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University of Southern California Dissertations and Theses
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Studies on methane functionalization: efficient carbon-hydrogen bond activation via palladium and free radical catalyses
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Studies on methane functionalization: efficient carbon-hydrogen bond activation via palladium and free radical catalyses
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Content
Studies on Methane Functionalization: Efficient Carbon-Hydrogen Bond
Activation via Palladium and Free Radical Catalyses
by
Sungah Kim
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2024
Copyright 2024 Sungah Kim
Acknowledgements
I would like to express my deepest gratitude to Professor Kyung Woon Jung, for the invaluable
guidance, support, and mentorship throughout this journey.
My sincere gratitude goes to my family for their unconditional love and encouragement; your
unwavering support has been the driving force behind this work. Finally, my sincere thanks to
all my beloved and those who hold me dear. Thank you all for being there for me every step of
the way.
ii
Table of Contents
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ii
List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi
List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
List of Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviii
Chapter 1: Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Methane And Its Functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Significance of Methane Functionalization . . . . . . . . . . . . . . . . . . 1
1.1.2 Challenges and Precedent Methods . . . . . . . . . . . . . . . . . . . . . . 3
1.1.2.1 Syngas and Fischer-Tropsch Technique . . . . . . . . . . . . . . 3
1.1.2.2 Methane Oxidation: Application of Pd Complexes . . . . . . . . 4
1.1.2.3 Radical Catalysis for Methane Sulfonation . . . . . . . . . . . . . 8
1.2 Scope and Objectives of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Chapter 2: Methane Sulfonation via a Free-Radical Mechanism
by Trifluoroacetylsulfuric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.1 Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.3 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.3.1 Sulfonation of Methane via Trifluoroacetyl Sulfuric Acid
(TFAOSO3H) Generated from H2SO4 and TFAA . . . . . . . . . . . . . . . 22
2.3.2 Proposed Free-radical Mechanism for Methane Sulfonation . . . . . . . . . 23
2.3.3 Three Forms of Products: TFAOSO2CH3, MSA, and MSAA . . . . . . . . . 25
2.3.4 Generation of Methanesulfonyl Fluoride (MSF) due to
Decomposition of Radical Intermediates TFAO• . . . . . . . . . . . . . . . 30
2.3.5 Significance of Radical Condition . . . . . . . . . . . . . . . . . . . . . . . 36
2.3.6 Significance of Radical Species in Methane Functionalization via TFAOSO3H 38
iii
2.3.7 Kinetic Isotope Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2.3.8 Optimization Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2.5 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
2.5.1 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
2.5.2 General Procedure for Sulfonation of Methane Using TFAOSO3H . . . . . 49
2.5.3 Three Different Forms of Products Before Quenching the Reaction :
Methanesulfonyl Trifluoroacetic Anhydride (5),
Methanesulfonic Anhydride (MSAA, 6),
and Methanesulfonic Acid (MSA, 1) . . . . . . . . . . . . . . . . . . . . . . 51
2.5.4 Generation of MSF in Methane Sulfonation Reaction Conducted at High
Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Chapter 3: Novel Methane Activation by Sulfur Dioxide and Molecular Oxygen via
Trifluoroacetylsulfuric Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
3.1 Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3.3 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.3.1 Synthesis of Trifluoroacetylsulfuric Acid (TFAOSO3H) using
Sulfur Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.3.2 Proposed Mechanism for in situ Activation of Sulfur Dioxide and Methane 62
3.3.3 Determination of Optimal Reaction Conditions . . . . . . . . . . . . . . . 64
3.3.4 Optimal Ratio of Sulfur Dioxide and Molecular Oxygen . . . . . . . . . . . 68
3.3.5 Significance of High Pressure and Anhydrous Conditions . . . . . . . . . . 71
3.3.6 Radical Initiator: H2O2 vs. K2S2O8 . . . . . . . . . . . . . . . . . . . . . . . 74
3.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
3.5 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.5.1 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3.5.2 General Procedure and Analysis for Methane Sulfonation using Sulfur
Dioxide and Molecular Oxygen . . . . . . . . . . . . . . . . . . . . . . . . 77
3.5.3 NMR Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.5.3.1 Generation of trifluoroacetylsulfuric acid (TFAOSO3H) . . . . . . 78
3.5.3.2 Unknown peak at 2.92 ppm . . . . . . . . . . . . . . . . . . . . . 79
3.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Chapter 4: Hydrogen-Deuterium Isotope Exchange of Methane via Non-redox Palladium
Catalysism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.1 Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
4.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
4.3 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
4.3.1 NMR Studies with Isotopically Labelled Pd Species 3 . . . . . . . . . . . . 88
4.3.2 Spectral Analysis for Protonated and Deprotonated Forms of Pd Complexes 92
4.3.2.1 IR analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
4.3.2.2 NMR analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
iv
4.3.3 NMR Studies: Monitoring H/D Exchange in J. Young Tubes . . . . . . . . . 100
4.3.4 Proposed Mechanism for Methane H/D Exchange via Pd Catalyst . . . . . 102
4.3.5 Comparative Studies: Pd Catalysts Under Acidic Conditions . . . . . . . . 103
4.3.6 Optimization: H/D Exchange Under Various Conditions . . . . . . . . . . 104
4.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4.5 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.5.1 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.5.2 General Procedure and Analysis for H/D Exchange on Methane using Pd
Catalyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.5.3 General Procedure for H/D Exchange on Methane under
High Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.5.4 Deprotonation of Pd Complex 4 using NaOCH3 . . . . . . . . . . . . . . . 108
4.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Chapter 5: Efficient Methane Activation via Novel Pd-NHC Catalysis: Synthesis of
Methyl Trifluoroacetate as a Protected Methanol Derivative . . . . . . . . . . . 113
5.1 Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
5.3 Results and Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
5.3.1 Prevention of Over-oxidation by Generating Methyl Ester . . . . . . . . . 116
5.3.2 Minimizing Background Radical Reaction through Oxidant
Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
5.3.3 Significance of Restraining the Radical-catalyzed Side Reactions . . . . . . 119
5.3.4 Development of the Solvent System
: Significance of Anhydrous Condition . . . . . . . . . . . . . . . . . . . . 122
5.3.5 Proposed Mechanistic Pathway for Methane Oxidation
: Formation of MeOTFA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
5.3.6 Comparison Between Two Different NHC-Pd Complexes 1 and 2 . . . . . 125
5.3.7 Single-crystal X-ray Diffraction: Discovery of an Actual Structure of
NHC-Pd Complex 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
5.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
5.5 Experimental Section . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
5.5.1 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
5.5.2 General Procedure and High Pressure Methane Oxidation using Pd Catalyst 129
5.5.3 X-ray Crystallography of Complex 1 . . . . . . . . . . . . . . . . . . . . . 130
5.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
v
List of Tables
1.1 Overview of Greenhouse Gas Emissions (Modified from source "Overview of
Greenhouse Gases" by United States Environmental Protection Agency.[19] . . . 2
1.2 Methane oxidation by Strassner. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1 Bond Dissociation Energy (BDE) of H2SO4 and CH4 . . . . . . . . . . . . . . . . . 24
2.2 Effect of TFAA in methane sulfonation.[a] To evaluate the significance of TFAA
in the reaction solution, 1) reduced amount of TFAA, and 2) additional water was
applied to the standard condition. . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.3 Methane sulfonation via TFAOSO3H under various conditions.[a]
. . . . . . . . . . 36
2.4 Incompetent radical generator for methane sulfonation via TFAOSO3H.[a] Other
known radical generators including NBS, AIBN, and tert-butylhydroperoxide
were not able to produce significant amount of MSA in methane sulfonation via
TFAOSO3H. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.5 Influence of radical inhibitor in the methane sulfonation reaction.[a]
. . . . . . . . 38
2.6 Inhibitory effect of the known radical generators (NBS and AIBN) in methane
functionalization in the presence of K2S2O8 as an radical initiator.[a] When other
known radical generators were employed in the presence of K2S2O8, drastic
decrease in percent yields in methane functionalization was detected, showing
the inhibitory effect in the radical pathway. . . . . . . . . . . . . . . . . . . . . . . 39
2.7 Radical quenching process by radial scavengers.[a] When the radical scavenger
(TEMPO or BHT) was added to the standard conditions, we observed decreased
yields in MSA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
2.8 Kinetic isotope effect studies: analysis of kH/kD.
[a]
. . . . . . . . . . . . . . . . . . 42
vi
2.9 Mesyl Fluoride (MSF) generation under various concentrations of K2S2O8 in
methane sulfonation reaction at high temperature.[a] At high temperature, MSF
was generated depending on the concentration of K2S2O8. . . . . . . . . . . . . . 45
2.10 Effects of time in methane sulfonation by using TFAOSO3H.[a] Time study was
conducted for the methane sulfonation using TFAOSO3H. . . . . . . . . . . . . . . 46
2.11 H2SO4 and Oleum as a substitute for TFAOSO3H.[a] H2SO4 and oleum (fuming
sulfuric acid, 20% SO3) were investigated for their suitability as a reactant for
methane sulfonation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.1 Methane sulfonation by using SO2 and O2.
[a]
. . . . . . . . . . . . . . . . . . . . . 64
3.2 Time study.[a]
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.3 Optimal ratio between sulfur dioxide and molecular oxygen during methane
sulfonation conducted with 0.27 mmol trifluoroperacetic acid.[a][b]
. . . . . . . . . 70
3.4 Effects of anhydrous condition with the use of TFAA.[a]
. . . . . . . . . . . . . . . 72
3.5 Effects of higher pressure in methane sulfonation.[a]
. . . . . . . . . . . . . . . . . 72
3.6 High methane conversion yields.[a]
. . . . . . . . . . . . . . . . . . . . . . . . . . 73
3.7 Comparison between two different radical initiators, hydrogen peroxide and
potassium persulfate, in methane sulfonation using sulfur dioxide at various
temperatures.[a]
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
3.8 Comparison between two different radical initiators, hydrogen peroxide and
potassium persulfate, in methane sulfonation using sulfur dioxide at various
temperatures.[a]
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
4.1 H/D exchange of benzene in D2O.[a]
. . . . . . . . . . . . . . . . . . . . . . . . . . 87
4.2 Pd catalyst screening with various acids.[a]
. . . . . . . . . . . . . . . . . . . . . . 103
5.1 Effects of H2O2 concentrations on the efficiency of Pd catalysis.a
. . . . . . . . . . 117
5.2 Determination of proper oxidant for methane oxidation generating MeOTFA.a
. . 118
5.3 Reduced productivity of the metal catalyzed oxidation due to addition of
TFAOSO3H generating reagent as additives.a
. . . . . . . . . . . . . . . . . . . . . 120
5.4 Consequence of additional water in the oxidation conditions for Pd-catalyzed
C-H activation.a
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
vii
5.5 Influence of the solvent ratio between TFA and TFAA in Pd catalyzed methane
oxidation.a
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
5.6 Comparison between catalyst 1 and 2 for their performance on methane oxidation.a
125
5.7 Crystal data and structure refinement for NHC-Pd Complex 1 . . . . . . . . . . . 130
5.8 Bond lengths [Å] for NHC-Pd Complex 1 . . . . . . . . . . . . . . . . . . . . . . . 131
5.9 Angles [°] for NHC-Pd Complex 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
viii
List of Figures
2.1 Three different forms of products before quenching the reaction: Methanesulfonyl trifluoroacetic anhydride (5), Methanesulfonic anhydride (MSAA, 6), and
Methanesulfonic acid (MSA, 1). 1H NMR spectrum (400 MHz, TFAOH-d1) . . . . . 25
2.2 Three different forms of products before quenching the reaction: Methanesulfonyl trifluoroacetic anhydride (5), Methanesulfonic anhydride (MSAA, 6), and
Methanesulfonic acid (MSA, 1). 13C NMR spectrum (101 MHz, TFAOH-d1) . . . . 26
2.3 Three different forms of products before quenching the reaction: Methanesulfonyl trifluoroacetic anhydride (5), Methanesulfonic anhydride (MSAA, 6), and
Methanesulfonic acid (MSA, 1). 19F NMR spectrum (376 MHz, TFAOH-d1) . . . . . 27
2.4 1H NMR spectrum (400 MHz, D2O) . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.5 13C NMR spectrum (126 MHz, D2O) . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.6 19F NMR spectrum (470 MHz, D2O) . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.7 1H NMR spectrum (400 MHz, D2O): Conversion of MSA to MSF in TFAOH :
TFAA : TFAOSO3H solution. Reaction conditions: MSA (0.1 mL); TFAOH : TFAA
: TFAOSO3H = 1 : 1 : 1 (0.86 mL, 2.5 mmol); 400 psi N2; temperature (100 °C); time
(18 h), (A) with radical initiator K2S2O8 (60 mg, 0.22 mmol), and (B) in absence of
radical initiator. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.8 1H NMR spectrum (400 MHz, D2O): Conversion of MSA to MSF in absence of
TFAOSO3H. Reaction conditions: MSA (0.1 mL); TFAOH : TFAA = 1 : 1 (0.86 mL);
400 psi N2; temperature (100 °C); time (18 h), (A) with radical initiator K2S2O8 (60
mg, 0.22 mmol), and (B) in absence of radical initiator. . . . . . . . . . . . . . . . . 35
2.9 1H NMR spectrum (400 MHz, D2O): Radical quenching process using TEMPO
and BHT. When the radical scavenger (A) TEMPO, and (B) BHT was added to
the standard conditions, decreased yields in MSA was observed. . . . . . . . . . . 41
ix
2.10 Effects of reaction conditions on the conversion of TFAOSO3H to MSA. MSA
yields were plotted under different conditions varying temperature. Reaction
conditions: solvent, TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.98 mL, 2.84 mmol);
radical initiator K2S2O8 (9.5 mol % based on TFAOSO3H, 0.27 mmol); 13CH4 (400
psi, 3.1 mmol); time (18 h). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.11 Effects of reaction conditions on the conversion of TFAOSO3H to MSA. MSA
yields were plotted under different conditions varying the amount of the initiator
(K2S2O8) with two different temperatures (gold diamond, 50 °C; blue star, 100 °C).
Reaction conditions: solvent, TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.98 mL, 2.84
mmol); radical initiator K2S2O8 (0.5–15.5 mol % based on TFAOSO3H, 0.014–0.44
mmol); 13CH4 (400 psi, 3.1 mmol); time (18 h). . . . . . . . . . . . . . . . . . . . . . 44
2.12 1H NMR Spectrum (400 MHz, D2O): Sulfonation of methane by Trifluoroacetylsulfuric Acid. Reaction conditions: Solvent, TFAOH : TFAA : TFAOSO3H = 1 : 1 :
1 (0.98 mL, 2.84 mmol); radical initiator K2S2O8 (9.5 mol% based on TFAOSO3H,
0.27 mmol); 13CH4 (400 psi, 3.1 mmol); temperature (50 °C); time (18 h). . . . . . . 50
3.1 Successful activation of sulfur dioxide and methane at various (a) trifluoroperacetic acid concentrations and (b) temperatures. MSA percent yields were based
on SO2. (a) Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL);
H2O2 (× 0.03 mmol, 4 mol% based on SO2; ◦ 0.15 mmol, 20 mol%); SO2 (40 psi,
0.73 mmol); O2 (× 20 psi, 0.07 mmol; ◦ 30 psi, 0.12 mmol); 13CH4 (200 psi, 3.3–3.4
mmol); time (18 h). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3.2 Successful activation of sulfur dioxide and methane at various (a) trifluoroperacetic acid concentrations and (b) temperatures. MSA percent yields were based
on SO2. (b) Reaction conditions: Solvent, TFAA (0.6 mL); H2O2 (0.03–1.2 mmol,
4–160 mol% based on SO2); SO2 (40 psi, 0.73 mmol); 13CH4 (200 psi, 3 mmol);
temperature (50 °C); time (18 h); O2 (□ 20 psi, 0.07 mmol, 10 mol% based on SO2)
or △ without SO2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
3.3 Yields of MSA under various ratios of sulfur dioxide and molecular oxygen. MSA
percent yields were based on SO2. Reaction conditions: Solvent, TFAOH (0.3 mL)
and TFAA (0.3 mL); H2O2 (0.027 mmol); SO2 (◦ 0.73 mmol, △ 1.3 mmol, □ 1.9
mmol); O2 (9–80 psi, 0.03–0.36 mmol); 13CH4 (200 psi, 2.8 mmol); temperature (50
°C); time (18 h). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
3.4 Determination of the optimal ratio of sulfur dioxide and molecular oxygen at
various trifluoroperacetic acid concentrations. The optimal ratios of SO2 and
O2 indicating the highest MSA yields were determined by the concentration of
TFAO-OH. MSA percent yields were based on SO2. Reaction conditions: Solvent,
TFAOH (0.3 mL) and TFAA (0.3 mL); H2O2 (◦ 0.027 mmol, ⋄ 0.27 mmol); SO2 (0.73
mmol); O2 (0–80 psi, 0.03–0.36 mmol); 13CH4 (200 psi, 2.8 mmol); temperature (50
°C); time (18 h). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
x
3.5 1H NMR spectrum. Three different forms of products were generated by the
methane sulfonation method using SO2 before quenching: methanesulfonyl
trifluoroacetic anhydride (7), methanesulfonic anhydride (MSAA, 8), and
methanesulfonic acid (MSA). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
3.6 Generation of trifluoroacetylsulfuric acid (TFAOSO3H): 19F NMR spectrum (470
MHz, DCM-d2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.7 Unknown peak at 2.92 ppm: 1H NMR spectrum (400 MHz, TFAOH-d1): Reaction
conditions: (A) When methanesulfonic anhydride (8) was added to the solution
of 0.3 mL TFAD and 0.2 mL TFAA, the formation of 7 was detected to exhibit
7 and 8. (B) When 3 µL of H2O2 was added to the solution of (A), no peak was
observed at around 2.92 ppm. (C) When 10 µL of TFAOSO3H was added to the
solution of (A), a small peak around 2.92 ppm was detected. . . . . . . . . . . . . . 79
4.1 Coupling patterns of Pd catalyst 3 around 15N atom. . . . . . . . . . . . . . . . . . 88
4.2 {1H}15N NMR (top) and 1H-coupled 15N NMR (bottom) spectra (40.5 MHz, CD3CN)
of 15N-labeled complex 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
4.3 1H NMR spectrum (400 MHz, CD3CN) of 15N-labeled Pd complex 3. . . . . . . . . 90
4.4 13C NMR spectrum (62.9 MHz, CD3CN) of 15N-labeled complex 3. . . . . . . . . . 91
4.5 IR spectroscopy of 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
4.6 IR spectroscopy of 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
4.7 IR spectroscopy of 1b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4.8 1H NMR spectrum (400 MHz, CD3CN) of complex 4 with BF4-. To a reaction
solution of 1b (15.5 µmol) in 0.5 mL of CD3CN, HBF4 (1 equiv.) was added.
Protonated structure 4 was obtained upon the addition and analyzed with 1H
NMR spectrum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.9 1H NMR spectrum (400 MHz, CD3CN) of compound 1b. To a 0.5 dram vial
having Pd complex 4 (6 mg, 15.5 µmol) in 0.5 mL CH3CN solution, 10 mg of
molecular sieves were added. Then the reaction mixture was stirred for 16 hours.
