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Bimolecular Coupling Reactions Involving
Single Electron Oxidations:
Method Development and Mechanistic Studies
Brian M. Casey
November 29, 2011
Outline of presentation
• Background and significance
• Objective 1: Synthetic and mechanistic studies involving the solvent-dependent chemoselective oxidative coupling of 1,3-dicarbonyls to styrene via Ce(IV) reagents
• Objective 2: Determination of the mechanistic factors involved in
the non-statistical oxidative heterocoupling of lithium-stabilized enolates
• Concluding remarks
2
Some initial perspective
3
Origins
• Faraday – Electrolysis of acetate
– Experimental observations
• Kolbe reaction
4 Faraday, M. Philosophical Transactions of the Royal Society of London. 1834, 124, 77.
Kolbe, H. Justus Liebigs Ann .Chem. 1849, 69, 257.
Interconversion of reactive intermediates
5
Anionic Radical
Cationic
Jahn, U.; Hartmann, P. Journal of the Chemical Society-Perkin Transactions 1. 2001, 2277.
Metal-based oxidants
6
Lanthanide (IV) metals
7
Ce(IV)-based reagents • Oxidation of functional groups
– Aromatics, alcohols, olefins/styrenes, hydroquinones, carbonyls, etc.
• Cerium(IV) ammonium nitrate [CAN] – Solubility – Cerium(IV) tetra-n-butylammonium nitrate [CTAN]
8
Ce(IV)-mediated bond forming reactions
• Carbon-carbon
• Carbon-heteroatom
9
Influencing reaction pathways
• Preferential oxidation of substrates
• Role of solvent
Zhang, Y.; Raines, A.J.; Flowers, R.A. Org. Lett. 2003, 5, 13, 2363.
Zhang, Y.; Raines, A.J.; Flowers, R. A. J. Org. Chem. 2004, 69, 6267
Organic chemist’s toolbox
10
11
Objective 1: Synthetic and mechanistic studies involving the
solvent-dependent chemoselective oxidative coupling of 1,3-dicarbonyls to styrene via Ce(IV) reagents
Objective 2: Determination of the mechanistic factors involved in
the non-statistical oxidative heterocoupling of lithium-stabilized enolates
12
Scope of synthesis
• Solvent-dependent chemoselectivity
• Yields and distributions (4:1 / 1:4)
• CTAN in CH2Cl2
Mechanism elucidation: time-resolved UV-Vis
13
Mechanism elucidation: observed rate constants in the absence of styrene
14
Substrate Intermediate Oxidant Solvent
Rate constant of
Ce(IV) decay at
380 nm
k1 (sec-1
)b
Rate constant of
radical cation
formation at 460
nm
k2 (sec-1
)b
Rate constant
of radical
cation decay at
460 nm
k3 (sec-1
)b
1
CAN
CTAN
MeOH
MeCN
MeCN
CH2Cl2
5.8 ± 0.6 x 102
8.3 ± 0.2
6.0 ± 0.3
3.4 ± 0.3
6.0 ± 0.2 x 102
8.7 ± 0.1
6.2 ± 0.1
3.4 ± 0.1
4.1 ± 0.1 x 10-2
5.8 ± 0.2 x 10-3
5.1 ± 0.5 x 10-3
1.7 ± 0.1 x 10-3
a[Ce(IV)]=1 mM, [substrate]=20 mM at 25oC. bAverage of at least two runs
MeOH > MeCN > CH2Cl2
15
Mechanism elucidation: kinetic isotope effect studies
• Monitor decay of radical cation
• Primary KIE:
MeCN and CH2Cl2: kH/kD > 2 MeOH: kH/kD ≈ 1.5
Mechanism elucidation: rate order of styrene in radical cation decay
16
Oxidant Solvent Styrene Rate Ordera,b
CAN MeOH 0.28 ± 0.01
CAN MeCN 0.97 ± 0.05
CTAN CH2Cl2 1.02 ± 0.06
Oxidant Solvent MeOH Rate Ordera,b
CTAN CH2Cl2 0.94 ± 0.05 aAverage of at least 2 runs.
bDetermined from the slope for the plot of lnkobs vs. ln[styrene].
17
What do we know?
