the hexadehydro-diels-alder (hdda) reaction hexadehydro-diels-alder reaction diels-alder...
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The HexaDehydro-Diels-Alder (HDDA) Reaction
CEM 958 Organic Seminar
Jun Zhang
Michigan State University
January 22, 2014
1
One Day in the Lab
Several hours later.
Test ResultsYes!
Unfortunately
Decision
Product!
Surprising!
Analysis Redo it
2
Unexpected Result
Intermediate
?
53%
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.3
Proposed Intermediate
Benzyne intermediate?
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.4
Proposed Mechanism
Retro-Brook Rearrangement
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.5
LUMO
HOMO
Benzyne
More electrophilic
Nucleophilic?
Electrophilic?
Rondan, N. G.; Domelsmith, L. N.; Houk, K. N.; Bowne, A. T.; Levin, R. H. Tetrahedron Lett 1979, 20, 3237-3240.
Frontier orbitals and energies (eV) by ab initio calculation on 4-31G basis set.6
The Hexadehydro-Diels-Alder Reaction
Diels-Alder
Didehydro-Diels-Alder
Tetradehydro-Diels-Alder (TDDA)
Hexadehydro-Diels-Alder (HDDA)
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.7
First Reported Triyne Cyclization
Stepwise or Concerted Mechanism ?
Bergman Stepwise Cyclization ?
Bradley, A. Z.; Johnson, R. P. J Am Chem Soc 1997, 119, 9917-9918.8
Bergman Cyclization
Calicheamicin ϒ1
Walker, S.; Landovitz, R.; Ding, W. D.; Ellestad, G. A.; Kahne, D. P Natl Acad Sci USA 1992, 89, 4608-4612.
Bergman
Cyclization
9
Possible Mechanism
Only A is observed after the reaction
Bradley, A. Z.; Johnson, R. P. J Am Chem Soc 1997, 119, 9917-9918.
A B
Concerted
Pathway
Stepwise
Pathway
10
A Concerted or Stepwise Mechanism?
Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust, K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P.
J Org Chem 2011, 76, 9320-9328.
0.5 kcal/mol
difference.
CCSD(T)//M05-2X energetics of diyne−yne cycloadditions.
Concerted
TS 1
36.5 kcal/mol
Stepwise
TS 2
37.0 kcal/mol
Stepwise
TS 3
35.8 kcal/mol
30.8 kcal/mol
-51.4 kcal/mol 0.0 kcal/mol
Concerted
Stepwise
2.78Å
2.24Å
1.81 Å
11
First Reported Triyne Cyclization
Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett 1997, 38, 3943-3946.
Ueda, I.; Sakurai, Y.; Kawano, T.; Wada, Y.; Futai, M. Tetrahedron Lett 1999, 40, 319-322.
Miyawaki, K.; Ueno, F.; Ueda, I. Heterocycles 2000, 54, 887.
Stepwise Mechanism ?
Or
12
Mechanism Difference
Ueda’s Work Hoye’s Work
Mechanism: Radical pathway
Intermediate: Diradical benzene
Evidence: Cyclization with alkyne
Mechanism: 2 electron transfer
Intermediate: Benzyne
Evidence: Retro-Brook rearrangement
Alkane desaturation14
Solvent Role in HDDA Reaction
75%
Where do the 2 H come from?
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.15
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.
THF Desaturation
H-Product Deuterated-Product
Solvent Product ratio (H : D)
THF-h8 100:0
THF-d8 0:100
THF-h8 : THF-d8 (1:1) 6:1
THF-h8 : THF-d8 (1:6) 1:1
No mono-deuterated product is observed.
16
Alkane Desaturation
Benzyne
intermediate
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.17
2H Donor
Entry 2H donor Product Yield (%)
1 Cyclooctane 97
2 Cycloheptane 94
3 Cyclopentane 84
4 Norbornane 86
5 Cyclohexane 20
6 THF 60
7 1,4-Dioxane 0
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.18
Desaturation Requirements
Dominant Conformer
Cyclopentane
84 %
Cyclohexane
20 %
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.19
Desaturation Requirements
Cycloheptane
94 %
Cyclooctane
97 %
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.
Dihedral Angle Argument
20
HDDA Reaction Scope
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.21
HDDA Intramolecular Trapping
Diels-Alder Type Reaction
Ene Type Reaction
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.22
Only Diels-Alder
Product, 83 %
2 Atom Spacer
Only Aromatic Ene
Product, 88 %
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.24
3 Atom Spacer
Only Diels-Alder
Product, 85 %
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.
Spacer R Ene product yield D-A product yield
2 H N/A 83
2 Me 88 N/A
3 Me N/A 85
25
22
13.214.4
45.6
18.3
1310
20
30
40
50
1 2 3Spacer number
TS energy
kcal/mol
Or
Aromatic Ene
TS
Diels –Alder
TS
Calculation Summary
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.
Energies in
kcal/mol
26
Rearrangement
No Reaction
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.