According to 1H NMR spectra, the ratio between 4 and 1b was 1:1. . . . . . . . . . 96
4.10 13C NMR spectrum (100.5 MHz, CD3CN) of compound 1b. . . . . . . . . . . . . . 97
xi
4.11 1H NMR spectrum (400 MHz, CD3CN) of compound 5. The reaction solution of
0.5 mL CD3CN with 6 mg of 4 (15.5 µmol) was prepared in a NMR tube, and 50 µL
of D2O (0.833 mmol) was added. On 1H NMR, N-H signal at 7.1 ppm disappeared
in 10 minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
4.12 2H NMR spectrum (61.4 MHz, CD3CN) of compound 5. As the N-H signal at 7.1
ppm disappeared in 10 minutes on 1H NMR, singlet at 7.3 ppm developed on 2H
NMR spectrum as time goes by. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4.13 H/D exchange of methane in J. Young NMR tubes monitored by (A) 1H and (B)
2H NMR. Reaction condition: 2b (15.5 µmol), AgBF4 (46.5 µmol), D2O (0.6 mL),
CH4 (1 atm), temperature (60 °C); Poly(dimethylsiloxane) (PDS) was used as an
external reference. Over 6 hours, 44% decrease of the CH4 signal was observed
on 1H NMR spectra. H/D conversions (%) were determined every 2 hours up to 6
h: % (2 hours), 42% (4 hours), 44% (6 hours). Formation of black precipitates was
first observed within 1 hour. As the reaction progressed, a gradual increase in
black precipitates was detected. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.1 ORTEP style plot of the single-crystal structure of Pd catalyst 1. . . . . . . . . . . 127
xii
List of Schemes
1.1 Methane oxidation by Periana using H2SO4. . . . . . . . . . . . . . . . . . . . . . 5
1.2 Methane oxidation in TFAA by Sen. . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3 Oxidation of methane under mild temperature by Ingrosso. . . . . . . . . . . . . . 6
1.4 Strassner’s methane oxidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.5 Methane sulfonation by Snyder . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.6 Radical-initiated methane sulfonation by Sen . . . . . . . . . . . . . . . . . . . . . 9
1.7 Methane sulfonation by Bell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.1 Methane activation via (a) trifluoroperacetic acid and (b) trifluoroacetyl sulfuric
acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.2 Sulfonation of methane via trifluoroacetyl sulfuric acid (TFAOSO3H) generated
from H2SO4 and TFAA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.3 Proposed mechanistic pathway for methane sulfonation via trifluoroacetyl
sulfuric acid (TFAOSO3H, 2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.4 Hydrolysis of methanesulfonyl trifluoroacetic anhydride (TFAOSO2CH3, 5) and
methanesulfonic anhydride (MSAA, 6) generating methanesulfonic acid (MSA,
1) in the presence of water. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
xiii
2.5 Decomposition of radical intermediates (TFAO•) generating methanesulfonyl
fluoride (MSF) from MSA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.1 Methane sulfonation using trifluoroacetylsulfuric acid (TFAOSO3H) generated
from (a) sulfuric acid or (b) sulfur dioxide and molecular oxygen. . . . . . . . . . . 59
3.2 Facile preparation of trifluoroacetyl sulfuric acid (1). The formation of
TFAOSO3H was confirmed comparatively by 19F NMR spectral analysis between
the previously reported methods[18, 19] and our new technique using sulfur
dioxide and molecular oxygen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
3.3 Rationale for mechanistic pathways to generate (a) trifluoroacetylsulfuric acid
and (b) its following methane sulfonation. . . . . . . . . . . . . . . . . . . . . . . 62
3.4 Rationale for mechanistic pathways to generate (a) trifluoroacetylsulfuric acid
and (b) its following methane sulfonation. . . . . . . . . . . . . . . . . . . . . . . 63
4.1 Pd catalyst of NHC-amidate-ether ligand and its activation method. . . . . . . . . 86
4.2 Protonated and deprotonated forms of the Pd(II) catalyst and their IR frequencies. 92
4.3 Potential mechanism of H/D exchange: participation of the amidate nitrogen
atom allowing the metal to maintain the oxidation state. . . . . . . . . . . . . . . 102
4.4 H/D exchange of methane under various conditions. Reaction conditions for
(2)∼(4): Activated catalyst, 2b (15.5 µmol) was dissolved in D2O (0.6 mL), then
added to a high-pressure reactor bomb. After charging the reactor bomb with
400 psi of CH4, the reaction was run for 16 h. . . . . . . . . . . . . . . . . . . . . . 104
5.1 Pd catalysts of NHC-amidate-ether ligand and H/D exchange of methane. . . . . . 115
xiv
5.2 Precedent methane functionalization via radical catalysis (a) generating acetic
acid from TFAA and H2O2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5.3 Precedent methane functionalization via radical catalysis (b) conducting methane
sulfonation by using trifluoroacetylsulfuric acid (TFAOSO3H). . . . . . . . . . . . 119
5.4 Proposed mechanistic pathway generating MeOTFA via Pd catalysis . . . . . . . . 124
5.5 Pd complex 1. trans-[Pd(NHC)Cl2(CH3CN)] . . . . . . . . . . . . . . . . . . . . . . 126
xv
Abstract
In the studies of methane functionalization, we have utilized two different pathways for efficient
C-H activation: Pd-catalysis and radical-catalysis.
First, TFAOSO3H was identified as a key intermediate in radical-catalyzed methane sulfonation. Upon addition of the radical initiator, the crude TFAOSO3H solution activated the strong
C-H bonds of methane and generated methanesulfonic acid (MSA). TFAOSO3H and methane were
converted to MSA under optimal conditions, achieving high conversion yields using potassium
persulfate at 50 °C. The free-radical mechanism was elucidated with the identification of the key
intermediate and radical species involved. Furthermore, additional experiments demonstrated the
economic feasibility of scaling up this method for industrial applications by achieving methane
functionalization under 1 atm conditions.
When various feedstocks were explored as sulfur sources, we discovered that not only H2SO4
and oleum, but also SO2 was able to produce TFAOSO3H to facilitate methane sulfonation. Accordingly, practical conditions for the utilization of SO2 to generate TFAOSO3H was developed
which can perform methane sulfonation. Consequently, SO2, O2, and methane were successfully
converted to MSA via a free-radical mechanism promoted by trifluoroperacetic acid. SO2 and CH4
were selectively converted to MSA in 74% and 95% yields, respectively, when they were employed
as limiting reagents.
xvi
Secondly, metal-catalyzed C-H activation was investigated for oxidative functionalization of
methane using Pd catalysts. The water-stable Pd complex containing N-heterocyclic carbene
ligand was activated by removal of the chloride ligand and facilitated H/D exchange on methane,
exhibiting a high deuterium conversion of 44% and an outstanding turnover number (TON) of 346
under mild conditions. Furthermore, spectral analysis confirmed a distinctive non-redox catalytic
system derived from the amidate nitrogen on the catalyst. As the amidate nitrogen behaved as an
internal base, facile protonation and deprotonation on the nitrogen were observed. Consequently,
the Pd metal center maintained its oxidation state during the H/D exchange reactions, resulting
in unique non-redox catalysis.
Further studies on Pd complexes validated the successful conversion of methane to methyl trifluoroacetate (MeOTFA) with high a TON. As the background radical reaction and over-oxidation
inhibited the desired metal-catalyzed methane oxidation, optimal reaction conditions were determined through comprehensive studies. Suppressing the background radical pathway corroborated higher productivity in Pd-catalyzed methane activation, resulting in a TON of 154.
xvii
Preface
Most of the data and analysis discussed in the thesis has been published in indexed peer-reviewed
chemistry journals:
• Justin O’Neill, Joo Ho Lee, Sungah Kim, Nima Zargari, Bijan Ketabchi, Jason Akahoshi,
Felicia Yang, and Kyung Woon Jung. Nitrohydroxylation of Olefins with Nitric Acid Using
Tridentate NHC–Amidate–Alkoxide Containing Palladium Catalysts. Top Catal 61, 630–635
(2018).
• Sungah Kim, Jen-Chieh Wang, Joo Ho Lee, and Kyung Woon Jung. “Methane Sulfonation
via a Free-Radical Mechanism by Trifluoroacetyl-sulfuric Acid”. In: The Journal of Organic
Chemistry 87.15 (2022), pp. 10539–10543.
• Sungah Kim, Jen-Chieh Wang, Joo Ho Lee, and Kyung Woon Jung. “Novel methane activation by sulfur dioxide and molecular oxygen via trifluoroacetylsulfuric acid”. In: Green
Chemistry 24.20 (2022), pp. 7918–7923.
• Sungah Kim, Joo Ho Lee, Jamie Jarusiewicz, Jen-Chieh Wang, and Kyung Woon Jung.
“Hydrogen-Deuterium Isotope Exchange of Methane via Non-redox Palladium Catalysis”. In:
European Journal of Inorganic Chemistry 26.6 (2023), e202200615.
xviii
• Jen-Chieh Wang, Sungah Kim, Joo Ho Lee, Carlos Ascencio, Lynn Chung, Julia Cashman,
and Kyung Woon Jung. "Mechanistic Investigations on the Direct Regioselective Sulfonation
of Gaseous Light Hydrocarbons by Sulfur Dioxide". In progress.
xix
Chapter 1
Introduction
1.1 Methane And Its Functionalization
1.1.1 Significance of Methane Functionalization
Methane is the simplest hydrocarbon with a low reactivity due to its strong chemical bond.[1]
According to the National Oceanic & Atmospheric Administration (NOAA),[2] the global average methane concentration in 2022 is 1911.8 + 0.6 ppb, which is approximately 2.5 times greater
than pre-industrial levels[3] Underlying causes of the abundance of methane. in the atmosphere
depend on both natural sources and anthropogenic emissions. Massive emissions from natural
sources originate from various locations such as on/off-shore marine areas,[4] wetlands,[5–8]
plant soil,[9] and permafrost.[10, 11] However, the majority of emissions of released methane,
ranging from 50-65%, are anthropogenic.[5] Livestock farming[12, 13] and waste treatment[14,
15] contribute as human-induced sources of methane, while significant anthropogenic emissions
come from fossil fuel industries, including the production, flaring, and usage of natural gas, oil,
and coal.[16, 17] Since humanity relies on fossil fuels in global aspects, the concentration and
1
emissions of atmospheric methane are expected to continue to increase in the future. As a result,
large quantities of methane can be utilized as a competitive leverage asset through the development of appropriate utilization methods.
Along with the significance of developing an application for the massive quantity of methane,
its detrimental influence on the environment is another reason to pay attention to the utilization
of methane. In the historical period, methane is one of the largest anthropogenic climate forcing factors with severe consequences.[18] Even though 80% of greenhouse gas emissions come
from carbon dioxide (Table 1.1),[19] the comparative impact of methane is much higher than that
of carbon dioxide[20] due to its strong warming potential[5] and competence for the radiation
trapping. Additionally, given the fact that it can function as a precursor for tropospheric ozone,
methane can be considered as one of the most destructive human-induced greenhouse gasses.[21]
entry Greenhouse Gas Percentages
1 CO2 79.4 %
2 CH4 11.5 %
3 NO2 6.2 %
4 HFCs, PFCs, SF6, and NF3 3.0 %
Table 1.1: Overview of Greenhouse Gas Emissions (Modified from source "Overview of Greenhouse Gases" by United States Environmental Protection Agency.[19]
2
Considering its extensive potential as a feedstock along with its destructive effects on the environment, the scientific community has been endeavoring to exploit the applications for methane;
however, efficient ways to utilize methane are not yet established due to certain difficulties, which
will be discussed later in section 1.1.2.
1.1.2 Challenges and Precedent Methods
Since methane is the shortest hydrocarbon with a strong C-H bond and a high bond dissociation
energy (BDE), its characteristics lead to some challenges for methane functionalization.[1] Despite the fact that numerous approaches for catalytic methane conversion have been discovered
and presented in various publications, these new routes always remain with an inherent problem associated with the high BDE: requirements for harsh condition that followed by catalyst
instability, low conversion rates, and substantial over-oxidation of the products.[22]
1.1.2.1 Syngas and Fischer-Tropsch Technique
Syngas generation and Fischer-Tropsch technique are among the widely applied methods for
functionalization of hydrocarbons. Syngas generation followed by the Fischer-Tropsch process
would convert natural gas into value-added hydrocarbons and oxygenated hydrocarbons such as
alcohols.[23] Syngas, a mixture of hydrogen and carbon monoxide, is produced primarily through
steam reforming and partial oxidation of natural gas. In the presence of a nickel catalyst, natural
gas, consisting primarily of methane (∼ 94%), reacts with steam to produce hydrogen and carbon
monoxide.[24]
3
Fischer-Tropsch technique then employs syngas as a feedstock to produce liquid hydrocarbons in the presence of metal catalysts at high temperatures and pressures. As a result of a series
of chemical reactions, the Fischer-Tropsch process produces a variety of hydrocarbons that can
be further used as synthetic lubricants and fuels.[25–27]
Even though Syngas production and Fischer-Tropsch method are widely used due to their
high efficiency, they confront disadvantages such as harsh conditions, high cost, energy demand,
and high carbon dioxide emissions.[28]
1.1.2.2 Methane Oxidation: Application of Pd Complexes
Contemporary, substantial numbers of metal catalysis have been established and demonstrated
their efficiency for methane functionalization since metal catalysts can facilitate the functionalization of methane by increasing its reactivity through coordination and activation of C-H bonds.
As a result, the strong C-H bonds of methane can be cleaved in relatively mild conditions to convert methane into a product carrying a functional group. Various metal catalyses in different
conditions have been discussed, and Pd is one of the widely used transition metal catalysts used
for methane functionalization, especially methane oxidation.
4
One of the most outstanding oxidative methane functionalization was discovered by the Periana group, where direct and selective conversion of methane was conducted at relatively high
temperatures.[29] When 13C-enriched methane was subjected to H2SO4, the reaction was catalyzed by Pd(II) catalyst to generate acetic acid and methanol with 4.1 and 1.9 turnovers, respectively (Scheme 1.1).
Scheme 1.1: Methane oxidation by Periana using H2SO4.
Acetic acid was generated in situ as the produced methanol underwent C-H activation followed by oxidative carbonylation. C-13 isotope labeling studies demonstrated that both carbons
in acetic acid were derived from methane, supporting the tandem catalysis of the process. Overall
turnover numbers (TON) of 18 were achieved while the ratio of 17 : 72 : 11 was observed for the
carbon selectivity of methanol, acetic acid, and carbon dioxide.
In the field of alkane oxidation, over-oxidation of primary products to carbon dioxide is one
of the persistent problems. Consequently, Sen and the colleagues developed a selective oxidation method using trifluoroacetic anhydride (TFAA).[30] Excess TFAA in the reaction mixture
prevented the hydrolysis of easily oxidized methanol by removing water, which led to the generation of methyl ester as the product. As a result, methane was oxidized to methyl trifluoroacetate, CF3COOCH3 in the presence of peroxytrifluoroacetic acid and Pd(II) catalyst (Scheme 1.2).
5
Improved catalytic efficiency was demonstrated under anhydrous conditions, while further oxidation of CF3COOCH3 was observed at longer reaction times. Similar results were obtained with
other metal ions, but in reduced amounts.
Scheme 1.2: Methane oxidation in TFAA by Sen.
Under similar conditions, the Ingrosso group successfully converted methane gas to
CF3COOCH3 as a major liquid product.[31] When Pd(hfacac)2
(hfacac = 1,1,1,5,5,5-hexafluoropentane-2,4-dionate) was applied, methane oxidation was conducted under mild conditions at temperatures as low as 50 °C (Scheme 1.3). H2O2 concentration
played an important role in the reaction with the catalyst demonstrating the highest efficiency at
35% of H2O2. The stability of the Pd catalyst was confirmed, as its activity remained undiminished
even after five recycles. Furthermore, the electrophilic mechanism of the reaction was confirmed
by the observation that 2,6-di-tert-butyl-4-methylphenol (BHT), a powerful radical scavenger,
had no effect on the catalytic activity in methane oxidation.
Scheme 1.3: Oxidation of methane under mild temperature by Ingrosso.
6
With continued improvements in Pd catalysis, Pd complexes with N-heterocyclic carbene
(NHC) ligands have been developed. Previously, Strassner and co-workers reported a series of
Pd catalysts bearing bis-NHC chelating ligands.[32–34] The NHC ligands were able to stabilize
the strong Lewis acidic metal centers while maintaining the outstanding thermal and chemical stability of the system. The improved stability enabled the Pd-NHC complexes to perform
methane oxidation under acidic conditions in the presence of strong oxidants. Further investigation discovered the significance of counterions and length of the alkyl bridges on the catalytic
activity (Table 1.2).
entry Pd Catalysts TON
1 PdBr2L1 30
2 PdCl2L1 24
3 PdI2L1 0
4 PdCl2L2 33
Table 1.2: Methane oxidation by Strassner.
As a result, a yield of 3300% compared to the Pd catalyst (TON 33) was achieved under mild
conditions at 90 °C in acidic medium (Scheme 1.4).
Scheme 1.4: Strassner’s methane oxidation.
7
Despite the successful establishment of the novel catalytic systems, there are still some drawbacks, such as low yields and selectivity, mediocre TONs, and further decomposition of the products into carbon dioxide. Consequently, there is still potential for further improvements, necessitating the development of more efficient methods.
1.1.2.3 Radical Catalysis for Methane Sulfonation
Since over-oxidation of primary products is one of the major concerns in methane oxidation,
sulfonation of methane has emerged as an alternative method to utilize methane.
In the early 1950s, Snyder reported a remarkable method of methane functionalization using
oleum (fuming sulfuric acid, 30% SO3).[35] Using HgSO4 as a catalyst, methane and sulfur trioxide
reacted under high temperature and pressure to form a mixture of oxygenated and sulfonated
derivatives of methane including methanol, formic acid, methanesulfonic acid (MSA), and various
forms of methyl esters (Scheme 1.5).
Scheme 1.5: Methane sulfonation by Snyder
8
Further investigation of methane functionalization using oleum was conducted with the help
of radical initiators. Sen and the colleagues reported radical-initiated methane sulfonation using various initiators.[36] K2S2O8 appeared to be the most competent initiator among the others,
with yields of CH3SO3H exceeding 35% relative to the limiting reagent, SO3 (Scheme 1.6).
Scheme 1.6: Radical-initiated methane sulfonation by Sen
Using radical initiators such as K2S2O8 or urea/H2O2, and metal chloride salts as additives, the
Bell group increased SO3 conversion up to 95% at mild temperatures.[37, 38] Even at a lower
pressure of 100 psi, the conversion of methane to MSA was approximately 29-36%, with a selectivity of 99.9% (Scheme 1.7).
Scheme 1.7: Methane sulfonation by Bell
9
In contrast to previous sulfonation that mainly focuses on free-radical mechanisms, DiazUrrutia and Ott reported electrophilic C-H activation of methane using SO3.[39] When Oleum
(20 - 60% SO3) and methane were treated with electrophilic initiators at 50 °C under super acidic
and high pressure conditions (1450 psi), MSA was produced with 99% yield and 99% selectivity.
Electrophilic initiators were prepared by mixing H2O2, MSA, and H2SO4 to generate various forms
of sulfonyl peroxide derivatives. These electrophilic initiators are protonated under superacidic
conditions to produce electrophilic oxygen atoms that can activate the C-H bonds of methane. As
a result, CH3
+ was proposed to be the key intermediate in this cationic chain reaction mechanism.
However, Singleton disputed the fundamental mechanism of the electrophilic cationic chain
reaction and proposed a potential free-radical mechanism based on the free energy–favored faceto-face complex of CH3• and SO3.[40]
Direct synthesis of MSA from methane and oleum via a free–radical mechanism has been
demonstrated to be efficient with high conversion yields based on SO3 under comparatively mild
conditions. However, considering the fact that typical SO3 content in oleum is w/w 20-30%, H2SO4
is inevitably employed in large quantities, leading to a relatively low percent yield based on the
entire sulfur source.
10
1.2 Scope and Objectives of the Study
The ultimate goal of the research is to develop a novel and effective method for methane functionalization through metal- and radical-catalysis.
In chapter two, the identification of a key intermediate, trifluoroacetyl sulfuric acid
(TFAOSO3H), for methane sulfonation is discussed. While previous methods have primarily
focused on the utilization of SO3, our group has highlighted the significance of the intermediate TFAOSO3H, aiming to develop a more efficient and selective pathway for radical-catalyzed
methane sulfonation under mild conditions. The study seeks to elucidate the free-radical mechanism and its key intermediate facilitating methane sulfonation while determining the optimal
reaction conditions to maximize the yield and selectivity of the products. Furthermore, a scale-up
reaction for industrial use is deliberated for this sulfonation technique to evaluate the economic
potential.
Chapter three explores the novel use of sulfur dioxide (SO2) in methane sulfonation by developing a new method converting greenhouse gasses with molecular oxygen into a transportable
liquid, MSA. As an extension of previous research, the study focuses on practical conditions of
SO2 transforming into TFAOSO3H, where in situ generated TFAOSO3H carries out the functionalization of methane. The study investigates the free-radical pathway facilitating the conversion
of methane to MSA and explores the unique roles of each reagent in the mechanism. Throughout
optimization studies, high yield of MSA and methane conversion are expected to be achieved.
11
Additionally, this chapter emphasizes the environmental and economical values of the one-pot
two step synthesis utilizing toxic gas to produce useful liquid products.
Chapter four mainly focuses on the N-heterocyclic carbene (NHC) ligand-Pd complex and
its potential for the methane C-H activation via hydrogen-deuterium isotope exchange (H/D exchange). In previous research, our group developed a water stable Pd catalyst and demonstrated
H/D exchange for various hydrocarbons. To discover the reactivity and stability of the novel catalyst, we extended our scope to determine its feasibility for methane functionalization at relatively
low temperatures. Spectral analysis evaluates non-redox Pd catalysis and the stability based on
its unique structure containing amidate nitrogen while figuring out the underlying mechanisms.
As the study scrutinizes the optimal reaction conditions, we aim to achieve high efficiency and
selectivity in HD exchange.
The last chapter discusses practical applications of the NHC-Pd catalysts for methane oxidation. Since C-H activation on methane validated the competence of the Pd species via H/D
exchange, this research focuses on the development of an oxidative C-H activation method using
Pd complexes, as well as the efficient and chemoselective conversion of methane to methyl trifluoroacetate (MeOTFA). Mechanistic studies highlight the significance of diminishing the undesired side reactions such as over-oxidation and radical-catalyzed sulfonations, leading to optimal
conditions for methane oxidation with high TON.
