Mechanism of Ni-Catalzyed C-C Bond
Formation
Versatility of the Negishi Reaction
Paul White
Stahl Group
03/25/10
Challenges of Carbon-Carbon Cross-Coupling
Strategy of Homocoupling vs Cross-Coupling
Obtain a mixture
Choice of X, MT, M
Allred-Rochow electronegativity scale
MT: Tunable Reactivity/Functional Group Tolerance
MT = B (Suzuki-Miyaura), Sn (Stille), Zn (Negishi), Mg (Kumada-Tamao), Li
X: Easy to activate R-X
X = Halide or Pseudohalide (e.g. –OSO2CF3)
M: Rapid reaction with R-X
Focus: Group 10 M (Ni, Pd, Pt)
Knochel, P. et. al. Angew. Chem. Int. Ed. 2000, 39, 4414-4435
Pearson, R. G.; et. al. J. Am. Chem. Soc. 1980, 102, 1541-1547.
2
Typical Mechanism for Cross-Coupling
0/+2 or +2/+4
-Characteristic Pd-catalysis
-Commonly proposed for Ni
+1/+3 (Ni)
-1,4 conjugate additions using MT
-Some Ni-containing enzymes
Why Nickel?
Why Not Nickel?
-More affordable than Pd
-More reactive than Pd towards RX
-Does not always do predictable
2e- chemistry like Pd
What set of oxidation states does Ni-catalyzed R-R formation operate under?
Does mechanism differ between sp2-sp2 and sp3-sp3 couplings?
By understanding the mechanism, is it possible to rationalize the chemistry?
3
In the Beginning
First nickel organic-halide coupling reaction:
cod = 1,5 cyclooctadiene
Immediate advantage over previous methods
1) Ullmann chemistry
2) Organo-lithium and -magnesium + M
- limits range of functional groups
Uses stoichiometric amount of Ni
Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J. Am. Chem. Soc. 1971, 93, 5908-5910
4
Milestone Study: Kochi’s Mechanistic Work
Kochi recognized the need to evaluate the variety of mechanisms proposed to better
understand the chemistry
Step 1: Oxidative Addition
Step 2: Three Proposed Mechanisms
Disproportionation/Reductive Elimination
Oxidative Addtion/Reductive Elimination
Homolysis/Radical dimerization
Approach of Study: Observe how ArNiIIXLn-2 reacts
Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 7547-7560
5
Disproportionation/Reductive Elimination
Proposed Pathway:
Experimental Evidence Against:
*No disproportionation occurs under reaction conditions*
6
Oxidative Addition/Reductive Elimination – NiII/NiIV
Proposed Pathway:
Experimental Evidence Against:
Aryl scrambling
Halide scrambling w/o aryl exchange
*Due to NO aryl exchange,
NiII/NiIV not operating*
7
Presence of an Induction Period
Additive Effects
0.2% PEt3
MeOTf
NiBr2
None
Reduce induction period:
-MeOTf: methylates phosphine
-NiBr2: acts as a phosphine sink
Increase induction period
-0.2% PEt3: >> 0.2% = no reaction
Induction period involves dissociation of a phospine ligand
8
Aryl Radical Addition/Reductive Elimination – NiI/NiIII
Proposed Pathway:
Evidence against:
Trapping by 1,4 dihydrobenzene
Experiment 1
TATM + DHB + (ArNiIIBr)
Result: No change in rate of decomposition
and trapping with or without ArNiIIBr
Experiment 2
11% TATM + DHB + ArNiIIBr + PhI
*Aryl radicals are NOT intermediates*
Result: No effect on rxn or induction period
9
Inhibition by 1e- Acceptors
Additive:
O2
10 mol%
Resume once consumed
Strongly retards rate
Complete inhibition
*Suggests an odd-electron pathway (+1/+3)*
10
Review of Experimental Results
Previously proposed mechanisms:
1. Disproportionation/Reductive Elimination
*Does not occur under
reaction conditions*
2. Oxidative Addition/Reductive Elimination
*NO aryl exchange observed*
3. Aryl Radicals
*Aryl radicals not present in
solution (trapping study)*
None of the proposed mechanisms fit the data!
11
A New Mechanism Proposed
Knowns:
1) Clearly not 2e- chemistry (+0/+2, +2/+4)
2) Affected by 1e- acceptors (+1/+3)
3) Does not involve aryl radicals
4) Phosphine dependence in induction period
Proposal: Test the viability of a NiIII radical species
Oxidation of ArNiIIX
Achieved chemically
and electrochemically
Reduction of ArX
Reduction potential matches induction period
ArI (2 min) < ArBr (60 min) < ArCl (80 min)
Initiation Event:
12
Proposed Mechanism – NiI/NiIII
Must account for:
NOTE!
