Proton Coupled Electron Transfer

Literature Seminar #3
2015.8.22 (Sat.)
Yusuke Shimizu (M2)

Respiration
2H2O

O2 + 4H+ + 4e-

6CO2 + 24e- + 24H+C6H12O6 + 6H2O

Photosynthesis

1

Today’s Topics
0. Introduction

1. Backgrounds of PCET
Brief introduction of definition and thermodynamics of PCET,
avoiding quantum mechanical discussion (difficult to understand for many of organic chemists!)

2. PCET in Biological Events
Some representative biological PCET will be highlighted

3. PCET in Organic Chemistry
Synthetic application of PCET, today’s main topic

4. Summary2

Backgrounds of PCET

3

Nernst Equation
Nernst equation
E°: standard potential
R : universal gas constant
T : abusolute temperature
F : Faradey constanta : activity
Redox reaction with dissociable proton (1 atm, 298K)

Nernst equation predicts the involvement of protons in redox potentials

4

pH-Dependent Thermodynamics
Variation of redox potential with pH for cis-[RuII(bpy)2(py)(H2O)]2+
For the RuIII/II couple(RuOH23+: pKaIII = 0.85 RuOH22+: pKaII = 10.6)

1) pH < pKaIII : 0H+/1e-pH independent2) pKaIII < pH < pKaII : 1H+/1e- pH dependent
E°'(RuIII/II) = E°'(RuOH23+/2+) – 0.059(pH – pKaIII)E°’: formal potential3) pKaII < pH : 0H+/1e-

pH independent
Binstead, R. A. and Meyer, T. J. J. Am. Chem. Soc. 1987, 109, 3287
(Figure) Huynh, M. H. and Meyer, T. J. Chem. Rev. 2007, 107, 5004

Generally, in the redox reaction
pH dependency can be described ase.g. E°‘ decreases by 118 mV/pH in pH < pKaIII region for the RuIV/III couple (2H+/1e-)5Proton-Coupled Electron Transfer
Comproportionation reaction between RuIV/II
Meyer first coined the term “Proton-Coupled Electron Transfer” and applied it to the reaction below.

Meyer. T. J.et al. J. Am. Chem. Soc. 1981, 103, 2987

Proposed Mechanisms (pH 2-9)

proton transfer is coupled with electron transfer
The term PCET was used to distinguish it from sequential ET-PT or PT-ET, and H-Atom Transfer
6Termiology
The term PCET has come to be used more broadly to describe reactions and half reactions
in which both electrons and protons are transferred without regard to mechanism.
Now, the new term to describe the concerted mechanism is needed.

Unfortunately, the nomenclature has not been standardized yetconcerted proton-electron transfer (CPET)
Cukier, R. I. and Nocera, D. G. Annu. Rev. Phys. Chem. 1998, 49, 337

concerted electron-proton transfer (CEP)
Hammarström, L et al. J. Am. Chem. Soc. 2005, 127, 3855

electron transfer proton transfer (ETPT)
Saveant, J. M. et al. J. Am. Chem. Soc. 2001, 123, 4886

electron-proton transfer (EPT)EPT will be used in this seminar

Decornez, H. and Hammes-Schiffer, S. J. Phys. Chem. A, 2000,104, 9370
7

Sequential vs Concerted
Comproportionation reaction between RuIV/II (at pH 7)

Both ET-PT and PT-ET impose high reaction barrier in initial steps∆G°’ in ET-PT and PT-ET are lager than experimental free energy of activation(ruling these mechanisms out as major contribution)
EPT has a significant advantage in avoiding high energy intermediate

8

HAT vs EPT
Alternative concerted pathway, H-atom transfer (HAT)

Both transferring e-/H+ come from the same bondEPTe-/H+ transfer from different orbitals on the donor to different orbitals on the acceptor

9MS-EPT
Oxidation of Tyrosine

ET-PT is slow because of high energy intemediate (kET-PT = 1.7 ✕ 102 M-1s-1)
With buffer base HPO32-

An electron−proton donor transfers e-/H+ to spatially separated acceptors
Multiple Site Electron-Proton Transfer (MS-EPT)
Thorp, H. H. et al. J. Am. Chem. Soc. 2006, 128, 11020