12
1.3 References
References for Chapter 1
[1] Branko Ruscic. “Active thermochemical tables: sequential bond dissociation enthalpies of
methane, ethane, and methanol and the related thermochemistry”. In: The Journal of Physical Chemistry A 119.28 (2015), pp. 7810–7837. doi: 10.1021/acs.jpca.5b01346.
[2] US Department of Commerce, NOAA, Earth System Research Laboratory. Globally averaged
marine surface annual mean data. https://gml.noaa.gov/webdata/ccgg/trends/ch4/ch4_
annmean_gl.txt. File creation March 5, 2024. Retrieved March, 2024. 2024.
[3] Kathryn McKain et al. “Methane emissions from natural gas infrastructure and use in the
urban region of Boston, Massachusetts”. In: Proceedings of the National Academy of Sciences
112.7 (2015), pp. 1941–1946. doi: 10.1073/pnas.1416261112.
[4] Alberto V Borges et al. “Massive marine methane emissions from near-shore shallow coastal
areas”. In: Scientific reports 6.1 (2016), p. 27908. doi: 10.1038/srep27908.
[5] M. Saunois et al. “The global methane budget 2000–2012”. In: Earth System Science Data 8.2
(2016), pp. 697–751. doi: 10.5194/essd-8-697-2016.
[6] Stephen J. Blanksby and G. Barney Ellison. “Bond Dissociation Energies of Organic Molecules”.
In: Accounts of Chemical Research 36.4 (2003), pp. 255–263. doi: 10.1021/ar020230d.
[7] Gary J Whiting and Jeffrey P Chanton. “Primary production control of methane emission
from wetlands”. In: Nature 364.6440 (1993), pp. 794–795. doi: 10.1038/364794a0.
[8] N Gedney, PM Cox, and Chris Huntingford. “Climate feedback from wetland methane emissions”. In: Geophysical Research Letters 31.20 (2004).
[9] Changwei Zhang et al. “Massive methane emission from tree stems and pneumatophores
in a subtropical mangrove wetland”. In: Plant and Soil 473.1 (2022), pp. 489–505.
13
[10] Rebecca B Neumann et al. “Warming effects of spring rainfall increase methane emissions
from thawing permafrost”. In: Geophysical Research Letters 46.3 (2019), pp. 1393–1401.
[11] Changchun Song et al. “Large methane emission upon spring thaw from natural wetlands
in the northern permafrost region”. In: Environmental Research Letters 7.3 (2012), p. 034009.
[12] E Gonzalez-Avalos and LG Ruiz-Suarez. “Methane emission factors from cattle manure in
Mexico”. In: Bioresource Technology 80.1 (2001), pp. 63–71.
[13] Kristen A Johnson and Donald E Johnson. “Methane emissions from cattle”. In: Journal of
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17
Chapter 2
Methane Sulfonation via a Free-Radical Mechanism
by Trifluoroacetylsulfuric Acid
18
2.1 Abstract
Using trifluoroacetyl sulfuric acid (TFAOSO3H), we discovered a new methane activation method
and revealed its radical pathway under mild conditions. Upon the addition of a radical initiator with methane, the crude solution of TFAOSO3H developed the methyltrifluoroacetylsulfate
radical ((TFAO)CH3S (OH)O2•). The resulting (TFAO)CH3S(OH)O2• behaved as a critical radical
propagator for carbon-hydrogen bond activation, culminating in successful methane sulfonation.
With 9.5 mol % of K2S2O8, TFAOSO3H and methane were selectively converted to methanesulfonic acid in 94 and 86 % conversion yields, respectively.
19
2.2 Introduction
Since the remarkable report by Snyder, oleum (fuming sulfuric acid) has been employed predominantly for methane sulfonation. The conditions required catalytic HgSO4 at elevated temperatures and produced a mixture of oxygenated and sulfonated compounds presumably by various mechanistic pathways.[1] Sen and Bell developed radical conditions for methane functionalization, which turned out to be efficient and selective. At moderate temperatures (90–160 °C),
methane and fuming sulfuric acid (27–33% SO3 content by weight) were converted to methanesulfonic acid (MSA) and methyl bisulfate in the presence of a persulfate radical initiator (S2O8
2–).[2,
3] Furthermore, metal-peroxo or metal-hydroperoxo species generated from urea/hydrogen peroxide (H2O2) in combination with metal chloride were able to sulfonate methane into MSA effectively in oleum at 65 °C.[4] Recently, Díaz-Urrutia and Ott[5] reported a selective conversion
of methane and oleum to methanesulfonic acid while using a sulfonyl peroxide derivative as an
electrophilic initiator. Through a mechanistic study, they proposed the activation of the C–H
bond of CH4 via the electrophilic oxygen atom of the sulfonyl peroxides, generating CH3
+
as a
key intermediate in the cationic chain reaction, whereas Singleton[6] proposed a potential freeradical mechanism on this reaction instead of a cation chain reaction on the grounds of a free
energy-favored face-to-face complex of CH3• with SO3.
As depicted in reaction (a), Scheme 2.1, our group clarified the background radical pathway in
Pd(II)-catalyzed methane oxidation, where acetic acid (AcOH) was observed as the unwanted side
product in addition to the desired product of methyl trifluoroacetate (TFAOMe).[7] Intermediate
trifluoroperacetic acid (TFAO–OH) prepared from H2O2 and TFAA produced the trifluoromethyl
20
Scheme 2.1: Methane activation via (a) trifluoroperacetic acid and (b) trifluoroacetyl sulfuric acid.
radical (•CF3), which effected the C–H bond activation of methane, and the resulting •CH3 radical reacted with TFAA to produce AcOH. Both previous and current protocols employed radical
pathways, yet our current method differed to avoid the formation of a trifluoromethyl radical
and AcOH product (reaction (b), Scheme 2.1). Another new feature of our sulfonation method is
the key intermediate, TFAOSO3H, and its following radical chain carrier. We believed that all of
the previous reactions of methane with SO3, including Díaz-Urrutia and Ott’s impressive methods, underwent radical pathways unlike their mechanistic claim via a methyl sulfonate radical
(CH3SO3•), which is reminiscent of our newly explored (TFAO)CH3S(OH)O2•. Both crucial intermediates would serve as propagation radicals to activate the C–H bond of methane and generate
methyl radical (CH3•) for the selective synthesis of MSA.[1]
21
2.3 Results and Discussion
2.3.1 Sulfonation of Methane via Trifluoroacetyl Sulfuric Acid
(TFAOSO3H) Generated from H2SO4 and TFAA
The functionalization of methane using trifluoroacetyl sulfuric acid, TFAOSO3H,[2] was carried
out in a closed stainless-steel reactor having a high-pressure valve (Scheme 2.2). TFAOSO3H (2)
was synthesized using the reported method of mixing H2SO4 and TFAA,[8, 9] and 13C-enriched
methane (13CH4) was employed to distinguish the methane-derived products from any other possible carbon sources and avoid any potential complications in analyzing the reaction results. Under typical conditions, 9 mol % of K2S2O8 was added to the solution of TFAOSO3H, and then the
reactor bomb was charged with 400 psi of 13CH4. When the sulfonation reaction was run at 50
°C for 18 h, MSA[1] was the predominant isotopically labeled product. The conversion yield was
94% based on the added TFAOSO3H and the CH4 conversion went up to 86%. Byproducts including methyl trifluoroacetate (TFAOMe) and overoxidation products were only found in negligible
amounts if detected at all.
Scheme 2.2: Sulfonation of methane via trifluoroacetyl sulfuric acid (TFAOSO3H) generated from
H2SO4 and TFAA.
22
2.3.2 Proposed Free-radical Mechanism for Methane Sulfonation
A free-radical mechanism for methane sulfonation was considered, as depicted in Scheme 2.3,
to account for MSA generation. Sulfate radical 3 generated from a radical initiator, K2S2O8, can
abstract hydrogen from CH4 and create a methyl radical (CH3•). As Singleton addressed SO3 as
electrophilic rather than nucleophilic,[6] the methyl radical may undergo nucleophilic radical
addition to TFAOSO3H (2) at the sulfur atom. The resultant methyltrifluoroacetylsulfate radical
complex 4 can spontaneously dissociate to produce methanesulfonyl trifluoroacetic anhydride
(TFAOSO2CH3, 5) and hydroxyl radical (•OH), which then reacts with methane to regenerate
methyl radical (CH3•) and keep the radical chain as the continuous C–H activation cycle.
Scheme 2.3: Proposed mechanistic pathway for methane sulfonation via trifluoroacetyl sulfuric
acid (TFAOSO3H, 2).
Previous studies on the radical mechanism by Sen and Bell proposed a direct sulfonation of
CH3• on SO3 to afford a methyl sulfate radical (CH3SO3•) that would propagate the radical chain
reaction. Likewise, in our case, methyltrifluoroacetylsulfate radical 4 ((TFAO)CH3S(OH)O2•) derived from TFAOSO3H (2) would be the radical chain carrier to drive the reaction forward.
23
There could be other competing radicals in the reaction solution which may perform hydrogen
atom abstraction (HAA). However, according to the bond dissociation energy (BDE) of the similar
compound H2SO4 (Table 2.1), more energy would be required to break a bond between O–H (133
kcal/mol) in H2SO4 than to break the C–H bond in CH4 (105 kcal/mol). Moreover, homolytic
cleavage between the S–O bond is more feasible than with the O–H bond as the BDE of the O–H
bond in H2SO4 is higher than the BDE of S–OH and S=O bonds, which are 88 and 110 kcal/mol,
respectively. Consequently, formation of radical complex 4 would be plausible in the mechanism
via the radical pathway.[10]
entry Bond Bond dissociation energy (BDE)
1 O-H (in H2SO4) 133 kcal/mol
2 C-H (in CH4) 105 kcal/mol
3 S-OH (in H2SO4) 88 kcal/mol
4 S=O (in H2SO4) 110 kcal/mol
Table 2.1: Bond Dissociation Energy (BDE) of H2SO4 and CH4
24
2.3.3 Three Forms of Products: TFAOSO2CH3, MSA, and MSAA
Before the reaction was quenched, products were observed in three different forms under equilibrium, although TFAOSO2CH3 (5) was always the major product and MSA (1) was the minor
product. Additionally, trace amounts of methanesulfonic anhydride (MSAA, 6) were detected
(Figure 2.1 - Figure 2.3).
Figure 2.1: Three different forms of products before quenching the reaction: Methanesulfonyl
trifluoroacetic anhydride (5), Methanesulfonic anhydride (MSAA, 6), and Methanesulfonic acid
(MSA, 1). 1H NMR spectrum (400 MHz, TFAOH-d1)
25
Figure 2.2: Three different forms of products before quenching the reaction: Methanesulfonyl
trifluoroacetic anhydride (5), Methanesulfonic anhydride (MSAA, 6), and Methanesulfonic acid
(MSA, 1). 13C NMR spectrum (101 MHz, TFAOH-d1)
26
Figure 2.3: Three different forms of products before quenching the reaction: Methanesulfonyl
trifluoroacetic anhydride (5), Methanesulfonic anhydride (MSAA, 6), and Methanesulfonic acid
(MSA, 1). 19F NMR spectrum (376 MHz, TFAOH-d1)
27
In separate experiments, the coupling of TFAA and MSA was confirmed to afford
TFAOSO2CH3 (5) and MSAA (6).[11] Both of these anhydrides (5 and 6) from our sulfonation
reactions were smoothly hydrolyzed and converted to MSA (1) upon being quenched with water
(Scheme 2.4). These results implied the generation of water during the reaction, which would
result in the conversion of incipient TFAOSO2CH3 (5) to MSA (1) and the ensuing formation of
an equilibrated mixture of products.
Scheme 2.4: Hydrolysis of methanesulfonyl trifluoroacetic anhydride (TFAOSO2CH3, 5) and
methanesulfonic anhydride (MSAA, 6) generating methanesulfonic acid (MSA, 1) in the presence of water.
28
When we employed reduced amounts of TFAA for the sulfonation reaction, we experienced
decreased yields in MSA, whereas the addition of water to the standard conditions led to further
reduction in percent yields (Table 2.2). Therefore, the use of TFAA was necessary for optimal
conditions by removing newly generated water and MSA.
entry Reaction solution MSA (yield, %)[c]
1 Absence of TFAA 25.6
2
[b] Addition of 2 µL of water 18.7
a Reaction conditions: Solvent, TFAOH: TFAOSO3H
= 1: 1 (0.566 mL, 2.84 mmol); TFAOH (0.414mL);
radical initiator K2S2O8 (0.95 mol% based on
TFAOSO3H, 0.027 mmol); 13CH4 (400 psi, 3.1 mmol);
temperature (50 °C); time (18 h).
b
2µL of water was added to the reaction solution.
c The percent yield of MSA was calculated based on
the initial amount of TFAOSO3H.
Table 2.2: Effect of TFAA in methane sulfonation.[a] To evaluate the significance of TFAA in the
reaction solution, 1) reduced amount of TFAA, and 2) additional water was applied to the standard
condition.
29
2.3.4 Generation of Methanesulfonyl Fluoride (MSF) due to
Decomposition of Radical Intermediates TFAO•
Additionally, decomposition of radical intermediates to produce side products encompassing
methanesulfonyl fluoride (MSF) was observed only when the reactions were attempted at high
temperatures, and its structure was elucidated out of crude products by 1H, 13C, and 19F NMR
spectral analysis as both proton-coupled 13C and 19F NMR exhibited two-bond coupling 13C–S–F
(JC–F = 19.7 Hz) (Figure 2.4 - Figure 2.6).
Figure 2.4: 1H NMR spectrum (400 MHz, D2O)
30
Figure 2.5: 13C NMR spectrum (126 MHz, D2O)
31
Figure 2.6: 19F NMR spectrum (470 MHz, D2O)
32
As shown in Scheme 2.5, the trifluoroacetate radical (TFAO•) can be generated from various
species such as complex 4, TFAOSO3H, or TFAOH at relatively high temperatures and then may
decompose into CO2 and traces of trifluoromethyl radical (•CF3),[7] which may undergo thermal
decomposition to create C2F4 and a fluoride radical (F•).[12] F• appeared to react with produced
MSA to furnish MSF (7) as a minor product.
Scheme 2.5: Decomposition of radical intermediates (TFAO•) generating methanesulfonyl fluoride (MSF) from MSA.
We verified the conversion of MSA to MSF in separate experiments, where the similar reaction was conducted with MSA as a substitute for CH4. MSF was generated from MSA even in the
absence of TFAOSO3H, suggesting the formation of TFAO• from the reaction solvent, TFAOH.
The conversion of MSA into MSF, however, was observed only when radical initiators including potassium persulfate (K2S2O8) were employed, corroborating the radical nature of the MSF
generation (Figure 2.7 - Figure 2.8).
33
Figure 2.7: 1H NMR spectrum (400 MHz, D2O): Conversion of MSA to MSF in TFAOH : TFAA
: TFAOSO3H solution. Reaction conditions: MSA (0.1 mL); TFAOH : TFAA : TFAOSO3H = 1 : 1
: 1 (0.86 mL, 2.5 mmol); 400 psi N2; temperature (100 °C); time (18 h), (A) with radical initiator
K2S2O8 (60 mg, 0.22 mmol), and (B) in absence of radical initiator.
34
Figure 2.8: 1H NMR spectrum (400 MHz, D2O): Conversion of MSA to MSF in absence of
TFAOSO3H. Reaction conditions: MSA (0.1 mL); TFAOH : TFAA = 1 : 1 (0.86 mL); 400 psi N2;
temperature (100 °C); time (18 h), (A) with radical initiator K2S2O8 (60 mg, 0.22 mmol), and (B) in
absence of radical initiator.
35
2.3.5 Significance of Radical Condition
We varied the reaction conditions to further prove the mechanism, clearly understand the reaction pathways in comparison with known methods, and develop optimal conditions (Table 2.3).
When we employed potassium persulfate, K2S2O8, a radical initiator, which was extensively studied in previous CH4 sulfonation studies, the optimal conditions of 9.5 mol % of K2S2O8 afforded
MSA (1) in 94% yield based on TFAOSO3H (Table 2.3, entry 1), whereas a reduced amount of product was obtained when a smaller amount of initiator was used (Table 2.3, entry 2). The results
were similar to the reactions with H2O2 (Table 2.3, entry 3). Compared to K2S2O8 used in mechanistic and optimization studies, a parallel trend was witnessed in the reactions with H2O2 as
an initiator only with the marginally reduced yields, which indicated that both radical initiators
facilitated the same mechanistic pathway.
entry Initiator MSA (yield, %)[b] 13CH4 conv. (%)
1 9.5 mol % of K2S2O8 94.1 86.0
2 0.95 mol % of K2S2O8 37.7 34.5
3 0.95 mol % of H2O2 30.1 27.6
a Under various conditions with different concentrations of K2S2O8,
competency of TFAOSO3H was determined. Reaction conditions:
solvent, TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.98 mL, 2.84 mmol);
radical initiator K2S2O8 (0.95 - 9.5 mol % based on TFAOSO3H,
0.027 - 0.27 mmol); 13CH4 (400 psi, 3.1 mmol); temperature (50
°C); time (18 h).
b The percent yield of MSA was calculated based on the initial
amount of TFAOSO3H.
Table 2.3: Methane sulfonation via TFAOSO3H under various conditions.[a]
36
Other than K2S2O8 and H2O2, however, known radical generators were not as efficient. When
NBS, AIBN, and tert-butylhydroperoxide were employed as a substitute of K2S2O8, none was able
to furnish MSA derivatives or functionalize methane Table 2.4.
entry Initiator MSA (yield, %)[b] 13CH4 Conv. (%)
1 0.95 mol% NBS - -
2 0.95 mol% AIBN 0.1 0.1
3 0.95 mol% tert-butylhydroperoxide - -
a Reaction conditions: Solvent, TFAOH: TFAA: TFAOSO3H = 1: 1: 1 (0.98 mL, 2.84
mmol); radical initiator K2S2O8 (0.95 mol% based on TFAOSO3H, 0.027 mmol);
13CH4 (400 psi, 3.1 mmol); temperature (50 °C); time (18 h).
b The percent yield of MSA was calculated based on the initial amount of
TFAOSO3H.
Table 2.4: Incompetent radical generator for methane sulfonation via TFAOSO3H.[a] Other known
radical generators including NBS, AIBN, and tert-butylhydroperoxide were not able to produce
significant amount of MSA in methane sulfonation via TFAOSO3H.
37
2.3.6 Significance of Radical Species in Methane Functionalization via
TFAOSO3H
In accordance with typical radical reactions, eliminating the radical initiator from the reaction
conditions prevented the formation of MSA or any 13C-labeled products, corroborating that 13CH4
would be activated via a radical mechanism (Table 2.5, entry 1). This radical pathway was almost
shut down upon addition of O2 to the reaction mixture containing K2S2O8, presumably due to
radical inhibition by molecular oxygen (entry 2). In this case, 13CH4 was transformed to MSA
only in a 1.8% yield (Table 2.5, entry 2).
entry Initiator MSA (yield, %)[b] 13CH4 conv. (%)
1 None 0.002 0.002
2 0.95 mol % of K2S2O8 with O2 1.8 1.8
a Under various conditions with different concentrations of K2S2O8, competency of TFAOSO3H was determined. Reaction conditions: solvent,
TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.98 mL, 2.84 mmol); radical initiator
K2S2O8 (0.95 - 9.5 mol % based on TFAOSO3H, 0.027 - 0.27 mmol); 13CH4
(400 psi, 3.1 mmol); temperature (50 °C); time (18 h).
b The percent yield of MSA was calculated based on the initial amount of
TFAOSO3H.
Table 2.5: Influence of radical inhibitor in the methane sulfonation reaction.[a]
38
In addition to oxygen, NBS and AIBN behaved as radical inhibitors when they were used with
equimolar amounts of K2S2O8, resulting in only 1% of MSA (Table 2.6).
entry Radical Initiator MSA (yield, %)[b]
1 0.95 mol% NBS with 0.95 mol% K2S2O8 0.4
2 0.95 mol% AIBN with 0.95 mol% K2S2O8 1.2
a Reaction conditions: Solvent, TFAOH: TFAA: TFAOSO3H = 1: 1:
1 (0.98 mL, 2.84 mmol); NBS and AIBN (equimolar amount of
K2S2O8, 0.95 mol% based on TFAOSO3H, 0.027 mmol); radical initiator K2S2O8 (0.95 mol% based on TFAOSO3H,0.027 mmol); 13CH4
(400 psi, 3.1 mmol); temperature (50 °C); time (18 h).
b The percent yield of MSA was calculated based on the initial
amount of TFAOSO3H.