Not catalytic in Ni
-forms NiX2 = unreactive
- Halide scrambling ✓
- Aryl scrambling ✓
- No aryl exchange ✓
Radical Chain
Propagation
13
Move Towards Catalysis
Problem associated with stoichiometric Ni reactions:
1) [NiX] generated by initiation is very small
- poor electron donors/acceptors
2) NiX2 is an unreactive form of Ni
Solution: Use reducing metals (Zn, Mg, Mn) to generate/regenerate NiI
Role of Zn
Pathway 1:
Pathway 2:
Kende, A. S.; et. al. Tet. Lett. 1975, 39, 3375-3368, Kumada, M.; et. al. Tet. Lett. 1977, 47, 4089-4092
14
Negishi Reaction – Expanding Cross-Coupling Reactions
Selective cross-coupling had been achieved with use of organometallics species
- MT = Mg -> Kumada Reaction
- MT = Li
- Catalyst = Ni or Pd
Negishi introduced the use of organozincs
Ni works as efficiently as Pd
Organozincs more functional group tolerant than RMgX or RLi
Negishi, E-I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821-1823
15
Summary of Mechanism and Methodology Highlights
Ni-catalyzed aryl-aryl couplings
Mechanism
Stoichiometric reaction in Ni operates via +1/+3 pathway
- different than Pd mechanisms (0/+2)
Made catalytic in Ni by using reducing metal (Zn)
- generates/regenerates NiI
Methodology – Negishi reaction
Ni performs as effectively as Pd
Organozincs more tolerant of functionality than tradional organometallics
- tolerant of C=O, CN and many more
16
Challenges of Alkyl-Alkyl Cross-Coupling
Problem 1: Slow reactivity towards R-X
Solution 1: Choose conditions that provide rapid activation (X = I, M = Ni, MT = Zn)
Problem 2: Rapid β-hydride elimination from M-R
Solution 2a: Use chelating ligands
Solution 2b: Use electron-deficient alkene additives
Withdraws e- density from M
- promotes reductive elimination
Cardenas, D. J. Angew. Chem. Int. Ed. 2003, 42, 384-287; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840-871
17
Method Development By Knochel
First selective Ni-catalyzed Csp3-Csp3 cross-coupling – requires alkene substrate
NO cross-coupling
Proposed mechanism based on work by
Yamamoto and Sustmann
Alkene Effect
- withdraw e- density from Ni
Knochel, P. et. al Angew. Chem. Int. Ed. 1995, 34, 2723-
18
Method Development
*Requires various additives*
*Primary electrophiles*
Additive Effects:
NMP co-solvent
- Increases yields
THF - 77% yield
2:1 THF:NMP - 90% yield
p-CF3-styrene
- Allows alkene-free substrates
70%
Bu4NI
- Allows use of RZnX instead of R2Zn
62%
**Proved Ni is a potential catalyst for alkyl-alkyl couplings**
Knochel, P.; et. al. Angew. Chem. Int. Ed. 1998, 37, 2387-2390; Knochel, P.; et. al. J. Org. Chem. 1999, 64, 3544-3553
19
Alternative Method By Fu
Recognized the need to use 2° alkyl electrophiles
78%
68%
s-Bu-Pybox
Typical phosphine ligands and Pd didn’t work
Does not need halide additive
First 2°, unactived, β-hydride containing alkyl halide cross-coupling (Ni or Pd)
2° alkyl halide + chiral ligand = asymmetric catalysis
Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727
20
Development of Asymmetric Catalysis
70%, 93% ee
78%, 95% ee
82%, 91% ee
69%, 94% ee
Asymmetric catalysis is stereoconvergent
Fu, G. C.; et. al. J. Am. Chem. Soc. 2005, 127, 4594-4595;
Fu, G. C.; et. al. J. Am. Chem. Soc. 2005, 127, 10482-10483
21
Csp3-Csp3 Negishi Mechanism
Around same time as Fu’s chemistry, Vicic observed reactivity of:
Key Observation 1:
No homocoupling
quant.
