FRUSTRATED LEWIS PAIRS FOR ORGANOCATALYTIC
HYDROGENATION REACTIONS
Tatiana Le Gall-Diop
Collins Group
Université de Montréal
Charette Meeting
Monday, March 14th, 2011
Outline
1.
What is a Frustrated Lewis Pair (FLP) ?
2. Heterolytic Cleavage of H2 by FLPs
3. Organocatalytic Hydrogenation Reactions
4. Organocatalytic Nitro Aldol Reaction
5. Potential for Future Use
2
What is a Frustrated Lewis Pair?
Classical Lewis Acid/Base Adducts
High-lying HOMO
DONOR
Low-lying LUMO
ACCEPTOR
Mutual Quenching
Mutual Neutralization
Classical Examples :
3
Stephan, D.; Erker, G. Angew. Chem. Int. Ed. 2010, 49, 46-76
What is a Frustrated Lewis Pair?
Sterically Frustrated Lewis Pairs
Wants to Accept
Wants to Donate
BUT!
No Mutual Quenching
This Pair is Sterically Frustrated!
Example :
4
Stephan, D.; Erker, G. Angew. Chem. Int. Ed. 2010, 49, 46-76
Towards Frustrated Lewis Pairs
 1923 : Lewis
 Lewis Base : an electron pair donor
 Lewis Acid : an electron pair acceptor
 1959 : Wittig and Benz
 Ancestor of the Frustrated Lewis Pair
 1966 : Tochtermann
 « Antagonistisches Paar »
Wittig, G.; Benz, E. Chem. Ber. 1959, 92, 1999-2013
Tochtermann, W. Angew. Chem. 1966, 78, 355-375
5
The trigger…
 2003 : Roesler and Piers
 Reactivity of an amino borane
 The first modern Frustrated Lewis Pair/Towards H2 activation
Can release H2 but not yet activate it
Roesler, R.; Piers, W.; Parvez, M. J. Organomet. Chem. 2003, 680, 218-222
6
Douglas W. Stephan
 1976 : B.Sc. (McMaster University)
 1980 : Ph.D (University of Western Ontario),
NSERC Scholar
 1980-1982 : NATO Postdoctoral Fellow (Harvard,
R.H. Holm)
 1982-2007 : Professor and Head of Department
(University of Windsor)
 2008- present :
 Professor (University of Toronto)
 Canada Research Chair in Inorganic Materials and
Catalysis
 His work :
 Frustrated Lewis Pairs
 C-H and P-H activation
 Phosphine based materials and polymers
7
The First Frustrated Lewis Pairs Capable of H2 Cleavage
 First use of the term « Frustrated Lewis Pairs »
H2 Activation
Orange Oil
Stephan, D. et al, Science. 2006, 314, 1124-1126
White solid
Air and Moisture Stable
8
Different systems…
 Internal main group FLPs
Erker, G. et al, Chem. Commun. 2007, 5072-5074
Stephan, D. et al, Science. 2006, 314, 1124-1126
Tamm et al, Angew. Chem. Int. Ed. 2008, 47, 7428-7432
 External main group FLPs
Chen, E. et al, Angew. Chem. Int. Ed. 2010, 49, 10158-10162
Stephan, D. et al, J. Am. Chem. Soc. 2009, 131, 52-53
9
Heterolytic Cleavage of H2 by FLPs
Why would an FLP activate H2?
1. Creation of a polar and frustrated environment
Facts on H2 bond
0.74 Å
432 kJ/mol
2. Polarization of H2
+
Important for FLPs
Sufficient steric influence
Matching L. acidity/basicity
-
3. Activation of H2
The system is not10frustrated anymore
Rieger, B. et al, J. Organomet. Chem. 2009, 694, 2654-2660
Heterolytic Cleavage of H2 by FLPs
How does one make a suitable catalyst for hydrogenation?
REVERSIBILITY
The first system
Stephan, D. et al, Science. 2006, 314, 1124-1126
Stephan, D. et al, Chem. Commun. 2009, 1118-1120
11
Heterolytic Cleavage of H2 by FLPs
Possible Mechanism of H2 release
Intermolecular
Proton Migration
Intermolecular
Hydride Migration
1,2-H2 Elimination
1,2-H2 Elimination
Stephan, D. et al, Science. 2006, 314, 1124-1126
12
Bernhard Rieger
 1986 : B.Sc. (Ludwig-Maximilians-Universität,
Munich)
 1988 : Ph.D (LMU, Pf. Beck)
 1988-1989 : Postdoc (University of Massachussets,
Pf. Chien)
 1995-2006 : Professor and Head of Department
(University of Ulm)
 2007- present :
 Professor Ordinarius (Technische Universität München)
 WACKER Chair of Macromolecular Chemistry
 Director : Institute of Silicon Chemistry at TU München
 His work :
 Materials Science
 Homogeneous Polymerization Catalysis
13
Heterolytic Cleavage of H2 by FLPs
Irreversible systems
Erker, G. et al, Dalton Trans. 2009, 1534-1541
Rieger: « How to turn an irreversible system into a reversible one »
Rieger, B. et al, J. Am. Chem. Soc. 2008, 130, 14117-14119
What influences reversibility?