Table 2.6: Inhibitory effect of the known radical generators (NBS and AIBN) in methane functionalization in the presence of K2S2O8 as an radical initiator.[a] When other known radical generators
were employed in the presence of K2S2O8, drastic decrease in percent yields in methane functionalization was detected, showing the inhibitory effect in the radical pathway.
39
When an equimolar amount of radical scavenger, TEMPO[13, 14] or BHT, was added to the
typical reaction condition containing 0.95 mol % of K2S2O8, a drastic decrease in the percent yield
was observed (Table 2.7, Figure 2.9). As a result, experimental results from the mechanistic studies
established the significance of radical species in methane functionalization via TFAOSO3H.
entry Radical Scavenger MSA (yield, %)[b]
1 TEMPO 1.8
2 BHT -
a Reaction conditions: Solvent, TFAOH:
TFAA: TFAOSO3H = 1: 1: 1 (0.98 mL, 2.84
mmol); radical initiator K2S2O8 (0.95 mol%
based on TFAOSO3H, 0.027 mmol); radical
scavenger TEMPO or BHT (0.027 mmol);
13CH4 (400 psi, 3.1 mmol); temperature (50
°C); time (18 h).
b The percent yield of MSA was calculated
based on the initial amount of TFAOSO3H.
Table 2.7: Radical quenching process by radial scavengers.[a] When the radical scavenger (TEMPO
or BHT) was added to the standard conditions, we observed decreased yields in MSA.
40
Figure 2.9: 1H NMR spectrum (400 MHz, D2O): Radical quenching process using TEMPO and
BHT. When the radical scavenger (A) TEMPO, and (B) BHT was added to the standard conditions,
decreased yields in MSA was observed.
41
2.3.7 Kinetic Isotope Effect
Furthermore, the involvement of C–H activation in this radical pathway was investigated with a
kinetic isotope effect by analyzing the percent yield of sulfonated products from non-isotopically
labeled methane (CH4) and deuterated methane (CD4).[15–18] Corresponding ratios of kH/kD
demonstrated the deuterium isotope effect and provided an additional proof for C–H activation
of methane (Table 2.8).
entry time (min) CH3SO3H (yield, %) [b] CD3SO3H (yield, %) [b] kH/kD
1 5 1.65 0.72 2.29
2 10 5.13 2.77 1.85
3 20 9.54 7.99 1.19
a Reaction conditions: solvent, TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.49 mL,
1.42 mmol); radical initiator K2S2O8 (0.98 mol % based on TFAOSO3H, 0.014
mmol); CH4 or CD4 (20 psi, 1.84 mmol); temperature (50 °C).
b The percent yield of MSA was calculated based on the initial amount of gas
(CH4 or CD4).
Table 2.8: Kinetic isotope effect studies: analysis of kH/kD.
[a]
42
2.3.8 Optimization Study
We extended mechanistic studies to optimize the reaction conditions, as described in Figure 1,
where the effects of temperature, initiator concentration, and reaction times were investigated.
Out of various attempted reaction temperatures, higher MSA yields were obtained at relatively
lower temperatures, with the highest yield and selectivity observed at 50 °C (Figure 2.10). When
the temperatures increased gradually, yields of MSA increased in parallel up to 50 °C and then
decreased sharply.
Figure 2.10: Effects of reaction conditions on the conversion of TFAOSO3H to MSA. MSA yields
were plotted under different conditions varying temperature. Reaction conditions: solvent,
TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.98 mL, 2.84 mmol); radical initiator K2S2O8 (9.5 mol % based
on TFAOSO3H, 0.27 mmol); 13CH4 (400 psi, 3.1 mmol); time (18 h).
43
As the concentration of the initiator increased at 50 °C (Figure 2.11, gold diamond), the percent
conversion improved proportionally up to 9.5 mol % of the initiator K2S2O8. A further increase of
the initiator did not lead to a significant increase in product formation, demonstrating the typical
pattern of radical-initiated reactions. At high temperatures, the decrease of MSA formation was
noticed with excess initiator over 9.5 mol % (Figure 2.11, blue star, 100 °C).
Figure 2.11: Effects of reaction conditions on the conversion of TFAOSO3H to MSA. MSA yields
were plotted under different conditions varying the amount of the initiator (K2S2O8) with two
different temperatures (gold diamond, 50 °C; blue star, 100 °C). Reaction conditions: solvent,
TFAOH/TFAA/TFAOSO3H = 1:1:1 (0.98 mL, 2.84 mmol); radical initiator K2S2O8 (0.5–15.5 mol
% based on TFAOSO3H, 0.014–0.44 mmol); 13CH4 (400 psi, 3.1 mmol); time (18 h).
44
These results align with the generation of MSF, which would be caused by the thermal decomposition of radical intermediates reacting with MSA (Table 2.9).
entry K2S2O8 (mol%) MSF (yield, %) [b]
1 0.95 1.3
2 1.88 2.1
3 3.76 4.1
4 5.64 4.8
5 7.52 7.3
6 9.40 6.7
7 11.28 6.8
8 15.50 8.9
a Reaction conditions: Solvent, TFAOH:
TFAA: TFAOSO3H = 1: 1: 1 (0.98 mL,
2.84 mmol); radical initiator K2S2O8 (0.95
- 15.5 mol% based on TFAOSO3H, 0.027
– 0.44 mmol); 13CH4 (400 psi, 3.1 mmol);
temperature (100 °C); time (18 h).
b The percent yield of MSA was calculated based on the initial amount of
TFAOSO3H.
Table 2.9: Mesyl Fluoride (MSF) generation under various concentrations of K2S2O8 in methane
sulfonation reaction at high temperature.[a] At high temperature, MSF was generated depending
on the concentration of K2S2O8.
45
Typical reactions were done in 18 h; however, most progress was exhibited within 8 h, and
only a minor increase in MSA formation was observed after 8 h. Additionally, 84% of their maximum yields were reached in 2 h (Table 2.10).
entry Time MSA (yield, %)[b] 13CH4 Conv. (%)[c]
1 2 79.4 72.6
2 4 88.1 80.5
3 8 94.0 86.0
4 18 94.1 86.0
a Reaction conditions: Solvent, TFAOH: TFAA:
TFAOSO3H = 1: 1: 1 (0.98 mL, 2.84 mmol); radical
initiator K2S2O8 (9.5 mol% based on TFAOSO3H, 0.27
mmol); 13CH4 (400 psi, 3.1 mmol); temperature (50
°C).
b The percent yield of MSA was calculated based on
the initial amount of TFAOSO3H.
c 13CH4 conversion (Conv.) was calculated based on
the initial amount of 13CH4.
Table 2.10: Effects of time in methane sulfonation by using TFAOSO3H.[a] Time study was conducted for the methane sulfonation using TFAOSO3H.
46
When H2SO4 and oleum (fuming sulfuric acid, 20% SO3) were further examined for their suitability as a reactant for methane sulfonation, both reactants were converted to MSA in 77 and 81%
yields, respectively, based on the added sulfur sources. It was clear that the reactions produced
compelling percent yields; however, presynthesized TFAOSO3H transpired as the most effective
reactant (Table 2.11).
entry Reactant MSA (yield, %)[b] 13CH4 Conv. (%)[c]
1 H2SO4 77.1 70.5
2 Oleum (fuming sulfuric acid, 20% SO3) 80.9 74.0
a Reaction conditions: Reactant, H2SO4 or oleum (2.84 mmol); Solvent (TFAOH: TFAA);
radical initiator K2S2O8 (9.5 mol% based on the reactant, 0.27 mmol); 13CH4 (400 psi,
3.1 mmol); temperature (50 °C).
b The percent yield of MSA was calculated based on the initial amount of reactant.
c 13CH4 conversion (Conv.) was calculated based on the initial amount of 13CH4.
Table 2.11: H2SO4 and Oleum as a substitute for TFAOSO3H.[a] H2SO4 and oleum (fuming sulfuric
acid, 20% SO3) were investigated for their suitability as a reactant for methane sulfonation.
Another intriguing feature we discovered was the feasibility of the sulfonation of methane
gas not only in pressurized reactors (400 psi of 13CH4) but also in glass flasks (1 atm of 13CH4).
When the sulfonation was run under 1 atm of methane with 9.5 mol % of K2S2O8, the reaction
smoothly afforded MSA with 14% conversion of pre-prepared TFAOSO3H, suggesting the potential for a large-scale reaction for practical use by adopting continuous flow techniques, which will
be reported in due course.
47
2.4 Conclusion
In conclusion, we employed trifluoroacetyl sulfuric acid (TFAOSO3H) for the efficient sulfonation
of methane. The participation of a radical species on methane activation through C-H activation
was confirmed with studies on kinetic isotope effect and experiments with radical scavengers,
TEMPO and BHT. A new radical mechanism was revealed using the key intermediate, methyltrifluoroacetylsulfate radical 4 ((TFAO)CH3S(OH)O2•), indicating similar radical species CH3SO3•
would play a part in the previously reported methods. We hope our current study will contribute
to the ongoing endeavors in methane sulfonation, with a better understanding of their unclear
and debated mechanisms.
48
2.5 Experimental Section
2.5.1 Materials and Methods
Prior to the reaction, all glassware and reactors were dried in an oven. All chemicals were purchased from commercial providers and used without further purification. NMR spectra were
recorded on either a Varian Mercury 400 two-channel NMR spectrometer or a Varian VNMRS-500
two-channel NMR spectrometer. Acetonitrile (CH3CN) and 3-(trimethylsilyl)propionic-2,2,3,3-d4
acid sodium salt (TMSP-d4) were used as internal references for 1H NMR, and trifluoroacetic acid
(TFAOH) was used as an internal reference for 13C and 19F NMR spectra. The chemical shifts
are reported in δ (ppm) values with the 1H NMR reference of the TMSP-d4 signal (δ 0 ppm), and
coupling constants (J) are reported in hertz (Hz). For 13C NMR and 19F NMR, chemical shifts were
referenced to TFAOH (δ 116.6 ppm for 13C NMR and δ -76.55 ppm for 19F NMR).
2.5.2 General Procedure for Sulfonation of Methane Using TFAOSO3H
TFAOSO3H was prepared based on the previously reported method of mixing a 1:2.1 molar ratio
of H2SO4 and TFAA in an ice bath for 3 h.[8, 9] Then, in a closed stainless-steel reactor, a radical
initiator was added to a reaction mixture of 1:1:1 molar ratio of TFAOSO3H, TFAOH, and TFAA.
After being charged with 13CH4, the mixture was stirred at 50 °C for 18 h. After being quenched
with D2O, 1H NMR and 13C NMR spectra were taken using CH3CN and TMSP-d4 as internal
references. The percent yield of MSA was calculated based on the initial amount of TFAOSO3H.
13CH4 conversion was calculated based on the initial amount of 13CH4.
49
Methanesulfonic acid (
13MSA): 1H NMR (400 MHz, D2O) δ 2.89 (d, JC–H = 136.4 Hz, 3H); 13C
NMR (126 MHz, D2O) δ 40.0 (q, JC–H = 136.7 Hz).
Figure 2.12: 1H NMR Spectrum (400 MHz, D2O): Sulfonation of methane by Trifluoroacetylsulfuric Acid. Reaction conditions: Solvent, TFAOH : TFAA : TFAOSO3H = 1 : 1 : 1 (0.98 mL, 2.84
mmol); radical initiator K2S2O8 (9.5 mol% based on TFAOSO3H, 0.27 mmol); 13CH4 (400 psi, 3.1
mmol); temperature (50 °C); time (18 h).
50
2.5.3 Three Different Forms of Products Before Quenching the Reaction
: Methanesulfonyl Trifluoroacetic Anhydride (5),
Methanesulfonic Anhydride (MSAA, 6),
and Methanesulfonic Acid (MSA, 1)
Before quenching the reaction with water, products were observed in three different forms under
equilibrium. Reaction conditions: Solvent, TFAOH: TFAA: TFAOSO3H = 1: 1: 1 (0.98 mL, 2.84
mmol); radical initiator K2S2O8 (9.5 mol% based on TFAOSO3H, 0.27 mmol); 13CH4 (400 psi, 3.1
mmol); temperature (50 °C); time (2 h).
Methanesulfonic acid (MSA, 1)
:
1H NMR (400 MHz, TFAOH-d1): δ 2.89 (d, JC–H = 140.87 Hz, 3H). 13C NMR (101 MHz, TFAOH-d1):
δ 40.7 (q, JC–H = 140.9 Hz).
Methanesulfonyl trifluoroacetic anhydride (TFAOSO2CH3, 5)
:
1H NMR (400 MHz, TFAOH-d1): δ 3.10 (d, JC–H = 143.12 Hz, 3H). 13C NMR (101 MHz, TFAOH-d1):
δ 153.9 (q, JC–F = 47.9 Hz), 115.5 (q, JC–F = 284.2 Hz), 41.8 (q, JC–H = 142.6 Hz). 19F NMR (376 MHz,
TFAOH-d1): δ -75.6.
Methanesulfonic anhydride (MSAA, 6)
:
1H NMR (400 MHz, TFAOH-d1): δ 3.05 (d, JC–H = 142.13 Hz, 6H). 13C NMR (101 MHz, TFAOH-d1):
δ 42.5 (q, JC–H = 142.6 Hz).
51
2.5.4 Generation of MSF in Methane Sulfonation Reaction Conducted at
High Temperature
Side product, methanesulfonyl fluoride (MSF) was observed when the reactions were conducted
at high temperatures over 70 °C. Reaction conditions: TFAOH (2.84 mmol), TFAA (2.84 mmol),
TFAOSO3H (2.84 mmol), K2S2O8 (15.5 mol% based on TFAOSO3H, 0.44 mmol), and 13CH4 (400 psi,
3.1 mmol) were reacted in a stainless- steel reactor at 100 °C for 18 hours. 1 mL of D2O was added
to the reaction mixture and CH3CN and TMSP-d4 were used as internal references.
Methanesulfonyl fluoride (MSF): 1H NMR (400 MHz, D2O) δ 3.42 (dd, JC–H = 142.2 Hz, JH–F
= 5.7 Hz, 3H); 13C NMR (126 MHz, D2O) δ 37.5 (qd, JC–H = 142.3 Hz, 2
JC–F = 19.7 Hz); 19F NMR
(470 MHz, D2O) δ 59.1 (dq, 2
JC–F = 19.7 Hz, 3
JH–F = 5.8 Hz).
52
2.6 References
References for Chapter 2
[1] John C Snyder and Aristid V Grosse. Reaction of methane with sulfur trioxide. US Patent
2,493,038. 1950.
[2] Naomi Basickes, Terrence E Hogan, and Ayusman Sen. “Radical-initiated functionalization
of methane and ethane in fuming sulfuric acid”. In: Journal of the American Chemical Society
118.51 (1996), pp. 13111–13112. doi: 10.1021/ja9632365.
[3] Ayusman Sen and Minren Lin. Process for the conversion of methane. US Patent 7,119,226.
2006.
[4] Sudip Mukhopadhyay and Alexis T Bell. “A High-Yield Approach to the Sulfonation of
Methane to Methanesulfonic Acid Initiated by H2O2 and a Metal Chloride”. In: Angewandte
Chemie International Edition 42.26 (2003), pp. 2990–2993. doi: 10.1002/anie.200350976.
[5] Christian Díaz-Urrutia and Timo Ott. “Activation of methane: a selective industrial route
to methanesulfonic acid”. In: Science 363.6433 (2019), pp. 1326–1329. doi: 10.1126/science.
aav0177.
[6] Vladislav A Roytman and Daniel A Singleton. “Comment on “Activation of methane to
CH3
+
: A selective industrial route to methanesulfonic acid””. In: Science 364.6440 (2019),
eaax7083. doi: 10.1126/science.aax7083.
[7] Nima Zargari et al. “Unexpected, latent radical reaction of methane propagated by trifluoromethyl radicals”. In: The Journal of Organic Chemistry 81.20 (2016), pp. 9820–9825. doi:
10.1021/acs.joc.6b01903.
[8] Lindsey J Anderson et al. “Blocky Ionomers via Sulfonation of Poly (ether ether ketone) in
the Semicrystalline Gel State”. In: 51.16 (2018), pp. 6226–6237. doi: 10.1021/acs.macromol.
8b01152.
53
[9] Brian W Corby et al. “Clean-chemistry sulfonation of aromatics”. In: Journal of Chemical
Research 2002.7 (2002), pp. 326–327. doi: 10.3184/030823402103172329.
[10] Sidney W Benson. “Thermochemistry and kinetics of sulfur-containing molecules and radicals”. In: Chemical Reviews 78.1 (1978), pp. 23–35. doi: 10.1021/cr60311a003.
[11] Themba E Tyobeka, Richard A Hancock, and Helmut Weigel. “The interaction of hexafluoroacetic anhydride with methane sulphonic acid and with sulphuric acid”. In: Tetrahedron
44.7 (1988), pp. 1971–1978. doi: 10.1016/S0040-4020(01)90340-0.
[12] JW Hodgins and RL Haines. “The formation of trifluoromethyl radicals in the gas phase”.
In: Canadian Journal of Chemistry 30.6 (1952), pp. 473–481. doi: 10.1139/v52-057.
[13] Bhavin V Pipaliya and Asit K Chakraborti. “Cross-dehydrogenative coupling of heterocyclic
scaffolds with unfunctionalized aroyl surrogates by palladium (II) catalyzed C (sp2)-H aroylation through organocatalytic dioxygen activation”. In: The Journal of Organic Chemistry
82.7 (2017), pp. 3767–3780. doi: 10.1021/acs.joc.7b00226.
[14] Kapileswar Seth et al. “Palladium catalyzed C sp2–H activation for direct aryl hydroxylation: the unprecedented role of 1, 4-dioxane as a source of hydroxyl radicals”. In: Chemical
Communications 51.1 (2015), pp. 191–194. doi: 10.1039/C4CC06864E.
[15] Bhavin V Pipaliya, Kapileswar Seth, and Asit K Chakraborti. “Ruthenium (II) Catalyzed C
(sp2)- H Bond Alkenylation of 2-Arylbenzo [d] oxazole and 2-Arylbenzo [d] thiazole with
Unactivated Olefins”. In: Chemistry–An Asian Journal 16.1 (2021), pp. 87–96. doi: 10.1002/
asia.202001304.
[16] Bhavin V Pipaliya and Asit K Chakraborti. “Ligand-Assisted Heteroaryl C (sp2)- H Bond
Activation by a Cationic Ruthenium (II) Complex for Alkenylation of Heteroarenes with
Alkynes Directed by Biorelevant Heterocycles”. In: ChemCatChem 9.22 (2017), pp. 4191–
4198. doi: 10.1002/cctc.201701016.
54
[17] Kapileswar Seth et al. “The palladium and copper contrast: a twist to products of different chemotypes and altered mechanistic pathways”. In: Catalysis Science & Technology 6.9
(2016), pp. 2892–2896. doi: 10.1039/C6CY00415F.
[18] Kapileswar Seth, Sudipta Raha Roy, and Asit K Chakraborti. “Synchronous double C–N
bond formation via C–H activation for a novel synthetic route to phenazine”. In: Chemical
communications 52.5 (2016), pp. 922–925. doi: 10.1039/C5CC08640J.
55
Chapter 3
Novel Methane Activation by Sulfur Dioxide and Molecular
Oxygen via Trifluoroacetylsulfuric Acid
56
3.1 Abstract
Sulfur trioxide and sulfuric acid have been used for the conversion of methane (CH4) to methanesulfonic acid (MSA), whereas their precursor sulfur dioxide (SO2) has rarely been used. Herein,
we report a novel methane sulfonation method using SO2 and its newly explored free radical
mechanism. We developed practical conditions to transform SO2 to trifluoroacetyl sulfuric acid
(TFAOSO3H) by reacting with molecular oxygen in trifluoroacetic acid. At 50 °C, the resulting TFAOSO3H facilitates the carbon–hydrogen bond activation of methane to efficiently generate MSA via a radical mechanism with hydrogen peroxide as the radical initiator. As limiting
reagents, SO2 and CH4 were selectively converted to MSA in 74 and 95% yields, respectively.
Since the greenhouse gas CH4 and the toxic gas SO2 can be fully used to produce MSA as a valueadded transportable liquid product, this pragmatic one-pot two-step protocol would have great
significance in environmental and economical applications.
57
3.2 Introduction
Methane (CH4), the most copious but least reactive hydrocarbon among natural gases,[1] remains
a severe environmental problem not only due to massive flaring emitting enormous carbon dioxide, but also its noxiousness.[2] Because of its pernicious effect as a greenhouse gas, it captured
the attention of the scientific community and became a focal concern to develop new strategies.
To address this environmental challenge, the syngas generation/Fischer–Tropsch technique has
been used. However, due to its energy-demanding drawbacks, a new strategy for converting
methane into transportable liquid products such as methanol, formic acid, or methanesulfonic
acid (MSA) with enhanced efficiency is preferred.