Key Observation 2:
NiI shows same reactivity as a
common Ni0 catalyst for Negishi
reactions
Key Observation 3
NiI/NiIII likely operative in sp3-sp3 Negishi reaction
Ni0/NiII NOT likely operative
Vicic, D. A.; et. al. J. Am. Chem. Soc. 2006, 128, 13175-13183
22
Discussion of Mechanisms
“Generally Accepted Mechanism for Alkanes” – ‘04
Ni0/NiII
Proposed Radical Mechanism – ‘06
NiI/NiIII
“Accepted” mechanism most likely proposed from analogous Pd chemistry
Oxidation state when transmetalation occurs is different
Anderson, T. J.; Vicic, D. A. Organometallics. 2004, 23, 623-625
23
Computational Evaluation of Ni0/NiII Mechanism
Ni0/NiII
Computational Detail
Method: B3LYP
Basis set: C,H,N,O,Ni,Zn – 6-31+G*
I – LANL2DZ + d (0.266)
Transmet/red. elim. is thermoneutral
Low-driving force for catalysis
Lin, X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680-3688
24
Analysis of Alkyl Iodides in NiI/NiIII Cycle
NiI/NiIII
Strong driving force for reductive elimination
Reduction elimination kinetically and thermodynamically favored
25
Explanation for Fu’s High Enantioselectivity
Stereoconvergent step
26
Conclusions
NiI/NiIII sp3-sp3
Ni0/NiII pathway commonly propsed
for Ni-catalyzed C-C bond formation
Both Ni-catalyzed sp3-sp3 Negishi
reactions and aryl-aryl couplings
undergo NiI/NiIII chemistry
Odd-electron chemistry doesn’t
necessarily mean uncontrolled
reactions
Nickel is an affordable and reactive catalyst for C-C bond formation
27
Future Directions
Activation of alkyl chloride bonds – traditionally most difficult
93%, 91% ee
Reducing catalyst loading
Fu, G. C.; et. al. J. Am. Chem. Soc. 2008, 130, 2756-2757; Knochel, P. et. al. Tetrahedron. 2006, 62, 7521-7533
28
Acknowledgements
Shannon Stahl
Practice Talk Attendees
Teresa Beary
Brad Ryland
Jiao Jiao
Rick McDonald
Nattawan Decharin
Alison Suess
Aaron McCoy
Nicky Stephenson
Adam Weinstein
Jamie Chen
James Gerken
Matt Rigsby
Jackie Brown
Kelsey Mayer
David Mannel
Jessica Hoover
Alison Campbell
Stahl Group – Awesome people to be around!!
29
A Sample of the Many Ni-Catalyzed Reactions
Cyclooligomerization of Alkynes - Cyclotrimerizations
Catalyst
(n-Bu3P)2NiBr2
(Ph3P)2NiI2
Yield
84%
85%
Ratio 1,3,5:1,2,4
100:0
0:100
1,4 Conjugate Addition
X = Br, I; R = sp3, sp2
Cyclozincation
30
Random Junk Slide
Palladium
Nickel
Electronic Structure:
[Kr] 4d10
[Ar] 4s13d9
Common Oxidation States:
0,+2,(+4)
0, +1, +2, +3, (+4)
EPR studies believe that the active site of nickel hydrogenase operates via a NiI/NiIII cycle
Acetyl CoA synthase: NiI/NiIII - Brunold
31
Visualization of SOMO
Spin-density plot of tpyNi-CH3
uB3LYP/m6-31+G*
32
33
Further Reactivity of Alkyl Radicals
fast
(S)-sBu-Pybox
Phapale, V. B.; Bunuel, E.; Garcia-Iglesias, M.; Cardenas, D. J. Angew. Chem. Int. Ed. 2007, 46, 8790-8795
34
Preparation of Organozinc Compounds
Direct Insertion
Aryls require more forcing conditions
-OH, -NO2 and -N3 not tolerated
When FG-RX is unactivated at α or β, and X = Br
Works with many forms of Zn
- dust, granules, powder, shot
Reduces I2 which then converts the RBr into a more reactive RI
35
Preparation of Organozinc Compounds
Metal Exchange
Boron Exchange
Stereocenter set at first asymmetric hydroboration is retained
36
Move Towards Catalysis
Observations:
1) Rate dependent on [Zn]
- e- transfer rate-limiting (NiII/NiI)
2) Activation parameters suggest
associative mechanism
-ΔH = 10 kcal/mol, ΔS = -36 eu
3) Excess halide promotes reaction
4) Bpy promotes reaction
- forces aryls cis to each other
37
Application to Total Synthesis
Suh, Y-G.; et. al. Angew. Chem. Int. Ed. 1999, 38, 3545-3547; Fu, G. C.; et. al. J. Am. Chem. Soc. 2008, 130, 2756-2757
38
Application to Total Synthesis
Reported Preparation
Asymmetric Negishi
39