10

Short Summary
PCET
concerted PCET
ET-PTHATEPTPT-ETMS-EPT

especially important in biological events
Concerted PCET have advantage in avoinding high-energy intermediate
11

PCET in Biological Events

12

Photosystem II
Key function of PS II is water oxidation

Iwata, S. et al. Science, 2004, 303, 1831

Photooxidation catalyzed by Oxygen-evolving complex(Kok cycle)

Dau, H. et. al. J. Biol. Chem. 2011, 286, 18222

13

PCET in Photosystem II
Yz oxidation to generate tyrosyl radical

S0-S1 transition (H-atom abstraction from CaMn4 cluster)

Too far for H+ transfer (>7Å)

H+ have short range nature
e- have relatively long range nature

Biesiadka, J. et al. Nature, 2005, 438, 1040
14

DNA Photolyase
Photoactivation of Escherichia coli DNA photolyase
RNNONHNOFADhvRNNHNONHOVos, M. H. et al. J. Am. Chem. Soc. 2008, 130, 14394

FADH

Trp chain works as a “wire” to transfer electron

15

Class I Ribonucleotide Reductase
Long-range EPT “shuttle”
Class I RNRs found in E. coli catalyze reduction of nucleotides

active site

radical transfer over 35 Åthiyl radical generation to initiate nucleotide reduction
Stubbe, J. et al. J. Am. Chem. Soc. 2006, 128, 1562
16

PCET in Organic Chemistry17

Robert R. Knowles
2003 B.S. in Chemistry, College of William and Mary2008 Ph.D. with David MacMillan, Caltech
NIH Postdoctoral Fellow with Eric Jacobsen, Harvard University
2011 Assistant Professor of Chemistry, Princeton University

Total Synthesis of Diazonamide A

Knowles, R. R.; MacMillan D. W. C. et al. Chem. Sci. 2011, 2, 308
18

Robert R. Knowles
2003 B.S. in Chemistry, College of William and Mary2008 Ph.D. with David MacMillan, Caltech
NIH Postdoctoral Fellow with Eric Jacobsen, Harvard University
2011 Assistant Professor of Chemistry, Princeton University

Enantioselective Thiourea-Catalyzed Cationic Polycyclizations

Noncovalent interactions

Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 5030
19

Robert R. Knowles
2003 B.S. in Chemistry, College of William and Mary2008 Ph.D. with David MacMillan, Caltech
NIH Postdoctoral Fellow with Eric Jacobsen, Harvard University
2011 Assistant Professor of Chemistry, Princeton University

Synthetic Application of PCET (Today’s Topic)

Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022
20

Precedent
Aerobic C-H oxidation with Pacman system

IE-kox correlation and KIE suggest
asynchronous PT-ET rather than HAT

Nocera, D. G. et al. J. Am. Chem. Soc. 2006, 128, 6546

21

Advantages of concerted PCET
How can we utilize concerted PCET for the development of catalyst system?

Bond dissociation free energy
HAT reactivity can be described by BDFE
BDFE = 1.37 pKa + 23.06 E° + CsolvnBordwell, F. G. et al. J. Am. Chem. Soc.1988,110, 1229

Unfortunately, pKa and E° are interdependent and inversely correlated
BDFE range is limited

OCPh2COPHVPCOPh2COV-H BDFE
55~58 kcal/mol

Norton, J. R. et al. J. Am. Chem. Soc. 2008, 130, 4250

(Even with one of the weakest HAT donor, BDFE > 50 kcal/mol)“Effective” bond dissociation free energy

Kinetic advantages of concerted PCETBDFE formalism can be applied to MS-EPT,
while no bond is homolytically cleaved‘BDFE’ = 1.37 pKa(HX) + 23.06 E°(Red) + Csolv
pKa and E° are independent with each other‘BDFE’ < 50 kcal/mol can be achieved?
With kinetic advantage and ‘BDFE’, PCET cangenerate the radicals inaccessible by HAT?