Sulfur dioxide (SO2) is another noxious gas that contributes to air pollution as an indirect
greenhouse gas and causes acid rain which can destroy our ecosystems. In addition, it poses
harmful effects on the human respiratory system, causing breathing difficulties and chronic lung
diseases. According to the United States Environmental Protection Agency (EPA), SO2 is the most
harmful sulfur oxide (SOx) among others as it is the most concentrated gaseous SOx in the atmosphere and the precursor of other sulfur oxides.[3] There have been efforts to efficiently transform
SO2 into useful compounds such as sulfur trioxide (SO3) or sulfuric acid (H2SO4) for practical use.
Typically, SO2 is converted to SO3 by reacting with O2 in the presence of catalysts such as platinum or activated carbon through energy-intensive processes,[4] requiring the development of a
new cost-efficient sulfonation technique using SO2.
Various catalytic systems have been developed for the direct conversion of methane into alcohol derivatives, and yet it poses several challenges including low yields and further overoxidation of incipient products.[5–9] Unlike the alcohol derivatives, methanesulfonic acid (MSA),
58
which is less prone to overoxidation, emerged as an alternative methane functionalization product due to its various applications such as cleaning agents, electrolytes, and protecting groups in
pharmaceutical chemistry.[10, 11] Consequently, methane sulfonation has been well established
by predominantly using oleum (20% SO3, fuming sulfuric acid) as the sulfur source. For instance,
Sen and Bell developed efficient methods for methane sulfonation using oleum under radical conditions,[12, 13] while Diaz-Urrutia and Ott reported direct methane functionalization through a
cation chain reaction between SO3 and CH3
+ generated from the electrophilic hydride abstraction
of CH4.[14] However, research on the techniques using sulfur dioxide (SO2) is still an ongoing
process that requires further studies. For example, direct sulfonation of methane using SO2 has
been developed in the presence of inorganic additives such as Ca salts or Pd- with Cu-salts but
resulted in low yields.[15, 16]
In our previous studies, we discovered a methane sulfonation method using trifluoroacetylsulfuric acid (TFAOSO3H) through a radical pathway under mild conditions (reaction (a),
Scheme 3.1).[17] In the presence of radical initiators, the crude solution of TFAOSO3H, arising
Scheme 3.1: Methane sulfonation using trifluoroacetylsulfuric acid (TFAOSO3H) generated from
(a) sulfuric acid or (b) sulfur dioxide and molecular oxygen.
59
from H2SO4 or SO3, successfully converted methane to methanesulfonyl trifluoroacetic anhydride (TFAOSO2CH3) followed by hydrolysis upon quenching with water into methanesulfonic
acid (MSA) in 94 and 86% conversion of TFAOSO3H and CH4, respectively. Recently, we embarked
on the development of practical conditions to use SO2 and the subsequent methane functionalization (reaction (b), Scheme 3.1). Our extensive screening led to the optimal conditions to react
SO2 and O2 by employing the radical initiator trifluoroperacetic acid (TFAO-OH). Then, in situ
produced SO3 afforded TFAOSO3H, which effected methane sulfonation similarly to our earlier
study. When 20 mol% H2O2 was added to a TFAOH/TFAA solution, SO2, O2, and 13CH4 were successfully converted to MSA. This one-pot two-step synthesis at 50 °C yielded MSA selectively in
74% based on SO2 gas added in 18 h. From an environmental standpoint, this protocol to furnish
MSA with the consumption of two toxic gases, CH4 and SO2, is exceptionally irresistible. Furthermore, it allows us to overcome the known harsh conditions using SO2 by adopting a possible
radical mechanism, where we carried out an in situ activation of both methane and sulfur dioxide
at low temperatures without applying much energy.
60
3.3 Results and Discussion
3.3.1 Synthesis of Trifluoroacetylsulfuric Acid (TFAOSO3H) using
Sulfur Dioxide
Since we envisioned that the methane sulfonation reaction with SO2 would proceed via trifluoroacetylsulfuric acid (TFAOSO3H, 1) as the crucial intermediate, we first developed a practical
method as shown in Scheme 3.2 to convert SO2 to TFAOSO3H and confirmed its efficient synthesis. By mixing TFAA and aqueous H2O2, we generated a catalyst solution of trifluoroperacetic
acid (TFAO-OH), to which SO2 and O2 gases were charged in a high-pressure bomb. This reaction solution was heated at 50 °C for 16 hours to smoothly afford TFAOSO3H (1), and its structure
was elucidated by comparative NMR spectral analysis with the same product generated by exploiting two different known methods: (1) mixing H2SO4 and TFAA[17–19] and (2) using TFAOH
and SO3.[20] The main peak and pattern of the 19F NMR spectrum of the crude sample from our
new protocol with SO2 overlapped with that of each sample from the known methods, verifying the successful synthesis of TFAOSO3H (1). With the preparation of the reactive intermediate
confirmed, we subjected the crude product to the sulfonation of methane and obtained MSA successfully (vide infra).
Scheme 3.2: Facile preparation of trifluoroacetyl sulfuric acid (1). The formation of TFAOSO3H
was confirmed comparatively by 19F NMR spectral analysis between the previously reported
methods[18, 19] and our new technique using sulfur dioxide and molecular oxygen.
61
3.3.2 Proposed Mechanism for in situ Activation of Sulfur Dioxide and
Methane
A proposed mechanism for SO2 oxidation producing trifluoroacetylsulfuric acid (TFAOSO3H, 1)
is presented in Scheme 3.3. Peracid TFAO-OH (2) can undergo radical dissociation to produce
TFAO• (3) and the hydroxyl radical (•OH). The subsequent reaction of •OH and SO2 may furnish
the radical •SO3H (4), which then reacts with O2 to generate SO3 and •OOH (5).[21, 22] The
resultant •OOH radical (5) and TFAA would regenerate TFAO-OH (2), propagating the radical
cycle. Ultimately, the reaction between the produced SO3 and TFAOH can lead to the formation
of TFAOSO3H, which is readily capable of methane sulfonation via a free radical mechanism as
discussed in our previous work.[17]
Scheme 3.3: Rationale for mechanistic pathways to generate (a) trifluoroacetylsulfuric acid and
(b) its following methane sulfonation.
62
The methyl radical generated from CH4 and a radical initiator reacted with TFAOSO3H (1) to
produce the key radical intermediate 6 ((TFAO)CH3S(OH)O2•) (Scheme 3.4). Subsequent decomposition smoothly afforded TFAOSO2CH3 (7), which was hydrolyzed upon the addition of water
to complete the two-step process from SO2 and CH4 to MSA.
Scheme 3.4: Rationale for mechanistic pathways to generate (a) trifluoroacetylsulfuric acid and
(b) its following methane sulfonation.
63
3.3.3 Determination of Optimal Reaction Conditions
We further investigated the initially optimized conditions for possible higher efficiency by carrying out the one-pot conversion of both SO2 and CH4 to MSA. When the reaction was set up,
all the reagents, gases, and solvents were placed in a closed stainless-steel reactor having a highpressure valve: SO2, O2, and 250 psi of 13CH4 gases were charged to a solution of TFAOH/TFAA
containing catalytic amounts of H2O2. After an 18-hour reaction at 50 °C, MSA was the predominant isotopically-labeled product in a 74% conversion yield based on the added SO2 (Table 3.1).
Only negligible amounts of byproducts were observed, suggesting the high selectivity of this
sulfonation method using SO2.
entry Temperature (°C) H2O2 (mol %) MSA (yield %)[b] Conv. (%, CH4)
1 50 15 67.6 15.0
2 50 20 74.3 16.5
3 60 15 73.1 12.9
4 60 20 75.2 18.5
a Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL); H2O2 (15-
20 mol% based on SO2, 0.11-0.15 mmol); SO2 (40 psi, 0.73 mmol); O2 (30 psi,
0.12 mmol); 13CH4 (200 psi, 3-3.3 mmol); time (18 h).
b The percent yield of MSA was calculated based on SO2.
Table 3.1: Methane sulfonation by using SO2 and O2.
[a]
64
While a typical reaction was conducted for 18 hours, over 90% of the maximum yield was
achieved within 2 hours (Table 3.2).
entry Time (h) MSA (yield %)[b] Conv. (%, CH4)
1 2 36.6 17.0
2 4 37.9 17.7
3 6 38.7 18.0
4 8 40.0 18.6
5 18 40.1 18.7
a Reaction conditions: Solvent, TFAA (0.6 mL); H2O2
(21 mol% based on SO2, 0.27 mmol); SO2 (80 psi, 1.3
mmol); O2 (50 psi, 0.2 mmol); 13CH4 (200 psi, 2.8
mmol); temperature (50 °C).
b The percent yield of MSA was calculated based on
SO2.
Table 3.2: Time study.[a]
65
Furthermore, the activation of SO2 and CH4 was successful at low temperatures such as 40 °C;
however, raising the temperature over 70 °C led to a decrease in MSA percent yields (Figure 3.1).
Regardless of the amount of the catalyst, MSA formation was optimal at around 50–60 °C.
Figure 3.1: Successful activation of sulfur dioxide and methane at various (a) trifluoroperacetic
acid concentrations and (b) temperatures. MSA percent yields were based on SO2. (a) Reaction
conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL); H2O2 (× 0.03 mmol, 4 mol% based on
SO2; ◦ 0.15 mmol, 20 mol%); SO2 (40 psi, 0.73 mmol); O2 (× 20 psi, 0.07 mmol; ◦ 30 psi, 0.12 mmol);
13CH4 (200 psi, 3.3–3.4 mmol); time (18 h).
66
To probe the significance of molecular oxygen in the reaction, we ran the reactions with and
without O2 under various concentrations of TFAO-OH. When O2 was excluded from the typical
reaction conditions, the percent yield of MSA diminished drastically (Figure 3.2 △) compared to
the conditions with oxygen (Figure 3.2 □). Moreover, additional amounts of TFAO-OH such as
50 mol% or higher did not lead to a meaningful increase in the generation of MSA in the absence
of O2, implying that TFAO-OH is not an O2 surrogate. Likewise, in the presence of 10 mol% O2,
excess amounts of TFAO-OH did not lead to higher yields, while 15–40 mol% TFAO-OH appeared
as the optimal concentrations (Figure 3.2 □). These results indicate that molecular oxygen would
function as a key reactant to be incorporated into the final product. Thus, TFAO-OH would not be
able to replace O2 as a reactant, playing a restricted role primarily as a radical initiator/propagator.
Figure 3.2: Successful activation of sulfur dioxide and methane at various (a) trifluoroperacetic
acid concentrations and (b) temperatures. MSA percent yields were based on SO2. (b) Reaction
conditions: Solvent, TFAA (0.6 mL); H2O2 (0.03–1.2 mmol, 4–160 mol% based on SO2); SO2 (40 psi,
0.73 mmol); 13CH4 (200 psi, 3 mmol); temperature (50 °C); time (18 h); O2 (□ 20 psi, 0.07 mmol, 10
mol% based on SO2) or △ without SO2.
67
3.3.4 Optimal Ratio of Sulfur Dioxide and Molecular Oxygen
Molecular oxygen behaved as a reactant in the TFAOSO3H generation, but it acted as an inhibitor
in methane sulfonation,[17] preventing the increase in O2 concentration over a certain extent. As
illustrated in Figure 3.3, the optimal ratio of SO2 and O2 was sought by varying the amounts of SO2
and O2 in the presence of a catalyst—0.027 mmol TFAO-OH (1 mol% based on CH4). Upon raising
the O2 concentration gradually, MSA yields increased up to a certain point and then decreased
distinctly for all three tested concentrations of SO2. More O2 was required to reach the maximum
yield as we increased the SO2 concentration, yet the molar ratio of SO2 and O2 for each peak at
Figure 3.3: Yields of MSA under various ratios of sulfur dioxide and molecular oxygen. MSA
percent yields were based on SO2. Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3
mL); H2O2 (0.027 mmol); SO2 (◦ 0.73 mmol, △ 1.3 mmol, □ 1.9 mmol); O2 (9–80 psi, 0.03–0.36
mmol); 13CH4 (200 psi, 2.8 mmol); temperature (50 °C); time (18 h).
68
which the reaction gave the highest yield remained the same regardless of the amount of SO2
(SO2:O2 = 10:1).
However, the optimal ratio of SO2 and O2 changed when the TFAO-OH concentration was
increased from 0.027 mmol (1 mol% CH4) to 0.27 mmol (10 mol% CH4). Similar to the aforementioned experiments, the percent conversion continuously grew until it reached the peak and then
diminished (Figure 3.4 and Table 3.3), while more O2 was required for the optimal yield, resulting
in a comparatively higher ratio of O2 (SO2/O2 = 3.7). This substantial increase in the amount of
Figure 3.4: Determination of the optimal ratio of sulfur dioxide and molecular oxygen at various
trifluoroperacetic acid concentrations. The optimal ratios of SO2 and O2 indicating the highest
MSA yields were determined by the concentration of TFAO-OH. MSA percent yields were based
on SO2. Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL); H2O2 (◦ 0.027 mmol,
⋄ 0.27 mmol); SO2 (0.73 mmol); O2 (0–80 psi, 0.03–0.36 mmol); 13CH4 (200 psi, 2.8 mmol); temperature (50 °C); time (18 h).
69
O2 required to reach the maximum yield suggested the significance of the radical initiator in determining the optimal ratio between SO2 and O2 during methane sulfonation, and the importance
of radical species in the initial step generating TFAOSO3H from SO2 is described in Scheme 3.3.
0.73 mmol SO2 1.3 mmol SO2 1.9 mmol SO2
No O2 9.7 % 5.6 % 3.4 %
20 psi O2 (0.07 mmol) 38 % 19 % 11%
30 psi O2 (0.12 mmol) 54 % 27 % 18 %
50 psi O2 (0.20 mmol) 64 % 40 % 26 %
80 psi O2 (0.36 mmol) 31 % 46 % 46 %
a Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL);
H2O2 (0.27 mmol); 13CH4 (200 psi, 3 mmol); temperature (50 °C); time
(18 h).
b The MSA yield was calculated based on SO2 added.
Table 3.3: Optimal ratio between sulfur dioxide and molecular oxygen during methane sulfonation conducted with 0.27 mmol trifluoroperacetic acid.[a][b]
70
3.3.5 Significance of High Pressure and Anhydrous Conditions
Similar to our previous studies, the application of TFAA was proved to be crucial for the optimal
conditions as it could behave as a dehydrating reagent, removing newly generated water during
methane sulfonation. Prior to aqueous quenching, the generation of MSA was confirmed by 1H
NMR spectral analysis (Figure 3.5), implying that the hydrolysis of anhydride products, methanesulfonyl trifluoroacetic anhydride TFAOSO2CH3 (7) and methanesulfonic anhydride (MSAA, 8)
took place during the reaction.
Figure 3.5: 1H NMR spectrum. Three different forms of products were generated by the methane
sulfonation method using SO2 before quenching: methanesulfonyl trifluoroacetic anhydride (7),
methanesulfonic anhydride (MSAA, 8), and methanesulfonic acid (MSA).
71
Since the inhibiting effect of water was verified with the decreased yields, (Table 3.4), addition
of an adequate amount of TFAA was necessary to prevent the inhibition.
entry H2O2 (mol %) Reaction solution MSA (yield %)[c]
1 20 Absence of TFAA (TFAOH only as a solvent) 32.8
2
[b] 20 Application of additional 2 µL of water 6.8
a Reaction conditions: Solvent, TFAA (0.122 mL); H2O2 (20 mol% based on SO2, 0.15
mmol); SO2 (40 psi, 0.73 mmol); O2 (30 psi, 0.12 mmol); 13CH4 (200 psi, 3 mmol); temperature (50 °C); time (18 h).
b Additional water was applied to the reaction mixture (0.002 mL, 0.11 mmol).
c The percent yield of MSA was calculated based on SO2.
Table 3.4: Effects of anhydrous condition with the use of TFAA.[a]
By adding an inert gas such as N2 to increase the overall pressure of the bomb reactors and
the solubility of the gases, we observed a trend towards higher conversion yields for both SO2
and CH4 compared to the reaction conducted without N2. It resulted in percent conversions of
around 50% for both gases when they were employed in similar amounts (Table 3.5).
entry H2O2 (mol %) Final pressure (psi) MSA (yield %)[b] Conv. (%, CH4)
1 15 58 psi with CH4 33.0 45.2
2 20 59 psi with CH4 33.1 46.2
3 15 400 psi with N2 48.7 56.0
4 20 420 psi with N2 47.3 54.5
a Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL); H2O2 (15-20
mol% based on SO2, 0.11-0.15 mmol); SO2 (40 psi, 0.73 mmol); O2 (30 psi, 0.1
mmol for entry 1-2, 0.04 mmol for entry 3-4); 13CH4 (0.5-0.6 mmol); temperature (50 °C); time (18 h).
b The percent yield of MSA was calculated based on SO2.
Table 3.5: Effects of higher pressure in methane sulfonation.[a]
72
Furthermore, when methane (26 mol% of SO2) was used as a limiting reagent with the use of
additional N2 gas, methane conversion went up to 95% based on methane (Table 3.6). In contrast,
methane conversion was less than 20% when SO2 was used as a limiting reagent presumably
because the overall pressure dropped as the reaction progressed. These results suggested that
high pressure would be crucial for the in situ activation of methane and SO2 and the addition
of inert gases would maintain high pressure to allow for the complete consumption of either or
both reacting gases.
entry H2O2 (mol %) N2 (psi) MSA (yield %)[b] Conv. (%, CH4)
1 15 230 23.2 93.6
2 20 210 24.5 94.6
a Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL);
H2O2 (20 mol% based on SO2, 0.15 mmol); SO2 (40 psi, 0.73 mmol);
O2 (30 psi, 0.04 mmol); 13CH4 (0.18-0.19 mmol); N2 (∼230 psi); temperature (50 °C); time (18 h).
b The percent yield of MSA was calculated based on SO2.
Table 3.6: High methane conversion yields.[a]
73
3.3.6 Radical Initiator: H2O2 vs. K2S2O8
To confirm the radical mechanism of the reaction, additional experiments were conducted without a radical initiator or with a radical scavenger (TEMPO, BHT) (Table 3.7). In all cases, only
negligible amounts of MSA were observed if detected at all. It was a significant decrease in MSA
generation compared to the reaction employing typical reaction conditions, indicating the free
radical mechanism of this methane sulfonation.
entry H2O2 (mol %) Radical Scavenger[b] MSA (yield %)[c] Conv. (%, CH4)
1 20 - 74.3 16.5
2 - - 0 0
3 20 20 mol% TEMPO 3.3 0.7
4 20 20 mol% BHT 0 0
a Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3 mL); H2O2 (20
mol% based on SO2, 0.15 mmol); SO2 (40 psi, 0.73 mmol); O2 (30 psi, 0.12 mmol);
13CH4 (200 psi, 3-3.3 mmol); time (18 h).
b
20 mol% based on SO2.
c MSA percent yields were based on SO2.
Table 3.7: Comparison between two different radical initiators, hydrogen peroxide and potassium
persulfate, in methane sulfonation using sulfur dioxide at various temperatures.[a]
After we confirmed the radical characteristic of the reaction, we compared the commonly
used K2S2O8 with H2O2 as a radical initiator in the one-pot activation of SO2 and CH4. Under
the typical SO2 reaction conditions at 50 °C, 74% MSA yield was observed with H2O2 as the radical initiator (Table 3.8, entry 1), while only 0.1% yield of MSA was detected when K2S2O8 was
used (Table 3.8, entry 2). However, at temperatures over 70 °C, K2S2O8 was able to produce MSA,
albeit in a slightly lower yield compared to the reaction conducted with H2O2 (entries 3 and 4).
Unlike TFAO-OH induced by H2O2, K2S2O8 would not be able to produce a hydroxyl radical at
74
entry Radical Initiator Temperatures (°C) MSA (yield %)[b]
1 H2O2 50 74.3
2 K2S2O8 50 0.1
3 H2O2 70 66.0
4 K2S2O8 70 51.4
5 H2O2 100 36.6
6 K2S2O8 100 50.6
a Reaction conditions: Solvent, TFAOH (0.3 mL) and TFAA (0.3
mL); H2O2 or K2S2O8 (20 mol% based on SO2, 0.15 mmol); SO2
(40 psi, 0.73 mmol); O2 (30 psi, 0.115 mmol); 13CH4 (200 psi, 3.3
mmol); time (18 h).
b MSA percent yields were based on SO2.