1. Rates of oxidation of substrates are solvent dependent
2. Rates of decay of radical cations are solvent dependent
3. In the absence of styrene, deprotonation of the radical cation is involved in the rate-limiting step
4. Styrene is first order in both MeCN and CH2Cl2 for the rate-limiting step
5. In the absence of styrene, MeOH is first order in CTAN/CH2Cl2 for the rate-limiting step
Proposed mechanism
18 Casey, B.M.; Eakin, C. A.; Jiao, J.; Sadasivam, D. V. ; Flowers, R.A. Tetrahedron. 2010, 66, 5719.
Significance
• Stability of radical cation
• Importance of intermediates
19
20
Objective 1: Synthetic and mechanistic studies involving the
solvent-dependent chemoselective oxidative coupling of 1,3-dicarbonyls to styrene via Ce(IV) reagents
Objective 2: Determination of the mechanistic factors involved in
the non-statistical oxidative heterocoupling of lithium-stabilized enolates
Oxidation of enolates
• Efficient bond formation
• Intramolecular couplings
• Intermolecular homocouplings
21
Kobayashi, Y.; Taguchi, T.; Morikawa, T.; Tokuno, E.; Sekiguchi, S. Chem Pharm Bull. 1980, 28, 262.
Baran, P.S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678.
Intermolecular heterocouplings
• Superstoichiometric
• Tethered silylenol ethers
• Limitations 22
23
Selective intermolecular oxidative heterocoupling of enolates
• Baran work
• Statistically predicted product distributions Baran, P.S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, 7083.
24
Heterocouplings based on preferential oxidation
• Dual nature of silylenolethers
• Extension to heterocoupling of enolates
Rates of enolate oxidations
• “Informatively unsuccessful”
• CTAN, Cu(OTf)2, and Fe(III)Cp2PF6
• Preliminary data on silylenol ethers
25
Common factor
26
Lithium enolates
27
Lithium enolate aggregates
28
• Dimeric
• Tetrameric
• Higher order aggregates
Liou, L.R.; McNeil, A. J.; Ramirez, A.; Toombes, G. E. S.; Gruver, J. M.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 4859.
Dimeric lithium enolate aggregate distributions
29
• Non-statistical dimeric aggregates
• Bimolecular process to unimolecular (Thompson)
Gruver, J.M.; Liou, L. R.; McNeil, A. J.; Ramirez, A.; Collum, D. B. J. Org. Chem. 2008, 73, 7743.
Extension to heterocoupling reactions of lithium enolates
• State of enolate aggregates
• 7Li NMR
• Experiments/conditions
• Energy barrier for rearrangement
30
31 A4 A3B1 A2B2 A1B3 B4
32 A4 A3B1 A2B2 A1B3 B4
7Li NMR results
33
Ketone A Ketone B 𝑨𝟐𝑩𝟐
𝑨𝟒 + 𝑩𝟒
15.7 : 1
14.7 : 1
14.3 : 1
8.5 :1
4.4 : 1
a Distributions obtained by integrating
7Li NMR spectra at -30
oC
b [A] = [B] = 0.15 M and [LiHMDS] = 0.304 M in 2.0 M THF:Toluene
Synthetic results
34
Ketone A Ketone B Heterocoupled Product Product
Distributionb
Yield
(%)c, d
13.8 : 1 62
12.8 : 1 58
12.4 : 1 62
7.0 : 1 46
3.0 : 1 47
a [A] = [B] = 0.12M in THF, [LiHMDS] = 0.26M in THF, [I2] = 0.12M in THF
b Ratios (heterocoupled product:homodimer of B) were determined by
1H NMR. Trace, if any, amounts of
homodimer of ketone A were observed by GC and 1H NMR.
c Determined by
1H NMR with ± 5 % error.
d 15-25% of ketone A was recovered in these reactions.
Impact of lithium aggregation on oxidative heterocouplings
0 5 10 15
0
6
12
Lit
hiu
m E
no
late
Ag
greg
ate
Dis
trib
uti
on
[A2B
2/(
A4 +
B4)]
ProductionDistribution
(Heterodimer/Homodimer)35
Additional synthetic observations
• Effect of counterion
• Effect of warming
• Effect of molar ratio
36
37
38
Previously reported synthesis (revisited)
39
Significance
• “Atom economy” and “protecting-group-free”
40
Significance (cont’d)
• 1,4-Dicarbonyls in natural products and pharmaceuticals
• Impact in fine chemicals industry
41
Conclusions
• Importance of understanding reactive intermediates in synthesis
• Role of solvent
• Impact of lithium enolate aggregate distributions
42
Acknowledgements
43
Dr. Robert Flowers Dr. Dhandapani Sadasivam Dr. Lawrence Courtney Dr. Esther Pesciotta Kimberly Choquette James Devery Cynthia Kearse Gabrielle Haddad Todd Maisano Niki Patel Sherri Young NIH