Knowles, R. R. et al. J. Am. Chem. Soc. 2013, 135, 10022
22

Photoredox Catalysis✕PCET23

Photoredox Catalyst

Tucker, J. W. and Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617

24

Photoredox Catalyst
Redox potential can be tuned by changing metal and ligands
N
Redox potential (vs SCE)
NN
N

II
RuN

N

N

E1/2(RuIII/II) = +1.86 VN

E1/2(RuII/I) = -0.80 V

E1/2(IrIV/III) = +0.77 VIII
Irstrong oxidant

NNN

N

Redox potential (vs SCE)

NNE1/2(IrIII/II) = -2.19 V
strong reductant

NRu(bpz)32+fac-Ir(ppy) 3

Tunable redox potential = Tunable ‘BDFE’‘BDFE’ = 1.37 pKa(HX) + 23.06 E°(Ox) + Csolv

Photoredox catalysts are ideal partner for PCET!
25

Ketyls
SmI2 mediated keyl-olefine cyclization

Molander, G. A. et al. J. Org. Chem., 2003, 68, 9533

Titanocene catalyzed enantioselective cyclization

Gellrich, U. et al. Angew. Chem. Int. Ed. 2012, 51, 8661

Ketyls are versatile radical intemediate26

Challenges in Ketyl GenerationThermodynamic challenges in reductive HAT

Thermodynamic challenges in sequential PCET

Both HAT and sequential PCET are highly demanding27

Reaction Design'B
DF
E'X-

H-X
H+OAr

Keq (PCET)
MeO
Ar

eMn

'BDFE' (kcal/mol) =2.3RTpKa(HX) + 23.06E0(Mn) + Csolv

HMe
Mn+1

O-H BDFE ~26 kcal/mol

28

Optimization
HEH

HEH

EtO2C

RuII(bpy) 3EThv

CO2Et

MeN

CO2Me

MeO

H-X

Ph

RuI(bpy) 3

entryacid catalyst

redox catalyst'BDFE'(MeCN)% yield

cis:trans1none

Ru(bpy)3(BAr F)2—0—

2BzOH

Ru(bpy)3(BAr F)2450—

3NEt3•HBF4Ru(bpy)3(BAr F)2410—F

4lutidine•HBF4Ru(bpy)3(BAr )2350—5(PhO)2PO2HRu(bpy)3(BAr F)2

3378

4.6:1

6pTSA

Ru(bpy)3(BAr F)2

2774

4.3:1

7(PhO)2PO2H

Ir(ppy)2(dtbpy)PF6

2993

4.8:1

8(PhO)2PO2H

fac-Ir(ppy)3

2492

4.8:1

9lutidine•HBF4

Ir(ppy)2(dtbpy)PF6

3374

4.9:1

10a(PhO)2PO2HRu(bpy)3(BAr F)23189PT

EtO2C
MeCO2Et
NMePCET

X-RuII(bpy) 3

CO2MeHO

RuI(bpy) 3

Ph
X-C-C bondformation

ET
hv

10:1

RuII(bpy) 3
H
EtO2C
Mea

BT was used in place of HEH

X-

MeO2C

CO2Et
N
H

RuII(bpy) 3Ph
OH

X-Me

H-atom transfer

S
Ph
NH

MeO2C

SmI2 shows reversed selectivity

PhOH

H H
EtO2C
Me

Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022

CO2Et
NH

MeHEH(reductant)29

Substrate Scopesubstrateproducts
H
MeO2COOHOOCO2MeMeO

OMe

OMe
12:178%
H
MeO2C
O

O
CO2MeHOO

MeMe

Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022

6:186%

Me30

Substrate Scope

substrate

products
OH

MeO2C

O
CO2MeHOO
H

H
16:182%

O

MeO

O

MeOH

Me
CO2Me

H

CO2Me

2:196%OO
MeO

MeMeCO2Me

H
CO2MeOH

1.2:1
78%

Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022

31

Mechanism
Flueorescenece quenching technique

pKa difference
pKa in MeCNOPhH-0.1
Me(PhO)2PO2H

13

too slow considering 1.9 µs lifetime of IrIII excited state✕ET-PT✕PT-ET○MS-EPT
32

Tarantino, K. T.; Liu, P.; Knowles, R. R. J. Am. Chem. Soc. 2013, 135, 10022

Chiral Brønsted Acid Chemistry
✕PCET

33

Chiral Brønsted Acid Chemistry
Ground-breaking thiourea catalyzed asymmetric Strecker reaction

Sigman, M. S. and Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901
Vachal, P. and Jacobsen, E. N. Org. Lett. 2000, 2, 867
Sigman, M. S. and Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279

Vachal, P. and Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012
34

Chiral Brønsted Acid Chemistry
Another Class of Chiral Brønsted Acid － Phosphoric Acid Catalyst

Uraguchi, D. and Terada, M. J. Am. Chem. Soc. 2004, 126, 5356

Akiyama, T. et al. Angew. Chem. Int. Ed. 2004, 43, 1566

cat.
Rueping, M. et al. Org. Lett. 2005, 7, 3781

35

Enantioselective Aza-Pinacol Cyclization
Working Hypothesis

If this H-bond complex persist during C-C bond formation...