14
Heterolytic Cleavage of H2 by FLPs
Reversibility of H2 activation
The importance of « Dihydrogen Bonding » (DHB)
Must be less than 1.9 Å to
favor the liberation of H2
15
Rieger, B. et al, J. Am. Chem. Soc. 2008, 130, 14117-14119
Heterolytic Cleavage of H2 by FLPs
X-Ray Structure of
Rieger, B. et al, J. Am. Chem. Soc. 2008, 130, 14117-14119
16
Heterolytic Cleavage of H2 by FLPs
Elaborating a New System
Rieger, B. et al, J. Am. Chem. Soc. 2008, 130, 14117-14119
Rieger, B. et al, J. Organomet. Chem. 2009, 694, 2654-2660
17
Heterolytic Cleavage of H2 by FLPs
Illustrating the Energy of the System
Energies (kJ/mol) of the hydrogen activation reaction by 1 calculated at the PBE/6-31G(d) level of theory: black color, gas
phase; blue color, solution in benzene.
18
Some Classics in Hydrogenation Reactions
Transition Metal Catalysts
Pd/C
Raney Ni
Crabtree’s Catalyst
Wilkinson’s Catalyst
Organic/Main Group Reducing Agents
Why Frustrated Lewis Pairs?





Avoid the use of expensive transition metals
Organic system that hydrogenates catalytically
Since not stoechiometric, less waste
Milder conditions than other organocatalytic systems (eg 200°C, 100atm H2)
No heavy metal pollutant
19
Organocatalytic Hydrogenation Reactions
Classical reaction set up
 Anhydrous conditions
 H2 atmosphere : Schlenck tube, autoclave, sealed
tube
Common Substrates :
And also limitation…
20
Reduction of Ketimines and Aldimines
Internal N/B Catalyst
24h, 4%
12h, 99%
48h, 60%
Forms a classical
LA/LB adduct with
catalyst
Rieger, B. et al, J. Am. Chem. Soc. 2008, 130, 14117-14119
6h, 99%
6h, 99%
EDG facilitates
protonation
21
Reduction of Ketimines and Aldimines
Mechanism
1. Fast H2 Activation
3. Slow Release
of Substrate
2. Reduction
Rieger, B. et al, J. Am. Chem. Soc. 2008, 130, 14117-14119
22
Reduction of Aldimines
Internal B/P Catalyst
12h, 80°C
79%
10.5h, 120°C
97%
1h, 140°C
88%
e- poor imine,
Protonation less easy
Stephan, D. et al, Angew. Chem. Int. Ed. 2007, 46, 8050-8053
48h, 120°C
5%
46h, 120°C
57%
Forms a classical
LA/LB adduct with
catalyst
23
Reduction of Aldimines
Mechanism
1. Fast H2 activation
2. Slow protonation
3. Hydride transfer
4. Slow substrate release
Stephan, D. et al, Angew. Chem. Int. Ed. 2007, 46, 8050-8053
24
Reduction of Protected Nitriles
Longer reaction times, type of substrate harder to activate
24h, 75%
24h, 84%
Stephan, D. et al, Angew. Chem. Int. Ed. 2007, 46, 8050-8053
Internal B/P Catalyst
48h, 99%
25
Reduction of Protected Nitriles
Mechanism
H2 Activation
Hydride Transfer
Protonation
Protonation
H2 Activation
Hydride Transfer
Li, S. et al, Inorg. Chem. 2010, 49, 3361-3369
26
Reduction of Aldimines, Ketimines and an Aziridine
Substrate as a Lewis Base
Aldimines
External B/N System
Ketimines
2h, 89%
1h, 99%
41h, 94%
Aziridine
1h, 98%
2h, 95%
Stephan, D. et al, Chem. Commun. 2008, 1701-1703
8h, 94%
48h, 0%
Too bulky to allow
for hydride transfer
27
Reduction of Aldimines, Ketimines and an Aziridine
Mechanism
1. H2 Activation + Protonation
3. Substrate Release
2. Hydride Transfer
28
Stephan, D. et al, Chem. Commun. 2008, 1701-1703
Reduction of a Deactivated Aldimine and Protected Nitriles
External B/P System
49h, 91%
48h, 94%
8h, 98%
Shorter Reaction Time
29
Stephan, D. et al, Chem. Commun. 2008, 1701-1703
Reduction of a Deactivated Aldimine and Protected Nitriles
2. Imine to Amine
Mechanism
Stephan, D. et al, Chem. Commun. 2008, 1701-1703
1. Nitrile to Imine
30
Reduction of Silyl Enol Ethers
Very mild conditions
External B/P Catalyst
93%
89%
86%
85%
16%
60atm, 3h
31
Erker, G. et al, Chem. Commun. 2008, 5966-5968
Reduction of N-Heterocycles
Again, a certain steric hindrance is necessary to avoid
the formation of classical Lewis Acid/Base adducts
2h, 80%
4h, 80%
16h, 74%
Stephan, D. et al, Chem. Commun. 2010, 46, 4884-4886
External B/N System
10mol%, 6h, 80°C
88%
3h, 84%
32
Reduction of N-Heterocycles
Mechanism
1,2 Hydride Transfer
H2 activation + Protonation
1,2 or 1,4 Hydride Transfer
H2 activation + Protonation
Isomerization
Stephan, D. et al, Chem. Commun. 2010, 46, 4884-4886
33
Reduction of Enamines
Internal B/P System
5 mol% cat.