Keto-enol Type Tautomerization
Possible ways:
27
Rearomatization
Can H2O catalyze the reaction?
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.28
Bimolecular Alder Ene Reaction
Single diastereomer
1) HDDA Reaction
2) Aromatic Ene Reaction
3) Alder Ene Reaction
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.30
Reaction Scope
X=O, N-PG
55 %~ 90 %
X=Y: O=C, TsN=C
63 %~ 85 %
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.31
HDDA Intermolecular Trapping
R=(CH2)3OAc
Benzene solvent
70%Norbornene
(0.1 M) 63%
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.32
HDDA Intermolecular Trapping
PhNHAc (0.15 M) 82%
19:1 ratio of isomers
Acetic acid (0.8 M) 89%
Single isomer
Phenol (0.1 M), 85%
Single isomer
R=(CH2)3OAc
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.33
Trapping agent
(Nuc)
Yield (Ratio)
91%
(12.5:1)
80%
(3:1)
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.
4,5-Indolyne Regioselectivity
34
∠3=110°∠4=125°∠5=129°
∠3=118°∠4=112°∠5=137°
∠3=108°∠4=134°∠5=115°
C-5 Attack C-4 Attack
4,5-Indolyne Distortions
B3LYP/6-31G(d)-optimized structures.
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.
ΔE ‡ = 3.5 kcal/mol
ΔH ‡ = -0.9 kcal/mol
ΔG‡ = 9.9 kcal/mol
ΔE‡ = 4.9 kcal/mol
ΔH ‡ = 1.6 kcal/mol
ΔG‡ = 12.9 kcal/mol
34
5
34
5
35
Trapping agent
(Nuc)
Yield (Ratio)
91%
C-6 Single
53%
C-6 Single
6,7-Indolyne Regioselectivity
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.36
6,7-Indolyne Distortions
B3LYP/6-31G(d)-optimized structures.
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.
ΔE‡ = 8.8 kcal/mol
ΔH‡ = 5.5 kcal/mol
ΔG‡ = 18.4 kcal/mol
7
6
37
Large C angle: More p character and a slight positive charge
+
Benzyne Distortions
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.
ΔE‡ = 4.0 kcal/mol
ΔG‡ = 9.1 kcal/mol
B3LYP/6-31G(d)-optimized structures.38
θC-4 θC-5
125°
1
129°
3.3
θC-5 θC-6
129°
1.7
127°
1
θC-6 θC-7
135°
19
116°
1
θC-1 θC-2
122° 130°
θC-1 θC-2
128° 127°
θC-1 θC-2
130° 126°
Preferred side of attack.
lm, G. Y.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.; Houk, K. N.; Garg, N. K.
J Am Chem Soc 2010, 132, 17933-44.
Preferred Site of Attack
Product ratio of Nuc= CN- , optimized geometries by B3LYP/6-31G(d)
39
θC-2 θC-3
119° 135°
θC-2 θC-3
134° 122°
Steric factors
Electronic factors Mixture
Preferred Site of Attack
lm, G. Y.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.; Houk, K. N.; Garg, N. K.
J Am Chem Soc 2010, 132, 17933-44.
Aniline
2
1
40
Model Summary
1• Building the structure
2• Calculation work
3• Attack from large angel ( >4°)
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.
lm, G. Y.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.; Houk, K. N.; Garg, N. K.
J Am Chem Soc 2010, 132, 17933-44.
Procedure
41
∠a=135°∠b=119°
How to tune the regioselectivity of HDDA reaction?
Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.
HDDA Regioselectivity
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.42
4.8: 1
Single
major
Bu vs SiEt3
Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.
+
43
1.4:1major
Single
Steric Effect
Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.
+
44
1:1.8
9:1
major
Electronic Effect
Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.
+
+
major
45
Ways to Tune the Regioselectivity
• Electron donating groups
• Silicon effect
• Oxygen nucleophile attack.
• Building bulky R2 groups
• Nitrogen bulky nucleophile attack.
Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.46
Summary
The Hexadehydro Diels-Alder reaction:
• Alkane desaturation
• Intramolecular trapping: ene reaction
• Alter the regioselectivity of HDDA
reaction
• Distortion of the aryne
47
Acknowledgements
Dr. Babak Borhan
Dr. Xuefei Huang
Dr. Chrysoula Vasileiou
All my group members: Ipek, Bardia, Kumar, Nastaran,
Ding, Wei, Hadi, Liz, Yi, Edy, Arvind, Tanya, Calvin,
Carmin.
Liz, Ding, Xiaopeng
All my friends.
48
Calculation based on Density Functional Theory (DFT, M062X18/6-31G(d)).
Calculation Study of 2 Atom Spacer
0.0 kcal/mol
TS-1
13.2 kcal/mol
TS-2
18.3 kcal/mol
-40.9 kcal/mol-46.7 kcal/mol
-83.8 kcal/mol
Aromatic Ene
Diels-Alder
n = 2
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.49