Radical Cations

Synthetic Applications and Investigation of Reactivity

G.F. Morehouse

Burke Group Literature Seminar

22 March 2013

Radical Cation?

• Synthetically useful for umpolung of electron rich π systems

neutral radical:

C is neutral (has formally 4 e-) but low-valent

localized reactive center

radical cation:

one C neutral (formally 4 e-); one C cationic (formally 3 e-)

delocalized reactive center

Figures from: Ischay, M.A. Yoon, T.P. Eur. J. Org. Chem. 2012, 3359-3372

K.D. Moeller, Synlett 2009, 1208 –1218; F. Tang, K.D. Moeller, Tetrahedron 2009 , 65 , 10836 –10875; A. Sutterer , K. D. Moeller , J. Am. Chem. Soc. 2000 , 122 , 5636 –5637; H. Wu , K. D. Moeller , Org. Lett. 2007 , 9 , 4599 –4602. Figure from: Ischay, M.A. Yoon, T.P. Eur. J. Org. Chem. 2012, 3359-3372

Oxidative π Cyclizations

Preparative

Electrochemistry

Carbonyl Umpolung

SOMO Catalysis

Figure from: Ischay, M.A. Yoon, T.P. Eur. J. Org. Chem. 2012, 3359-3372

Formal Cycloaddition

Photoredox Catalysis

M. A. Ischay , Z. Lu , T. P. Yoon , J. Am. Chem. Soc. 2010 , 132 , 8572 –8574; Figure from: Ischay, M.A. Yoon, T.P. Eur. J. Org. Chem. 2012, 3359-3372

C-H Functionalization Photoredox

Catalysis

Condie AG, González-Gómez JC, Stephenson CR. J. J. Am. Chem. Soc. 2010; 132: 1464; Rueping M, Leonori D, Poisson T. Chem. Commun. 2011; 47: 9615; DiRocco DA, Rovis T. J. Am. Chem. Soc. 2012; 134: 8094; Hari DP, König B. Org. Lett. 2011; 13: 3852

Biological Examples

• Carotenoids

• Iron porphryn oxidation

A.L. Focsan, M.K. Bowman, P. Molnar, J. Deli, and L. D. Kispert J. Phys. Chem. B 2011, 115, 9495–9506; X. Li, R. Fu, S. Lee, C. Krebs, V.L. Davidson, A, Liu. PNAS 2008 105, 8597-8600

Reactivity Investigation: Nu: Competition

X, Y: EDG (OR, SR) or H

pKa TsNHR: ~12

pKa ROH: ~16

pKa 2,6-lutidinium: 6.75

pKa MeOH: 15.5

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Initial Hypothesis: Curtin-Hammett

• Known previously that strong base

(LiOMe) favors sulfonamide

cyclization

• Known that under these conditions,

equilibrium between radical cations,

amine radical

• Curtin-Hammett control?

Neutral

Intermediate

Zwitterionic

Intermediate

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

First Investigations: Solvent Polarity

• Less polar solvent/electrolyte with MeO-: better ratio/yield of N-trapped

• Without MeO-: only O-trapped

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

First Investigations: Solvent Polarity

• Less polar solvent/electrolyte with MeO-: better ratio/yield of N-trapped

• Without MeO-: only O-trapped

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Looking Deeper: Oxidation Potentials

• Under basic conditions, sulfonamide anion oxidizes before olefins

• Given that alcohol cyclization can be competitive, implies that sulfonamide/olefin electron transfer rapid

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Looking Deeper: Computation

• No local energy minima found for

alcohol pathway

• Deprotonation in transition state?

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Alcohol Capture & Reaction Temperature

• At lower temperatures, alcohol trapping dominates

– ΔH‡ROH< ΔH‡

RNTs-

• Alcohol kinetic, sulfonamide thermodynamic?

-or-

• ΔS‡ROH< ΔS‡

RNTs-; RNTs- kinetic at high T, ROH kinetic at low T?

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Alcohol Capture & Reaction Temperature

• At lower temperatures, alcohol trapping dominates

– ΔH‡ROH< ΔH‡

RNTs-

• Alcohol kinetic, sulfonamide thermodynamic?

-or-

• ΔS‡ROH< ΔS‡

RNTs-; RNTs- kinetic at high T, ROH kinetic at low T?

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Current Density

k2 < k-1: thermodynamic

k2 ~ k-1: steady state

k2 > k-1: kinetic

• k2 increased with increased current (increasing [e-])

• Isothermal rxn removes ΔS‡

variation

ROH KINETIC; RNTs- THERMODYNAMIC

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344

Conclusion

John M. Campbell; Hai-Chao Xu; Kevin D. Moeller; J. Am. Chem. Soc. 2012, 134, 18338-18344