88%
3 mol% cat.
78%
Erker, G. et al, Angew. Chem. 2008, 47, 7543-7546
10 mol% cat.,
50 atm H2, 70°C
80%
10 mol% cat.
q.
34
Enantioselective Hydrogenation Reaction
Chiral Internal B/P Catalyst
95% 79%ee
99% 81%ee
37% 74%ee
93% 80%ee
0%
96% 81%ee
96% 83%ee
Klankermayer, J. et al, Angew. Chem. Int. Ed. 2010, 49, 9475-9478
35
Enantioselective Hydrogenation Reaction
Making the catalyst
2S, 3S
2R, 3R
Separated by crystallization!
Klankermayer, J. et al, Angew. Chem. Int. Ed. 2010, 49, 9475-9478
36
Enantioselective Hydrogenation Reaction
X-Ray Structure of
π-stacking
Formation of a « pocket »
Klankermayer, J. et al, Angew. Chem. Int. Ed. 2010, 49, 9475-9478
37
Summary for Hydrogenation
 Summary:
 Usually P/B and N/B systems
 May use substrate as a LB
 Need adjustable bulk (release of product vs approach of
catalyst)
 In P/B : Substrate nucleophilic enough for proton transfer
from P
 Minus
 Substrate scope is limited
 Rare examples of enantioselectivity
 B(C6F5)3 : ~160$/g (Pd/C ~40$/g)
 Plus :




No use of transition metals
Little waste compared to classic organic systems
Low catalyst loading
Good yields
38
Nitro Aldol Reaction Using Frustrated Lewis Pairs
Different Nitro Alkanes
Internal N/B Catalyst
1h, 95%
1h, 84%
Saito, S. et al, Chem. Lett. 2008, 37, 1294-1295
1h, 71%
2h, 77%
39
Nitro Aldol Reaction Using Frustrated Lewis Pairs
Different Aldehydes
Internal N/B Catalyst
8h, 1.5eq. CH3NO2
95%
30h, 3eq. CH3NO2
98%
Saito, S. et al, Chem. Lett. 2008, 37, 1294-1295
48h, 3eq. CH3NO2
77%
24h, 1.5eq. CH3NO2, 25°C
99%
40
Nitro Aldol Reaction Using Frustrated Lewis Pairs
α-deprotonation
of nitroalkane
Aldol
Saito, S. et al, Chem. Lett. 2008, 37, 1294-1295
41
What FLPs can also do…
 Activation of small molecules




THF
Ethylene
Dioxane
CO2
 Activation of bigger molecules





Olefins
Alkynes
Aldehydes
Disulfides
Cyclopropanes!
42
FLP Stoechiometric Reduction of CO2 to MeOH
Reversible CO2 Activation
Equilibrium between the classical adduct and the FLP
Reduction to MeOH
Stephan, D. et al, J. Am. Chem. Soc. 2010, 132, 1796-1797
43
Conclusion
Frustration can be productive!
 Metal free systems that can activate H2
 Can effect hydrogenation of imines, enamines, silyl enol
ethers
 Potential for H2 storage
 A lot of work to do for enantioselective hydrogenation
 Their reactivity (catalytic or stoechiometric) with a variety
of substrates shows they still have a lot of potential
 Chemistry still young but promising
44