36
Knowles, R. R. et al. J. Am. Chem. Soc. 2013, 135, 17735

Optimization Study
HEH

entry

acid catalyst

solvent% yield% ee

1(PhO)2PO2H

THF

91

—EtO2C

IrIII(ppy)2(dtbpy)

ET

HEH

Ohv

CO2EtN

2

1

THF

89

0

3

2

THF

84

30

4

3

THF

96

58

54

THF

80

68

65

THF

84

82

76

THF

92

89

8

7

THF

90

0

98

THF

85

0

10

6

DME

90

88

11

6

C6H6

30

86

12

6

CH2Cl299

88

136

MeCN

77

81

146

dioxane

9492

MeN

MePT

MeMePCETO

CO2EtN

IrII(ppy)2(dtbpy)

III

15b6dioxane

90

3 hr, 2 mol% photocatalyst

Ir (ppy)2(dtbpy)

R

1 R=H
2 R = 2-naphtyl

OO

3 R = MesitylOH

4 R = 2,4,6-iPr3C6H2PO
R

MeN

MeO

IrIII(ppy)2(dtbpy)

5 R = iPr3Si

9 R = Ph

6 R = Ph3Si

10 R = 2-naphtyl

Knowles, R. R. et al. J. Am. Chem. Soc. 2013, 135, 17735

O

OP(O)(OR)2H

MeCO2EtNH

H
N

NMe2OHNHNMe2O

PORORPh
NMe2H

MePhO

IrIII(ppy)2(dtbpy)

H H
EtO2C
MeCO2EtNH

MeHEH(reductant)P

Ph

C-C bondformation

H-atom transfer

R RO

hv

EtO2C

O OPOHOOHH92
R RO

OP(O)(OR)2ET

bNMe2

H

IrII(ppy)2(dtbpy)

EtO2C

Ph

H-OP(O)(OR)237

OROR

Substrate Scope38
Knowles, R. R. et al. J. Am. Chem. Soc. 2013, 135, 17735

Further Study
Cleavage of N-N BondDFT Evaluation of Ketyl-phosohate H-bonding

39
Knowles, R. R. et al. J. Am. Chem. Soc. 2013, 135, 17735

Bond-Weakening Chemistry✕PCET40

Bond Weakening Chemistry

Chirick, P. J. et al. J. Am. Chem. Soc. 2014, 136, 9211

Cuerva, J. M. et al. Angew. Chem. Int. Ed. 2006, 45, 5522

41

Bond-Weakening Catalysis
Tin-free Barton-McCombie Deoxygenation

Wood, J. L et al. J. Am. Chem. Soc. 2005, 127, 12513

Reduction of B-Alkylcatecholboranes to Alkanes

Renaud, P. et al. J. Am. Chem. Soc. 2005, 127, 14204

42

Reaction Design
Working Hypothesis

Requirement

43Optimization Study✕ less bulky○ sufficiently bulky

Knowles. R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440

44

Proposed Catalytic CycleCp*2TiIIIClO
PhN

NH

O

CO2MeOET

coordinationO[TiIVCl(Cp*2)]+

Ph

N
H

TiIIICl(Cp*2)
O

CO2MeN
CO2MeN

O

Ph

O

NOO
PT

PCET

IV
O Ti Cl(Cp*2)

NOH

MeO
OO

N Ph
O

Knowles. R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440

C-N bond
formation

Ph

N

N

TiIVCl(Cp*2)O

OH
CO2Me45DFT Calculations

Knowles. R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440

46

Compatibility of Cp*2TiCl & TEMPO
Isodesmic Estimation

EPR Spectra

Knowles. R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440

47

Substrate Scope

Knowles. R. R. et al. J. Am. Chem. Soc. 2015, 137, 6440

48

Hydrogen Atom TransfervsPCET

49

Limitation of HAT activation
Reactivity of HAT donor is highly correlated with BDFE of broken bondMayer, J. M. et al. Science, 2001, 294, 2524

Homolytic activation of strong N-H bondin the presence of weaker C-H bond by HAT is difficult
50

Carboamination
Working Hypothesis

weaker C-H bondOArNHAr

photoredox cat.
Brønsted base cat.