Table 3.8: Comparison between two different radical initiators, hydrogen peroxide and potassium
persulfate, in methane sulfonation using sulfur dioxide at various temperatures.[a]
low temperatures, which is crucial for the generation of TFAOSO3H from SO2. Due to the lack
of hydroxyl radicals at relatively low temperatures, methane sulfonation employing SO2 in the
presence of K2S2O8 was viable only at high temperatures (Table 3.8, entry 6), while higher temperatures caused the decomposition of radical species in methane sulfonation with H2O2 leading to
lower yield (Table 3.8, entry 5). Moreover, the generation of the inorganic salt potassium bisulfate
(KHSO4) as a byproduct was inevitable when K2S2O8 was employed. In contrast, H2O2 produces
water, which only leads to the generation of TFAOH by reacting with TFAA and the production
of MSA by hydrolysis of TFAOSO2CH3. Considering all these factors, TFAO-OH generated from
H2O2 would be the most suitable radical initiator for the intended methane functionalization at
low temperatures using SO2 and O2 via trifluoroacetylsulfuric acid.
75
3.4 Conclusion
Reported herein is the coupling of the three gaseous components methane, sulfur dioxide, and
molecular oxygen to efficiently produce methanesulfonic acid (MSA) under mild conditions. Trifluoroacetylsulfuric acid (TFAOSO3H), a key intermediate for methane functionalization, was successfully generated from sulfur dioxide and molecular oxygen under radical conditions and then
reacted with methane to produce MSA efficiently. Sulfur dioxide and methane were converted to
MSA in comparatively high yields at temperatures as low as 50 °C without requiring much energy.
Furthermore, when methane was employed as a limiting reagent, near-complete consumption of
methane was observed. These one-pot two-step procedures for converting two harmful gases,
CH4 and SO2, into a transportable and valuable liquid, MSA, would contribute to the broad efforts in tackling environmental issues
76
3.5 Experimental Section
3.5.1 Materials and Methods
Trifluoroacetic anhydride (TFAA), aqueous hydrogen peroxide (30% solution), sulfur dioxide,
molecular oxygen, and 13C-labeled methane (13CH4) were purchased from commercial providers,
and oven-dried reactors and glassware were employed for the reactions. 1H, 13C, and 19F NMR
spectra were recorded on a Varian Mercury 400 two-channel NMR spectrometer or a Varian
VNMRS-500 two-channel NMR spectrometer. The chemical shifts were reported in δ (ppm) values with the coupling constants (J) in hertz (Hz). Acetonitrile (CH3CN) and 3-(trimethylsilyl)
propionic-2,2,3,3-d4 acid sodium salt (TMSP-d4) were used as internal references for the 1H NMR
spectrum while trifluoroacetic acid (TFAOH) was used as an internal reference for 13C and 19F
NMR spectra (δ 116.6 ppm for 13C NMR and δ -76.6 ppm for 19F NMR).
3.5.2 General Procedure and Analysis for Methane Sulfonation using
Sulfur Dioxide and Molecular Oxygen
A radical initiator, H2O2, was added to an oven-dried 0.5 dram vial containing 0.3 mL of TFAOH
and TFAA each. The reaction mixture in a closed stainless-steel reactor was cooled down to -78
°C in a dry ice bath and charged with SO2, O2, and CH4. The mixture was stirred at 50–60 °C for
18 hours. After quenching with D2O, 1H NMR and 13C NMR spectra were recorded using CH3CN
and TMSP-d4 as internal references. The percent yield of methanesulfonic acid (MSA) and CH4
conversion (Conv.) were calculated based on the initial amount of SO2 and CH4, respectively.
77
3.5.3 NMR Analysis
3.5.3.1 Generation of trifluoroacetylsulfuric acid (TFAOSO3H)
After the reaction mixture containing TFAA, TFAOH, H2O2, SO2 and O2 was stirred at 50 °C for
16 h, TFAOSO3H was extracted with DCM-d2 for NMR analysis. TFAOH, TFAA and H2O diluted
in DCM-d2 were added separately to distinguish the observed peaks from each other. Depending
on the amount and the ratio of TFAOH and TFAOSO3H, TFAOH and TFAOSO3H peaks shifted,
however, the pattern between TFAOSO3H, TFAOH, and TFAA remained the same in 19F NMR
(Figure 3.6).
Figure 3.6: Generation of trifluoroacetylsulfuric acid (TFAOSO3H): 19F NMR spectrum (470 MHz,
DCM-d2)
78
3.5.3.2 Unknown peak at 2.92 ppm
In Figure 3.5, we identified 7, 8, and MSA; however small peaks at 3.18 and 2.82 ppm were not
elucidated unambiguously. However, we conducted the experiments using isotopically-unlabeled
MSAA (8) and obtained NMR spectra as shown here. We identified 7 and 8 along with MSA in
these solvent systems, and observed a minor peak at 2.92 ppm, which would correspond with
the small peaks at 3.18 and 2.82 ppm in the previous experiment and its NMR spectrum. Thus
we speculate the peak at 2.92 ppm as one of the methanesulfonic anhydride derivative such as
(trifluoromethyl sulfuric) methanesulfonic anhydride which was hydrolyzed to provide MSA after
work-up (Figure 3.7).
Figure 3.7: Unknown peak at 2.92 ppm: 1H NMR spectrum (400 MHz, TFAOH-d1): Reaction
conditions: (A) When methanesulfonic anhydride (8) was added to the solution of 0.3 mL TFAD
and 0.2 mL TFAA, the formation of 7 was detected to exhibit 7 and 8. (B) When 3 µL of H2O2
was added to the solution of (A), no peak was observed at around 2.92 ppm. (C) When 10 µL of
TFAOSO3H was added to the solution of (A), a small peak around 2.92 ppm was detected.
79
3.6 References
References for Chapter 3
[1] Stephen J Blanksby and G Barney Ellison. “Bond dissociation energies of organic molecules”.
In: Accounts of chemical research 36.4 (2003), pp. 255–263.
[2] Katherine Bourzac. “Methane cuts could slow extreme climate change”. In: Chem. Eng. News
99.39 (2021), pp. 28–33.
[3] United States Environmental Protection Agency (EPA). Sulfur Dioxide Basics. https://www.
epa.gov/so2-pollution/sulfur-dioxide-basicsre-duce. Accessed: July 2022.
[4] Naonobu KATADA et al. “Oxidation of sulfur dioxide to sulfuric acid over activated carbon catalyst produced from wood”. In: Journal of the Japan Petroleum Institute 46.6 (2003),
pp. 392–395.
[5] Roy A Periana et al. “Catalytic, oxidative condensation of CH4 to CH3COOH in one step
via C-H activation”. In: Science 301.5634 (2003), pp. 814–818.
[6] Minren Lin, Terrence Hogan, and Ayusman Sen. “A highly catalytic bimetallic system for
the low-temperature selective oxidation of methane and lower alkanes with dioxygen as
the oxidant”. In: Journal of the American Chemical Society 119.26 (1997), pp. 6048–6053.
[7] Lien Chung Kao, Alan C Hutson, and Ayusman Sen. “Low-temperature, palladium (II)-
catalyzed, solution-phase oxidation of methane to methanol derivative”. In: Journal of the
American Chemical Society 113.2 (1991), pp. 700–701.
[8] Giovanni Ingrosso and Nicola Midollini. “Palladium (II)-or copper (II)-catalysed solutionphase oxyfunctionalisation of methane and other light alkanes by hydrogen peroxide in trifluoroacetic anhydride”. In: Journal of Molecular Catalysis A: Chemical 204 (2003), pp. 425–
431.
80
[9] Michael Muehlhofer, Thomas Strassner, and Wolfgang A Herrmann. “New catalyst systems
for the catalytic conversion of methane into methanol”. In: Angewandte Chemie International Edition 41.10 (2002), pp. 1745–1747.
[10] Abraham E Mathew et al. “Synthesis and evaluation of some water-soluble prodrugs and
derivatives of taxol with antitumor activity”. In: Journal of medicinal chemistry 35.1 (1992),
pp. 145–151.
[11] CTJ Low and FC Walsh. “Electrodeposition of tin, copper and tin–copper alloys from a
methanesulfonic acid electrolyte containing a perfluorinated cationic surfactant”. In: Surface and Coatings Technology 202.8 (2008), pp. 1339–1349.
[12] Naomi Basickes, Terrence E Hogan, and Ayusman Sen. “Radical-initiated functionalization
of methane and ethane in fuming sulfuric acid”. In: Journal of the American Chemical Society
118.51 (1996), pp. 13111–13112.
[13] Sudip Mukhopadhyay and Alexis T Bell. “A High-Yield Approach to the Sulfonation of
Methane to Methanesulfonic Acid Initiated by H2O2 and a Metal Chloride”. In: Angewandte
Chemie International Edition 42.26 (2003), pp. 2990–2993.
[14] Christian Díaz-Urrutia and Timo Ott. “Activation of methane: a selective industrial route
to methanesulfonic acid”. In: Science 363.6433 (2019), pp. 1326–1329.
[15] Sudip Mukhopadhyay and Alexis T Bell. “Direct sulfonation of methane to methanesulfonic
acid with SO2 using Ca salts as promoters”. In: Journal of the American Chemical Society
125.15 (2003), pp. 4406–4407.
[16] Sudip Mukhopadhyay and Alexis T Bell. “Direct catalytic sulfonation of methane with SO2
to methanesulfonic acid (MSA) in the presence of molecular O2”. In: Chemical communications 13 (2003), pp. 1590–1591.
[17] Sungah Kim et al. “Methane Sulfonation via a Free-Radical Mechanism by Trifluoroacetylsulfuric Acid”. In: The Journal of Organic Chemistry 87.15 (2022), pp. 10539–10543.
81
[18] Lindsey J Anderson et al. “Blocky Ionomers via Sulfonation of Poly (ether ether ketone) in
the Semicrystalline Gel State”. In: Macromolecules 51.16 (2018), pp. 6226–6237.
[19] Brian W Corby et al. “Clean-chemistry sulfonation of aromatics”. In: Journal of Chemical
Research 2002.7 (2002), pp. 326–327.
[20] Bert H Bakker and Hans Cerfontain. “Sulfonation of alkenes by chlorosulfuric acid, acetyl
sulfate, and trifluoroacetyl sulfate”. In: European journal of organic chemistry 1999.1 (1999),
pp. 91–96.
[21] Yoan Dupart et al. “Mineral dust photochemistry induces nucleation events in the presence
of SO2”. In: Proceedings of the National Academy of Sciences 109.51 (2012), pp. 20842–20847.
[22] Yu-Ping Kuo, Bing-Ming Cheng, and Yuan-Pern Lee. “Production and trapping of HOSO2
from the gaseous reaction OH+ SO2: the infrared absorption of HOSO2 in solid argon”. In:
Chemical physics letters 177.2 (1991), pp. 195–199.
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Chapter 4
Hydrogen-Deuterium Isotope Exchange of Methane via
Non-redox Palladium Catalysism
83
4.1 Abstract
Under mild conditions, Pd(II) catalysts coordinated to tridentate NHC-amidate ether ligand successfully activated the carbon-hydrogen bond to facilitate the hydrogen/deuterium isotope exchange on methane. The structural features and catalytic behavior suggested an intriguing nonredox catalytic system derived from the amidate nitrogen. As the amidate nitrogen acts as an
internal base, the metal center was able to maintain the oxidation state throughout the reaction. Accordingly, the catalytic system demonstrated its reactivity and stability during the H/D
exchange on methane resulting in a high degree of deuterium conversions (44%) and turnover
number (346) under low temperature conditions.
84
4.2 Introduction
The significance of isotopic labeling has increased with various usage in drug discoveries and
developments,[1–4] analytical detection,[5] structural analysis,[6] and mechanistic studies for
catalyst and reaction pathways.[7] The conventional synthetic routes including the use of isotopically labeled precursors have been utilized successfully,[6, 8] however, exploration of a new
pathway with a low-risk, cost-efficient procedure is essential, considering the high cost of an
isotopically labeled starting material easily lost during long synthesis. Among others, the direct
exchange of hydrogen and deuterium atoms is one of the most studied and well-constructed methods as a rapid and cost-effective way of preparing isotopically labeled compounds since it could
be implemented in the late intermediate stage of synthesis.[9] Moreover, hydrogen-deuterium exchange (H/D exchange) can also probe the possibility of carbon-hydrogen bond activation (C-H
activation) for further functionalization.
Replacement of a hydrogen bonded to carbon by its heavier isotope can be done by one of
the oldest methods: acid/base catalyzed reactions. Nevertheless, metal catalysts are preferable
due to their mild conditions, high regioselectivity, diverse options for solvent, and high tolerance
of functional groups.[9] Consequently, efficient methods of H/D isotope exchange via transition
metal catalysis on aromatics and alkanes have been established since the 1960s.[10–19] It demonstrates the opportunity for direct functionalization of hydrocarbons via C-H bond activation as
well. Among other alkanes, methane is one of the most intriguing hydrocarbons to conduct C-H
activation due to its specific feature as the most abundant but least reactive component in natural
gas. There has been great progress in developing organometallic species for C-H bond activation
on methane;[20, 21] however, challenges remain with its unusually high C-H bond strength. With
85
that in mind, we embarked on the development of a novel catalyst. We accomplished facile H/D
exchange on methane via a novel tridentate N-heterocyclic carbene (NHC) ligand-Pd complex,
offering the potential for efficient methane functionalization.
In our previous research, our group developed a water-stable catalyst 1 (Scheme 4.1) and
clarified its structural analogs by elucidating its structures via single crystal x-ray crystallographic studies.[22] Our previously reported N-heterocyclic carbene (NHC)-amidate-ether palladium complexes have a highly electron-rich metal center due to the strong σ-donating ability of the N-heterocyclic carbene and the amidate nitrogen providing an additional σ-donating
chelation. Compared to other known Pd catalysts, these ligands furnished a stronger trans effect
allowing our catalysts to react more efficiently. We applied our catalyst to C-H activation and
confirmed the ability of our Pd(II) catalysts in facile H/D exchange on several different hydrocarbons.[23]
Scheme 4.1: Pd catalyst of NHC-amidate-ether ligand and its activation method.
As we prepared the activated catalyst 2 by removing the chloride ligand using silver salts
(Scheme 4.1), H/D exchange on benzene was initially studied with 2a among several different
86
motifs of our NHC Pd (II) catalyst. The high efficiency in deuterium incorporation was only
observed at high temperatures, as described in Table 4.1 (entries 1–2). When we extended the
structural motifs to various tridentate ligands, 2b exhibited superior results regardless of the
temperatures (Table 4.1, entries 3–4). Experimentally, 2b resulted in 95% conversion at low and
high temperatures, showing enhanced catalytic efficacy. Furthermore, 2b demonstrated its capability in H/D exchange on various organic substrates. For instance, cyclohexane was transformed
to its deuterated form with 93% deuterium content, where the catalytic turnover reached 536 at
a mild temperature (55°C). Aromatic hydrocarbons, such as toluene, were also facile in the H/D
exchange, providing up to 87% deuterium content.[23]
entry Catalyst Catalyst conc. (mol %) Temp. (°C) D-incorporation (%)[b]
1 2a 5 55 20
2 2a 5 100 83
3 2b 1.7 55 96
4 2b 1.7 100 95
a Reactions were carried out in a J-Young NMR tube with the reaction mixture
containing 20 µL of benzene, the palladium catalyst, and 700 µL of deuterium
oxide.
b 1H NMR determined the deuterium incorporation.
Table 4.1: H/D exchange of benzene in D2O.[a]
87
4.3 Results and Discussion
4.3.1 NMR Studies with Isotopically Labelled Pd Species 3
To further investigate the mechanism of the NHC-amidate-ether ligated Pd(II) catalyst during
H/D exchange and to confirm its stability during the reaction, spectral analyses using NMR and
IR techniques were employed. When the structurally well-defined complex 1a was synthesized
with isotopic labeling and prepared as 3 with 15N (Figure 4.1), distinct evidence of amide proton
was observed upon treating with water.
Figure 4.1: Coupling patterns of Pd catalyst 3 around 15N atom.
88
Even though there could be other competing sites where protonation may occur, we observed
the anionic nitrogenous ligand in the catalyst behaving as an internal base to facilitate the traffic
of protons, while the neutral Pd complex was converted to its amide form. According to protoncoupled 15N NMR, an isotopically labeled nitrogen peak at -261 ppm was detected as a doublet
(Figure 4.1, JN-H=90.0 Hz; coupling mode a), while only a singlet was observed on the {1H}15N
NMR spectrum. (Figure 4.2)
Figure 4.2: {1H}15N NMR (top) and 1H-coupled 15N NMR (bottom) spectra (40.5 MHz, CD3CN) of
15N-labeled complex 3.
89
Further evidence was observed in the 1H NMR. Due to additional 15N-H coupling (coupling
mode a, Figure 4.1), the amide proton at 6.72 ppm appeared as a doublet of doublets (JN-H=90.1
Hz and JH-H=9.2 Hz). (Figure 4.3) Considering the fact that 6.72 ppm peak appeared as a doublet
(JH-H=9.2 Hz) from the unlabeled complex 1a,[22] these spectral features indicated the protonation occurred on the nitrogen atom, instead of the oxygen of the carboxamide.
Figure 4.3: 1H NMR spectrum (400 MHz, CD3CN) of 15N-labeled Pd complex 3.
90
Structural integrity during the protonation/deprotonation was determined with {1H}13C NMR
techniques. (Figure 4.4) The carbene carbon on complex 3 exhibited a doublet with the coupling
constant JC-N=1.1 Hz (coupling mode d, Figure 4.1).
Figure 4.4: 13C NMR spectrum (62.9 MHz, CD3CN) of 15N-labeled complex 3.
The small two-bond coupling between the carbene carbon and the isotopically labeled amide
nitrogen suggested the weak coordination of 15N to the Pd center, indicating a fairly long bond
length and a bonding angle ∠
15N-Pd-C of close to 90 degrees. Furthermore, the NMR spectra
showed almost identical patterns during the protonation/deprotonation besides the N-H peaks
and their neighboring methylene protons. This conformity indicates that the nitrogen atom
would still be bound to the Pd center in both amide and amidate forms, aligning explicitly with
the reported precedents.[24–26] Accordingly, our catalysts demonstrated notable stability in both
protonated and neutral forms.
91
4.3.2 Spectral Analysis for Protonated and Deprotonated Forms of Pd
Complexes
4.3.2.1 IR analysis
Scheme 4.2: Protonated and deprotonated forms of the Pd(II) catalyst and their IR frequencies.
Similarly to the derivative form 1a, the amidate nitrogen on Pd catalyst 1b was protonated
easily in the presence of water to produce the amide form 4 (Scheme 4.2). Two amide compounds,
Pd species 4 (Figure 4.5) and its free ligand 6 (Figure 4.6) exhibited similar wavelengths at ∼1670
cm-1 for C=O stretch along with the strong NH peaks on IR spectra. The amidate form 1b (Figure 4.7), however, did not produce any NH peaks while presenting a significantly shifted C=O
frequency at 1567 cm-1. The IR spectral analysis clearly implied the presence of two different
catalyst forms: amidate 1b and amide 4 species.
92
Figure 4.5: IR spectroscopy of 4
Figure 4.6: IR spectroscopy of 6
Additionally, this IR data established the structural integrity of the Pd catalyst 1b during the
reaction. There are two possible coordination modes with a neutral amide ligand: either with a
nitrogen atom or a carbonyl oxygen atom. Due to the possible delocalization of nitrogen lone pair
electrons, it would be more favorable for an amide ligand to form O-coordination to the metal
center. In this case, significant changes in IR frequency compared to free ligands are expected as
93
Figure 4.7: IR spectroscopy of 1b
the v(CO) band shifts at least 30 cm-1 to lower energies depending on the electronic properties of
the conjugated system.[27–29] In our case, however, only a minute difference in v(CO) between
catalyst 4 and the free ligand 6 was observed (+2 cm-1). It conforms with the precedent examples
of Pd complexes where the nitrogen atom on the amide ligand was bound to the Pd center,[26]
demonstrating the structural notability of our Pd catalyst with the N-chelated amide ligand.
94
4.3.2.2 NMR analysis
Further evidence was observed from the NMR spectra. On the 1H NMR spectra, a new amide
proton on 4 was observed at 7.10 ppm as a broad triplet in CD3CN. (Figure 4.8) It disappeared
upon adding 4 Å molecular sieves as it reverted to its neutral form 1b (Scheme 4.2). (Figure 4.9 -
Figure 4.10)
Figure 4.8: 1H NMR spectrum (400 MHz, CD3CN) of complex 4 with BF4-. To a reaction solution
of 1b (15.5 µmol) in 0.5 mL of CD3CN, HBF4 (1 equiv.) was added. Protonated structure 4 was
obtained upon the addition and analyzed with 1H NMR spectrum.
95
Figure 4.9: 1H NMR spectrum (400 MHz, CD3CN) of compound 1b. To a 0.5 dram vial having Pd
complex 4 (6 mg, 15.5 µmol) in 0.5 mL CH3CN solution, 10 mg of molecular sieves were added.
