88
145
3
1.01
4
1.50
entry
a
P1
P2
Mnb
(Da)
PDI
Mnb
(Da)
PDI
128,900
6,100
2.2
n/a
n/a
5
139,600
9,400
2.7
10,900
2.4
145
5
145,800
11,100
3.3
12,600
2.6
145
5
145,800
16,400
3.6
16,300
2.5
Monomer concentration. b Molecular weights determined by GPC in THF against polystyrene standards.
Dimethylene Cyclobutene�
•� 3,4-Bismethylenecyclobutene (3,4-BMCB) is an isomer of benzene produced
by flash vacuum pyrolysis of 1,5-hexadiyne�
C
375°C
C
•� Reactivity and electronic structure largely influenced by energetic cost of
antiaromatic cyclobutadiene formation�
0.616 ± 0.002 D �
–� For this reason, s-cis diene formed by exocyclic methylene groups is not reactive
in Diels-Alder chemistry�
Coller, Aust. J. Chem., 1968, 21, 1807.
Ladder Polymers�
•� Polymers consisting of cyclic subunits connected by two links that
do not merge or cross�
n
•� Molecular weight remains constant when one bond is broken �
–� Potential for high-strength materials�
•� Difficulty of synthesis and processing prevented first generation
ladder polymers from gaining industrial importance�
•� Two main obstacles to ladder polymer synthesis�
–� Rigid backbone leads to inherent insolubility�
–� Side reactions can lead to cross-linking and defects�
Schluter, A.D. Materials Science and Technology., 1999, 20, 459.
Diels-Alder of 3,4-Bis(methylene)cyclobutene�
•� Used 1,3-diphenylisobenzofuran as diene
Ph
Ph
Ph
H
H
room temp.
+
O
O
O
PhCH3
H
Ph
H
Ph
25 (endo)
Ph
:
white crystals
1 (exo)
•� Reaction with maleic anhydride
Ph
Ph
O
H
H
H
O
reflux
+
O
O
O
O
PhCH3
H
H
O
Ph
H
Ph
O
white crystals
Becca Parkhurst
Towards Conjugated Ladder Polymers�
R
X
R
R
R
X
X
X
X
initiation
X
X
X
X
R
X
R
R
R
•� Using an electron-withdrawing group as “X” sould increase
reactivity towards DA reactions�
X
-(HX)
X
Becca Parkhurst
n
n
n
Diels Alder Reaction�
The most powerful reaction in organic chemistry
Stereochemistry
Multiple bonds produced
Products with confomational rigidity
High yeild and reversible
Applications in synthesis, from nature product
synthesis to materials science