R1R2O
ArN

R3

NR2olefin acceptorhv

HPCETO

R1R1
R2

selective N-H activation
51

Optimization Study‘BDFE’ < N-H BDFE

Choi. G. J. and Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226

52

Optimization StudyOPhN

3 mol% photocatalyst
25 mol% Brønsted acid

MeMeH

Ph
O

CO2MeN

3.0 equiv. methyl acrylate
0.4 M CH2Cl2hv, rt, 12 hr

MeMe

entry

photocatalyst

base'BDFE'% yield

9Ir(Fmppy)2(phen)PF6DMAP

90

610Ir(ppy)2(phen)PF6NBu4OBz

92

2011Ir(dF(CF3)ppy)2(dtbpy)PF6NBu4OP(O)(OBu)2

92

76

12Ir(dF(CF3)ppy)2(dtbpy)PF6

lutidine

93

2213Ir(Fmppy) 2(dtbbpy)PF6

NBu4OBz

93

5614Ir(Fmppy) 2(phen)PF6

NBu4OBz

95

35

15Ir(dF(CF3)ppy)2(bpy)PF6

NBu4OP(O)(OBu)2

97

92

16Ir(dF(CF3)ppy)2(bpy)PF6

lutidine

98

2417Ir(dF(CF3)ppy)2(dtbpy)PF6

DMAP

99

34

18Ir(dF(CF3)ppy)2(bpy)PF6

DMAP

103

1619Ir(dF(CF3)ppy)2(dtbpy)PF6

NBu4OBz

104

76

20Ir(dF(CF3)ppy)2(bpy)PF6

NBu4OBz

10850

Choi. G. J. and Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226

‘BDFE’ ~ N-H BDFE

53

Optimization StudyOPhN
H

3 mol% photocatalyst
25 mol% Brønsted acidMeMe

3.0 equiv. methyl acrylate
0.4 M CH2Cl2hv, rt, 12 hr

PhO

CO2MeN
Me
Me

entry

change from the best conditions (entry 15)% yield21

no light

022

no photocatalyst

023

no NBu4OP(O)(OBu)2<524

1 mol% Ir(dF(CF3)ppy) 2(bpy)PF676

25

10 mol% NBu4OP(O)(OBu)278

26

1.1 equivalent of acrylate

68270.1 M in CH2Cl280

Choi. G. J. and Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226

54

Proposed Catalytic Cycle
PhO

CO2MeNhv

MeMeB

O
Ph

IrIII(dF(CF3)ppy) 2(bpy)

MeN

MeH

PT

PCET

B H
IrIII(dF(CF3)ppy) 2(bpy)PhO

IrII(dF(CF3)ppy) 2(bpy)

CO2Me
O

N
Ph

MeMePhON

MeB H

C-N bond
formation

ET

B H

MePh

CO2MeONMe
Me

IrII(dF(CF3)ppy) 2(bpy)NMe

C-C bond
formation

Choi. G. J. and Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226

MeCO2MeB H
IrII(dF(CF3)ppy) 2(bpy)55

Substrate Scope

56
Choi. G. J. and Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226

Substrate Scope

57
Choi. G. J. and Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226

Summary58

Summary
Photoredox Catalysis
Chiral Brønsted Acid
Bond-Weakening Chemistry

Proton Coupled Electron Transfer
Ubiquitous in biology
Studied over decades

Well-established Chemistry

PCET Activation Chemistry
Novel catalysis platform
Providing catalytic access to valuable neutral free radical intermediates

59Appendix

Ambiguity between HAT and EPT

Manner, V. W. and Mayer, J. M. J. Am. Chem. Soc. 2009, 131, 9874

Essentially no communication between e-/H+ acceptor sites
MS-EPT character

60Appendix

Oxidation of Cumyl Alcohol
My Proposal

61

Appendix

Bond-Weakening EffectHomolytic bond-weakening is not a simple Lewis-acid-mediated process
62