Then the reaction mixture was stirred for 16 hours. According to 1H NMR spectra, the ratio
between 4 and 1b was 1:1.
96
Figure 4.10: 13C NMR spectrum (100.5 MHz, CD3CN) of compound 1b.
97
Moreover, the amide proton on catalyst 4 demonstrated facile deuterium exchange at room
temperature. When the catalyst was subjected to deuterated solvent (D2O), immediate changes in
both the 1H and 2D NMR spectra were observed. (Figure 4.11 - Figure 4.12) As the amide proton
peak at 7.10 ppm diminished, a deuterated amide peak emerged, indicating a deuterated intermediate 5. NMR patterns other than the amide peak remained the same, or only a negligible change
was observed. This dynamic feature inferred by spectral analysis addressed variable structures
of our Pd(II) catalysts and their significant roles in the applicable proton-deuterium exchange,
which we already confirmed with various organic substances.[23]
Figure 4.11: 1H NMR spectrum (400 MHz, CD3CN) of compound 5. The reaction solution of 0.5
mL CD3CN with 6 mg of 4 (15.5 µmol) was prepared in a NMR tube, and 50 µL of D2O (0.833
mmol) was added. On 1H NMR, N-H signal at 7.1 ppm disappeared in 10 minutes.
98
Figure 4.12: 2H NMR spectrum (61.4 MHz, CD3CN) of compound 5. As the N-H signal at 7.1 ppm
disappeared in 10 minutes on 1H NMR, singlet at 7.3 ppm developed on 2H NMR spectrum as time
goes by.
99
4.3.3 NMR Studies: Monitoring H/D Exchange in J. Young Tubes
Since the structural stability and efficacy of our water-stable Pd(II) in H/D exchange with several
organic substances were confirmed, we extended the research to gaseous hydrocarbons, particularly on methane. As the H/D exchange on methane was carried out in J. Young NMR tubes
with the most efficient catalyst 2b, the reaction progress was monitored by NMR. After dissolving the catalyst 2b in D2O, the J. Young NMR tube was charged with methane (1 atm) and
heated at 60 °C. 1H and 2H NMR spectra were acquired every hour, and proton and deuterium
peak concentration for methane was analyzed by comparing the peak with an internal standard,
poly(dimethylsiloxane) (PDS) in a capillary tube.
100
Figure 4.13: H/D exchange of methane in J. Young NMR tubes monitored by (A) 1H and (B) 2H
NMR. Reaction condition: 2b (15.5 µmol), AgBF4 (46.5 µmol), D2O (0.6 mL), CH4 (1 atm), temperature (60 °C); Poly(dimethylsiloxane) (PDS) was used as an external reference. Over 6 hours,
44% decrease of the CH4 signal was observed on 1H NMR spectra. H/D conversions (%) were
determined every 2 hours up to 6 h: % (2 hours), 42% (4 hours), 44% (6 hours). Formation of black
precipitates was first observed within 1 hour. As the reaction progressed, a gradual increase in
black precipitates was detected.
Over time, the proton peak gradually diminished (Figure 4.13, spectra A) as the corresponding
deuterium peak increased proportionally (Figure 4.13, spectra B). The overall catalysis for the potential C-H activation was facile at a low temperature, producing approximately 44 % deuterium
incorporation on methane with a catalytic turnover of 12. The catalysis began to slow after 6 h
as the concentration of methane decreased and the activated catalyst 2b possibly decomposed.
101
4.3.4 Proposed Mechanism for Methane H/D Exchange via Pd Catalyst
Via structural studies and spectral analysis, we could determine the significant role of amidate
nitrogen during the reaction, and its application for C-H activation was discovered in the mechanistic pathway illustrated in Scheme 4.3.
Scheme 4.3: Potential mechanism of H/D exchange: participation of the amidate nitrogen atom
allowing the metal to maintain the oxidation state.
After activating the catalyst using silver salt, AgBF4, 2b may undergo coordination with
methane to form the intermediate 7. Then, the proton would be transferred from the methane to
the amidate nitrogen on the catalyst to produce Pd-Me species 8. Unlike the typical oxidation or
reduction reaction observed in most coupling reactions,[30, 31] the amidate nitrogen would allow
the metal to remain in the same oxidation state during this step as it works as an internal base,
facilitating C-H activation. Finally, the formation of deuterated complex 9 via H/D exchange followed by the elimination of methyl group through deuterium transfer would produce deuterated
methane and regenerate 2b to keep the catalytic cycle going.
102
4.3.5 Comparative Studies: Pd Catalysts Under Acidic Conditions
In order to determine the competency of our catalyst, other known Pd catalysts were screened
under acidic conditions. Most of them exhibited around 10 % of deuterium conversion in the
presence of HBF4 (Table 4.2, entries 1-4). However, the same result was observed without any
catalyst (Table 4.2, entry 5), suggesting a background reaction of H/D isotope exchange in the
presence of HBF4. Unlike HBF4, p-toluenesulfonic acid (p-TsOH) could not show any conversions
(Table 4.2, entry 6). On the other hand, 1b validated its superior capacity in C-H activation by
presenting twice as high of a deuterium conversion yield as other palladium catalysts, either
with HBF4 or p-TsOH (Table 4.2, entries 7-8). When AgBF4 was introduced to all the tested Pd
catalysts, activated catalyst 2b produced a greater increase in D-incorporation (44 %, Table 4.2,
entry Catalyst Acid H/D conversions (%)[b]
1 Pd(OAc)2 HBF4 9.5
2 Pd(TFA)2 HBF4 8.0
3 PdCl2(PPh3)2 HBF4 9.4
4 PdCl2(CH3CN)2 HBF4 10
5 - HBF4 8.5
6 - p-TsOH -
7 1b HBF4 19.7
8 1b p-TsOH 19.9
9
[c] 1b - 44
a All reactions were performed with the Pd catalyst (15.5 µmol, except for
entries 5-6), acid (31 µmol for entries 1-6, 15.5 µmol for entries 7-9), D2O
(0.6 mL), and CH4 (1 atm).
b 1H NMR spectral analysis was used to calculate the H/D conversions.
c
Instead of acid, AgBF4 (46.5 µmol) was employed to activate the catalyst.
Table 4.2: Pd catalyst screening with various acids.[a]
103
entry 9) whereas other Pd catalysts in entries 1-4 exhibited negligible extents of H/D exchange.
This demonstrated the significance of activation in catalytic reactivity.
4.3.6 Optimization: H/D Exchange Under Various Conditions
By varying the conditions, we increased the catalytic productivity and produced higher TON
using our Pd complex 2b (Scheme 4.4).
Scheme 4.4: H/D exchange of methane under various conditions. Reaction conditions for (2)∼(4):
Activated catalyst, 2b (15.5 µmol) was dissolved in D2O (0.6 mL), then added to a high-pressure
reactor bomb. After charging the reactor bomb with 400 psi of CH4, the reaction was run for 16
h.
When H/D exchange was conducted under 400 psi of methane atmosphere in a closed stainless steel reactor bomb with a high-pressure valve, a substantial increase in TON was observed
due to the high pressure and increased methane concentration (Scheme 4.4 (2)). Various forms of
methane CDnH4-n (n=0∼4) were detected by GC/MS (CH3D : CD2H2 : CD3H : CD4 = 5.0 : 8.4 : 3.5
: 2.6), indicating multiple isotope exchange between hydrogen and deuterium atom via catalytic
104
cycle. Unlike previous work on benzene and other organic substrates, a higher temperature at
100 °C did not show a similar efficiency as low temperatures (Scheme 4.4 (3)). Additionally, we
demonstrated that the concentration of the deuterium source was not a critical factor in H/D
exchange. When acetonitrile with 5 % D2O was utilized as a reaction solvent, it afforded a higher
TON of 200, even at 100 °C (Scheme 4.4 (4)). Regardless of the abundance of the deuterium source
present in the solvent, the reaction employing acetonitrile as a cosolvent was 2.5 times more efficient than the reaction conducted only in D2O as both a solvent and a reagent, implying the
significance of the solvent choice for enhanced catalytic efficiency. By preventing the excessive
use of deuterated solvents, these conditions would provide a practical method for the H/D exchange of methane.
105
4.4 Conclusion
In conclusion, our novel catalysts showed intriguing capability in C-H activation of methane
by demonstrating its ability to conduct H/D exchange at relatively low temperatures. Our Pd(II)
catalysts showed unique and stable structural features while maintaining the same oxidation state
during the catalysis through protonation and deprotonation. This distinctive non-redox catalytic
process derived from amidate functionality would enlighten a new way of C-H activation and
facilitate the subsequent methane functionalization, including oxidation and sulfonation.
106
4.5 Experimental Section
4.5.1 Materials and Methods
Commercially available reagents and solvents were obtained from Aldrich and Acros chemical
and used without further purification. 1H NMR spectra was recorded on a 250 MHz Bruker 250
AC, 400 MHz Varian Mercury, or 400 MHz Varian-MR; 2H NMR spectra was recorded on a 61
MHz Varian-MR; 13C NMR spectra was recorded on a 63 MHz Bruker 250AC, 100.5 MHz Varian
Mercury, or 100.5 MHz Varian-MR; 15N NMR spectra was recorded on a 40.5 MHz Varian-MR. The
chemical shifts were reported in δ (ppm) values relative to TMS for 1H- and 13C- NMR spectra and
CH3NO2 (external standard) for 15N NMR spectra. GC/MS analysis was performed on a Shimadzu
GC-MS QP 5000 (ver. 2) equipped with a cross-linked methyl silicone gum capillary column (DB5).
IR spectra have been collected with FT/IR - 4100 type A by JASCO.
4.5.2 General Procedure and Analysis for H/D Exchange on Methane
using Pd Catalyst
For the activation, palladium catalyst 1 (15.5 µmol) and AgBF4 (3 equiv.) were stirred in 2 mL
of CH3CN for 30 minutes. The resulting suspension was passed through a celite column, and
the filtrate was dried in vacuo for further use. The activated catalyst 2 was dissolved in 0.6
mL of D2O and transferred to a J-Young NMR tube with a sealed capillary tube containing poly
(dimethylsiloxane) (PDS) in C6F6. After evacuating the head space of the NMR tube by a freezepump-thaw procedure three times, the head space was charged with 1 atmosphere of CH4 for the
reaction. The reaction mixture was heated at 60 °C for 6 h. H/D exchange on CH4 was monitored
107
by decreasing patterns of CH4 signals at 0.2 ppm on 1H NMR spectra, and H/D conversions (%)
were calculated by using the external reference, PDS.
4.5.3 General Procedure for H/D Exchange on Methane under
High Pressure
After stirring a reaction mixture of 1b (15.5 µmol) and 3 equivalents of AgBF4 in 2 mL of CH3CN
for 30 minutes, the resulting solution was passed through a celite column. The filtrate was dried
in vacuo and dissolved in 0.6 mL of D2O. The solution was transferred to a stainless-steel reactor
equipped with a high-pressure valve, and the reactor was pressurized to 400 psi using CH4. The
reactor was placed on a pre-heated aluminum block at 60 °C and stirred for 16 h. After cooling
down to ambient temperatures, CH4 was analyzed by GC/MS spectral analysis.
4.5.4 Deprotonation of Pd Complex 4 using NaOCH3
50 mg of 4 with BF4
-
(0.129 mmol) was dissolved in 30 mL of THF, and 27 mg of NaOCH3 (0.5
mmol) was added. After stirring the reaction mixture for 1 hour, salts were removed by celite
column, and the filtrate was dried in vacuo.
1H NMR (400 MHz, CD3CN): δ 7.58 ppm (m, 2 H),
7.39 (m, 2 H), 4.83 (s, 2 H), 4.20 (s, 3 H), 3.56 (s, 3 H), 3.52 (t, J = 5.5 Hz, 2 H), 3.40 (t, J = 5.6 Hz, 2
H); 13C NMR (101 MHz, CD3CN): δ 162.9, 154.5, 131.9, 130.8, 121.9, 121.6, 109.4, 109.0, 75.7, 59.7,
52.1, 45.7, 35.2
108
4.6 References
References for Chapter 4
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[8] Heyi Zhang and Hugo van Ingen. “Isotope-labeling strategies for solution NMR studies of
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[10] JL Garnett and RJ Hodges. “Homogeneous Metal-catalyzed isotopic hydrogen exchange
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[11] John L Garnett and RJ Hodges. “Homogeneous metal-catalyzed exchange of aromatic compounds. Isotopic hydrogen labeling procedure”. In: Journal of the American Chemical Society
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[12] John L Garnett et al. “Iridium (III) salts as homogeneous metal catalysts for hydrogen isotope exchange in organic compounds: a comparison with heterogeneous iridium for the
deuteriation of alkylbenzenes”. In: Journal of the Chemical Society, Chemical Communications 19 (1973), pp. 749–750.
[13] M. R. Blake et al. “Rhodium trichloride as a homogeneous catalyst for isotopic hydrogen
exchange. Comparison with heterogeneous rhodium in the deuteriation of aromatic compounds and alkanes”. In: J. Chem. Soc. Chem. Commun. (1975), pp. 930–932. doi: 10.1039/
C39750000930.
[14] Roy A Periana and Robert G Bergman. “Isomerization of the hydridoalkylrhodium complexes formed on oxidative addition of rhodium to alkane carbon-hydrogen bonds. Evidence for the intermediacy of. eta. 2-alkane complexes”. In: Journal of the American Chemical Society 108.23 (1986), pp. 7332–7346.
[15] NF Goldshleger et al. “Activation of saturated hydrocarbons-deuterium-hydrogen exchange
in solutions of transition metal complexes”. In: Russian Journal of Physical Chemistry 43.8
(1969), pp. 1222–1223.
[16] N. F. Gol’dshleger et al. “Alkane reactions in solutions of chloride complexes of platinum”.
In: Russian Journal of Physical Chemistry 46 (1972), pp. 785–786.
110
[17] Mark E. Thompson et al. “σ-Bond metathesis for carbon-hydrogen bonds of hydrocarbons and Sc-R (R = H, alkyl, aryl) bonds of permethylscandocene derivatives. Evidence
for noninvolvement of the π system in electrophilic activation of aromatic and vinylic
C-H bonds”. In: Journal of the American Chemical Society 109.1 (1987), pp. 203–219. doi:
10.1021/ja00235a031.
[18] A. E. Shilov. “In Activation and Functionalization of Alkanes”. In: Activation and Functionalization of Alkanes. Ed. by C. L. Hill. New York: Wiley, 1989.
[19] A. E. Shilov. Activation and Functionalization of Saturated Hydrocarbons. Dordrecht: Riedel,
1984.
[20] Roy A Periana et al. “Perspectives on some challenges and approaches for developing the
next generation of selective, low temperature, oxidation catalysts for alkane hydroxylation
based on the C-H activation reaction”. In: Journal of Molecular Catalysis A: Chemical 220.1
(2004), pp. 7–25.
[21] Karen I Goldberg and Alan S Goldman. “Activation and Functionalization of C-H Bonds”.
In: Activation and Functionalization of C-H Bonds. Washington D. C.: Oxford University
Press, 2004, pp. 1–43.
[22] Satoshi Sakaguchi et al. “Chiral Palladium (II) Complexes Possessing a Tridentate N-Heterocyclic
Carbene Amidate Alkoxide Ligand: Access to Oxygen-Bridging Dimer Structures”. In: Angewandte Chemie International Edition 47.48 (2008), pp. 9326–9329.
[23] Joo Ho Lee et al. “An Air/Water-Stable Tridentate N-Heterocyclic Carbene-Palladium (II)
Complex: Catalytic C–H Activation of Hydrocarbons via Hydrogen/Deuterium Exchange
Process in Deuterium Oxide”. In: Advanced Synthesis & Catalysis 351.4 (2009), pp. 563–568.
[24] Jr. Lee J. C. et al. “Complexation of an amide to iridium via an iminol tautomer and evidence
for an Ir–H...H–O hydrogen bond”. In: J. Chem. Soc., Chem. Commun. 8 (1994), pp. 1021–
1022.
111
[25] Jesse C Lee Jr et al. “An Unusual Coordination Mode for Amides: Lone-Pair Binding via
Nitrogen”. In: Inorganic Chemistry 34.25 (1995), pp. 6295–6301.
[26] Soonheum Park et al. “Synthesis and chemistry of new complexes of palladium (0) and platinum (0) with chelating phosphine amide ligands. X-ray structure of cis-bis
(o-diphenylphosphino)-N-benzoylanilino) palladium (II”. In:Organometallics 5.7 (1986), pp. 1305–
1311.
[27] Gregorio Sánchez et al. “New pentafluorophenyl complexes with phosphine-amide ligands”. In: Inorganica chimica acta 359.5 (2006), pp. 1650–1658.
[28] Martin Lamac et al. “Preparation of chiral phosphinoferrocene carboxamide ligands and
their application to palladium-catalyzed asymmetric allylic alkylation”. In: Organometallics
26.20 (2007), pp. 5042–5049.
[29] Martin Lamač, Ivana Císařová, and Petr Štěpnička. “Synthesis, Coordination and Catalytic
Utility of Novel Phosphanyl–ferrocenecarboxylic Ligands Combining Planar and Central
Chirality”. In: European Journal of Inorganic Chemistry 2007.16 (2007), pp. 2274–2287. doi:
10.1002/ejic.200700093.
[30] Kunihiko Murata et al. “Deprotonation of organic compounds bearing acid protons promoted by metal amido complexes with chiral diamine ligands leading to new organometallic compounds”. In: Organometallics 21.2 (2002), pp. 253–255.
[31] Datong Song and Robert H Morris. “Cyclometalated tridentate CNN ligands with an amine
or amido donor in platinum (II) and palladium (II) complexes and a novel potassium alkoxide aggregate”. In: Organometallics 23.19 (2004), pp. 4406–4413.
112
Chapter 5
Efficient Methane Activation via Novel Pd-NHC Catalysis:
Synthesis of Methyl Trifluoroacetate as a Protected
Methanol Derivative
5.1 Abstract
An oxidative C-H activation method was developed with the utilization of the novel Pd-Nheterocyclic carbene (NHC) catalysts, converting methane to methyl trifluoroacetate efficiently
and chemoselectively. Through mechanistic studies, the significance of minimizing undesired
side reactions including over-oxidation and radical catalysis was demonstrated. Accordingly, the
employment of K2S2O8 in TFA/TFAA suppressed the background radical pathway, and the NHCPd catalysts facilitated the oxidation of methane with a high turnover number (TON) of 154 under
the optimal conditions.
113
5.2 Introduction
Methane contributes significantly to climate change as one of the largest anthropogenic climateforcing factors in modern history.[1] With the rapid industrial development, the concentration of
atmospheric methane continued to grow due to its increased emission.[2] Along with its abundance, the radiative efficiency and strong warming potential of methane exceeds that of carbon
dioxide as a noxious greenhouse gas.[3] Due to its serious impact on our environment, several
research studies have been dedicated to the functionalization of methane, such as the oxidation of
methane via C-H activation, converting it to value-added chemicals.[4–20] By using Pd(II) sulfate,
the Periana group carried out the oxidative condensation of methane in sulfuric acid at elevated
temperatures (180 °C), generating acetic acid in the process.[19] Sen and others utilized hydrogen
peroxide with a commercially available Pd(II) catalyst and successfully developed a methane oxidation method.[21] Additionally, further advances in methane functionalization were established
by Strassner and Herrmann with Pd-N-heterocyclic carbene (NHC) complexes.[22–24] Upon the
use of K2S2O8 as an oxidizing agent, bis-NHC Pd(II) catalysts produced methyl trifluoroacetate
(MeOTFA) with a TON of 30.[22] The additional stability of the Pd complexes conferred by NHC
ligands has proven them suitable for C-H activation.[22–31]
Our previous research showcased a NHC-Pd complex 2 in a distinctive catalytic system for CH activation on methane.[32] Under mild conditions, our novel catalysts facilitated the hydrogendeuterium isotope exchange (H/D Exchange) on various hydrocarbons.[32, 33] The Pd (II) complex 2 showed catalytic productivity and achieved a high TON of 346 in a high-pressure reactor
while using D2O as both a solvent and a reagent (Scheme 5.1). Even under an ambient atmosphere, 44% of deuterium incorporation into methane was achieved. Furthermore, additional
114
Scheme 5.1: Pd catalysts of NHC-amidate-ether ligand and H/D exchange of methane.
spectral analysis confirmed the non-redox catalytic role of the Pd(II) complex during the reaction.
Through facile protonation and deprotonation on the anionic nitrogenous ligand, the catalyst 2
maintained a constant Pd(II) oxidation state while preserving its structural stability throughout
the reaction. Consequently, the successful development of the Pd catalysis system for efficient
H/D exchange under mild conditions illustrated its potential for C-H activation in the functionalization of methane. Recently, our group expanded the application of our Pd catalysts to oxidative
functionalization, successfully producing MeOTFA from methane. Under the high-pressure conditions, two different forms of NHC-Pd complexes were examined and our Pd-catalyzed oxidative
functionalization technique offered competent catalytic efficacy with high TONs.
115
5.3 Results and Discussion
5.3.1 Prevention of Over-oxidation by Generating Methyl Ester
To further investigate the Pd-NHC catalytic system, we performed a study on the oxidation of
methane along with the exploration of its mechanistic pathway. Under mild temperature conditions, the H/D exchange reaction was conducted in heavy water as both a solvent and a deuterium
source, which produced a high degree of deuterium incorporation.[32] Meanwhile, the oxidation
process conducted under the same conditions but in the presence of oxidants produced challenges, such as over-oxidation of its products due to their higher reactivities compared to that of
methane. To avoid this problem, a mixture of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) was utilized since the generation of methyl esters was able to prevent the further
oxidation on produced methanol. However, over-oxidation of MeOTFA occurred during extended
reaction hours, catalyzed by Pd(II) species as well.[21] Accordingly, comprehensive optimization
was performed on metal-catalyzed methane oxidation to minimize the side reactions including
over-oxidation.
116
5.3.2 Minimizing Background Radical Reaction through Oxidant
Optimization
On top of the solvent system, the use of proper oxidant is one of the essential features that governs
the oxidation reaction. H2O2 is a widely used oxidizing agent in previous methane oxidations;
however, background radical pathways caused in the TFAA/H2O2 system led to the generation of
acetic acid.[34] As a result, when Pd catalyst 1 was subjected to the precedent oxidation condition
using H2O2 in TFA/TFAA,[21] only a small amount of MeOTFA was detected, while acetic acid
or formic acid was confirmed as the major product (Table 5.1, entry 1). Higher yield of acetic
acid compared to MeOTFA emphasized the compatibility of H2O2 as a radical initiator rather
than the oxidizing reagent in metal catalysis. Furthermore, excessive amounts of H2O2 did not
lead to an increase in the desired product (Table 5.1, entries 2-4). It only affected the generation
of over-oxidized side products, such as formic acid, due to water being present in the reaction
mixture.
Yields (TON)b
entry H2O2 (equiv.) 3 + 4 5 6
1 100 5.7 19.5 1.5
2 200 3.6 1.3 12.4
3 400 1.6 1.1 10.0
4 800 1.0 0.7 5.3
a Reaction conditions: solvent TFA:TFAA = 3:1 (0.4 mL); Pd catalyst 1 (0.5 mg, 0.001 mmol);
13CH4 (400 psi); oxidants (H2O2, 100-800 equiv., 0.1-1 mmol); temperature (60 °C); time (16
h); b 1H NMR spectral analysis was used to calculate the TONs.
Table 5.1: Effects of H2O2 concentrations on the efficiency of Pd catalysis.a
117
On the contrary, when potassium persulfate (K2S2O8) was employed, a higher turnover of the
desired product was observed, demonstrating increased efficiency (Table 5.2, entries 1-2). Acetic
acid and formic acid were detected as side products from a background radical reaction and overoxidation yet in comparatively small amounts. Other oxidants, such as H2SO4, oxone, NaBO3,
KMnO4, and HNO3, were examined through systematic screening for methane oxidation with Pd
catalyst (Table 5.2, entries 3-7), but all showed efficiencies inferior to that of K2S2O8. In addition,
a substantial drop in MeOTFA formation was observed with the higher yield of acetic acid when
K2S2O8 was supplemented by H2O2 (Table 5.2, entry 8). This result corroborated the engagement
of the background radical reaction, competing with the desired metal-catalyzed oxidative reaction
facilitated by K2S2O8, and resulted in a great amount of side products.
Yields (TON)b
entry oxidant (400 equiv) 3 + 4 5 6
1 H2O2 2.2 0.8 12.0
2 K2S2O8 154 < 0.1 < 0.1
3 H2SO4 2.0 - -
4 Oxone 32.8 15.3 < 0.1
5 KMnO4 18.7 0.5 -
6
c NaBO3 2.5 19.5 1.8
7 HNO3 - - -
8
d K2S2O8 13.7 27.1 2.5
a Reaction conditions: solvent TFA:TFAA = 3:1 (0.4 mL); Pd catalyst 1 (0.5 mg, 0.001 mmol);
13CH4 (400 psi); oxidants (400 equiv., 0.5 mmol); temperature (100 °C); time (16 h); b 1H
NMR spectral analysis was used to calculate the TONs; c
100 equiv. of NaBO3 was used; d
Supplemental 50 equiv. of H2O2 was added in the reaction.
Table 5.2: Determination of proper oxidant for methane oxidation generating MeOTFA.a
118
5.3.3 Significance of Restraining the Radical-catalyzed Side Reactions
Along with the over-oxidation of products, side reactions inhibiting desired metal-catalyzed
methane oxidation was another problem. To achieve optimal oxidation conditions with higher
yield, figuring out possible side reactions was essential. As illustrated in Scheme 5.2, inclusion
of TFAA and H2O2 produced trifluoroperacetic acid (TFAOOH) to facilitate the radical reaction
generating acetic acid. Decreased yield on methane oxidation conducted with both K2S2O8 and
H2O2 confirmed its obstructive influence on the desired oxidative pathway (Table 5.2, entry 8).
Scheme 5.2: Precedent methane functionalization via radical catalysis (a) generating acetic acid
from TFAA and H2O2.
Furthermore, sulfonation via free-radical pathways inhibited the generation of desired products as well. In our previous research, we reported that trifluoroacetylsulfuric acid (TFAOSO3H),
which was generated from various sulfur sources such as H2SO4 and SO2, promoted direct sulfonation of methane via a free radical mechanism (Scheme 5.3).[35, 36] Both radical reactions
Scheme 5.2 and Scheme 5.3 were specialized in producing either acetic acid or methanesulfonic
acid (MSA), however, addition of such reagents to the Pd-catalysis obstructed the desired oxidation.
Scheme 5.3: Precedent methane functionalization via radical catalysis (b) conducting methane
sulfonation by using trifluoroacetylsulfuric acid (TFAOSO3H).
119
Similar to the aforementioned reaction in Table 5.2, entry 8, simultaneous methane functionalization of both oxidation and sulfonation failed to yield favorable outcomes (Table 5.3). When
H2SO4 was applied to the standard oxidative condition using K2S2O8 (Table 5.3, entries 1-2) under 200 psi methane condition, a decrease in MeOTFA+MeOH (3 + 4) formation was observed,
highlighting its adverse impact on the desired reaction. Likewise, the addition of SO2 and O2 as
additives yielded underwhelming results on the functionalization of methane (Table 5.3, entries
3-5). Due to the gradual in situ generation of TFAOSO3H from SO2,[36] slight increase in both
oxidation (3, 4) and sulfonation products (7 - 9) was observed in entry 5 compared to other entries in Table 5.3. Still, it exhibited a lower TON in oxidation compared to studies conducted only
under metal-mediated oxidative conditions, and also underscored the diminished productivity in
Additives Yields (TON)b
entry H2SO4 (µL) SO2 (psi) O2 (psi) 3 + 4 5 6 7 - 9
1 - - - 95.3 < 0.1 < 0.1 -
2 13 - - 18.2 0.6 0.3 8.4
3 - - 25 2.0 < 0.1 < 0.1 -
4 - 15 - 3.5 2.1 1.0 61.5
5 - 15 25 41.0 8.5 0.3 218
a Reaction conditions: solvent TFA:TFAA = 3:1 (0.4 mL); Pd catalyst 1 (0.5 mg, 0.001 mmol);
13CH4 (200 psi); oxidants (K2S2O8, 800 equiv., 1 mmol); temperature (100 °C); time (16 h); b
1H NMR spectral analysis was used to calculate the TONs.
Table 5.3: Reduced productivity of the metal catalyzed oxidation due to addition of TFAOSO3H
generating reagent as additives.a
120
methane sulfonation compared to the experiment performed in similar free-radical conditions
without metal catalysts. These results indicated the participation of the side reactions through
free-radical mechanisms via TFAOOH and TFAOSO3H, hindering the desired oxidation pathway
mediated by Pd catalysts. Accordingly, better catalytic yields were achieved with the enhanced
chemoselectivity when the background radical pathway was suppressed.
121
5.3.4 Development of the Solvent System
: Significance of Anhydrous Condition
Further studies demonstrated a significant impact of the solvent system on the performance of
our catalyst in respect of over-oxidation. The TFA/TFAA solvent system was required to produce
methyl ester, which would prevent methanol from being over-oxidized. Consequently, the inclusion of water in the system decreased the yield of MeOTFA substantially (Table 5.4) due to the
hydrolysis of MeOTFA into methanol, exposing them to further oxidation.
Yields (TON)b
entry H2O (µL) 3 + 4 5 6
1 10 2.9 1.7 15.1
2 50 3.3 1.4 16.6
a Reaction conditions: solvent TFA (0.4 mL); Pd catalyst 1 (0.5 mg, 0.001 mmol); 13CH4 (400
psi); oxidants (K2S2O8, 400 equiv., 0.5 mmol); temperature (60 °C); time (16 h); b 1H NMR
spectral analysis was used to calculate the TONs.
Table 5.4: Consequence of additional water in the oxidation conditions for Pd-catalyzed C-H
activation.a
122
Additionally, a certain amount of TFAA was vital to assist the anhydrous condition of the reaction, which was confirmed through a study varying the ratio between TFA and TFAA (Table 5.5).
However, considering the participation of TFA in the coupling reaction, excessive amounts of
TFAA in the finite volume of reaction solvent was detrimental (Table 5.5, entry 5-6), suggesting
the optimal ratio between TFA and TFAA as four to one (TTable 5.5, entry 2).
entry TFA:TFAAb 3 + 4 (TON)c
1 5:1 60.8
2 4:1 152
3 3:1 130
4 1:1 117
5 1:3 21.6
6 1:9 4.8
a Reaction conditions: Pd catalysts (0.5 mg, 0.001 mmol); 13CH4 (310
psi); oxidants (K2S2O8, 400 equiv., 0.5 mmol); temperature (60 °C); time
(16 h); b Total volume of the reaction solution was kept as 0.4 mL; c 1H
NMR spectral analysis was used to calculate the TONs.
Table 5.5: Influence of the solvent ratio between TFA and TFAA in Pd catalyzed methane
oxidation.a
123
5.3.5 Proposed Mechanistic Pathway for Methane Oxidation
: Formation of MeOTFA
As we expect that the Pd species would experience activation under the reaction conditions (i.e.,
high temperature in acidic media) generating active catalyst 10, both catalysts (1 and 2) may
follow a similar mechanistic pathway. Accordingly, a proposed mechanism for methane oxidation via Pd catalysis is illustrated in Scheme 5.4. The active catalyst 10 would undergo oxidative
addition to coordinate with methane and TFA, producing intermediate 11. After reductive elimination, yielding CH3OTFA, intermediate 10 could be regenerated to sustain the catalytic cycle.
Scheme 5.4: Proposed mechanistic pathway generating MeOTFA via Pd catalysis
124
5.3.6 Comparison Between Two Different NHC-Pd Complexes 1 and 2
In our previous H/D exchange studies, two forms of NHC-Pd complexes have been predominantly
utilized: 1 and its active form 2. Catalyst 2 was verified as an efficient catalyst for H/D exchange in
various hydrocarbons due to the facile protonation and deprotonation of the amidate nitrogen.[32,
33] Furthermore, the open site derived in 2 which was crucial for its coordination to methane for
further coupling demonstrated the adequate catalyst 2 for H/D exchange. However, unlike H/D
exchange reactions, better catalytic performance was observed with 1 in methane oxidation due
to the rapid decomposition and poor stability of 2 in current oxidation conditions (Table 5.6, entry
2-3).
Yieldsb
entry Catalysts CH4 (psi) 3 + 4
1 - 400 5.63 µmol -
2 1 400 99.4 µmol 154 TON
3 2 400 39.5 µmol 61 TON
a Reaction conditions: solvent TFA:TFAA = 3:1 (0.4 mL); Pd catalysts (0.5 mg);
oxidants (K2S2O8, 140 mg, 0.5 mmol); temperature (100 °C); time (16 h); b 1H NMR
spectral analysis was used to calculate the TONs.
Table 5.6: Comparison between catalyst 1 and 2 for their performance on methane oxidation.a
125
5.3.7 Single-crystal X-ray Diffraction: Discovery of an Actual Structure
of NHC-Pd Complex 1
However, we finally discovered the structure of the Pd complex 1 which was different from
what we had expected. According to single-crystal X-ray Diffraction (XRD), 1 had monodentate NHC ligand chelated to the Pd center, resulting trans-[Pd(NHC)Cl2(CH3CN)] (Scheme 5.5
and Figure 5.1). In consequence, further mechanistic studies should be followed to confirm its
corresponding intermediates and possible reaction pathway for methane oxidation using the catalysts.
Scheme 5.5: Pd complex 1. trans-[Pd(NHC)Cl2(CH3CN)]
126
Figure 5.1: ORTEP style plot of the single-crystal structure of Pd catalyst 1.
127
5.4 Conclusion
In summary, methane, emitted from various sources, including anthropogenic and natural
sources, is a significant contributor to climate change as a potent greenhouse gas. Due to environmental concerns, the scientific community has been heavily invested in devising a effective
method to functionalize methane into value-added chemicals. Reported herein is the coupling of
methane and TFA via Pd catalysis to effectively produce methyl trifluoroacetate (MeOTFA) as a
protected methanol derivative, offering reduced susceptibility to undesired oxidation.
Two different forms of NHC-Pd complexes were employed as possible candidates for methane
oxidation. Implication of the TFA/TFAA anhydrous solvent system established the significance
of the proper solvent in suppressing over-oxidation. Furthermore, through extensive screening, K2S2O8 emerged as the optimal oxidizing agent for the Pd-catalyzed oxidation of methane,
while reduced reactivity was observed upon adding H2O2, SO2, or H2SO4 to the optimal reaction
condition. This result confirmed the inhibiting effects on the desired metal-catalyzed methane
oxidation due to the radical catalysis via TFAOOH or TFAOSO3H. Consequently, by restraining
the background radical pathway, we validated the higher productivity of Pd catalytic systems for
methane activation.
128
5.5 Experimental Section
5.5.1 Materials and Methods
Commercially available reagents and solvents were obtained from Aldrich and Acros chemical
and used without further purification. 1H NMR spectra was recorded on a Varian Mercury 400
two-channel NMR spectrometer or a Varian VNMRS-500 two-channel NMR spectrometer for the
analysis. Single-crystal XRD was recoreded on a Bruker APEX DUO single-crystal diffractometer
equipped with an APEX2 CCD detector, Mo fine-focus and Cu micro-focus X-ray sources.
5.5.2 General Procedure and High Pressure Methane Oxidation using
Pd Catalyst
After dissolving NHC-Pd catalysts in TFA:TFAA solution followed by oxidants, a vial containing
reaction mixture was transferred to a stainless-steel reactor equipped with a high-pressure valve.
The reactor was pressurized to 200-400 psi using CH4. The reactor was placed on a pre-heated
aluminum block at 60-100 °C and stirred for 16 h. After cooling down to ambient temperatures,
products were analyzed using NMR spectral analysis.
129
5.5.3 X-ray Crystallography of Complex 1
Formula C15H20Cl2N4O2Pd, C2H3N
Molecular weight 465.67
Space group P¯1
Unit cell dimensions a = 8.6241(2) Å a=90.160(2)°
b = 11.3673(3) Å b=96.122(2)°
c = 11.8580(2) Å g=108.531(2)°
Cell volume 1095.08 Å3
Z, Z’ Z:2, Z’:1
Density (CCDC) 1.537
Goodness of fit 1.088
Table 5.7: Crystal data and structure refinement for NHC-Pd Complex 1
130
Pd1-Cl1 2.2884(8) C5-C6 1.394(3)
Pd1-Cl2 2.282(1) C6-H6 0.93
Pd1-N4 2.079(2) C6-C7 1.382(4)
Pd1-C1 1.941(2) C7-H7 0.93
O1-C10 1.222(3) C7-C8 1.389(3)
O2-C12 1.411(3) C9-H9A 0.97
O2-C13 1.413(3) C9-H9B 0.97
N1-C1 1.345(2) C9-C10 1.523(3)
N1-C2 1.453(3) C11-H11A 0.97
N1-C3 1.385(2) C11-H11B 0.97
N2-C1 1.346(2) C11-C12 1.499(3)
N2-C8 1.398(3) C12-H12A 0.97
N2-C9 1.457(2) C12-H12B 0.97
N3-H3 0.86 C13-H13A 0.96
N3-C10 1.341(3) C13-H13B 0.96
N3-C11 1.457(3) C13-H13C 0.96
N4-C14 1.123(3) C14-C15 1.453(3)
C2-H2A 0.96 C15-H15A 0.96
C2-H2B 0.96 C15-H15B 0.96
C2-H2C 0.96 C15-H15C 0.96
C3-C4 1.394(3) N5-C16 1.112(6)
C3-C8 1.384(2) C16-C17 1.430(8)
C4-H4 0.93 C17-H17A 0.96
C4-C5 1.370(3) C17-H17B 0.96
C5-H5 0.93 C17-H17C 0.96
Table 5.8: Bond lengths [Å] for NHC-Pd Complex 1
131
Cl1-Pd1-Cl2 177.74(3) C3-C8-C7 121.5(2)
Cl1-Pd1-N4 91.03(6) N2-C9-H9A 109.2
Cl1-Pd1-C1 88.08(6) N2-C9-H9B 109.2
Cl2-Pd1-N4 91.01(7) N2-C9-C10 112.1(2)
Cl2-Pd1-C1 89.83(6) H9A-C9-H9B 107.9
N4-Pd1-C1 176.97(8) H9A-C9-C10 109.2
C12-O2-C13 112.8(2) H9B-C9-C10 109.2
C1-N1-C2 125.0(2) O1-C10-N3 123.7(2)
C1-N1-C3 110.1(2) O1-C10-C9 122.3(2)
C2-N1-C3 124.9(2) N3-C10-C9 113.9(2)
C1-N2-C8 109.9(2) N3-C11-H11A 108.7
C1-N2-C9 124.6(2) N3-C11-H11B 108.7
C8-N2-C9 125.5(2) N3-C11-C12 114.1(2)
H3-N3-C10 119.3 H11A-C11-H11B 107.6
H3-N3-C11 119.3 H11A-C11-C12 108.7
C10-N3-C11 121.4(2) H11B-C11-C12 108.7
Pd1-N4-C14 171.8(2) O2-C12-C11 109.6(2)
Pd1-C1-N1 124.4(1) O2-C12-H12A 109.7
Pd1-C1-N2 128.3(1) O2-C12-H12B 109.7
N1-C1-N2 107.3(2) C11-C12-H12A 109.8
N1-C2-H2A 109.5 C11-C12-H12B 109.8
N1-C2-H2B 109.5 H12A-C12-H12B 108.2
N1-C2-H2C 109.5 O2-C13-H13A 109.5
H2A-C2-H2B 109.5 O2-C13-H13B 109.5
H2A-C2-H2C 109.4 O2-C13-H13C 109.5
H2B-C2-H2C 109.4 H13A-C13-H13B 109.5
N1-C3-C4 131.3(2) H13A-C13-H13C 109.4
N1-C3-C8 106.7(2) H13B-C13-H13C 109.5
C4-C3-C8 121.9(2) N4-C14-C15 177.8(3)
C3-C4-H4 121.8 C14-C15-H15A 109.5
C3-C4-C5 116.4(2) C14-C15-H15B 109.4
H4-C4-C5 121.7 C14-C15-H15C 109.5
C4-C5-H5 119.2 H15A-C15-H15B 109.5
C4-C5-C6 121.7(2) H15A-C15-H15C 109.5
H5-C5-C6 119.2 H15B-C15-H15C 109.5
C5-C6-H6 118.9 N5-C16-C17 178.4(5)
C5-C6-C7 122.1(2) C16-C17-H17A 109.4
H6-C6-C7 118.9 C16-C17-H17B 109.5
C6-C7-H7 121.9 C16-C17-H17C 109.5
C6-C7-C8 116.2(2) H17A-C17-H17B 109.4
H7-C7-C8 121.9 H17A-C17-H17C 109.5
N2-C8-C3 106.0(2) H17B-C17-H17C 109.5
N2-C8-C7 132.5(2)
Table 5.9: Angles [°] for NHC-Pd Complex 1
132
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Abstract (if available)
Abstract
In the studies of methane functionalization, we have utilized two different pathways for efficient C-H activation: Pd-catalysis and radical-catalysis.
First, TFAOSO3H was identified as a key intermediate in radical-catalyzed methane sulfonation. Upon addition of the radical initiator, the crude TFAOSO3H solution activated the strong C-H bonds of methane and generated methanesulfonic acid (MSA). TFAOSO3H and methane were converted to MSA under optimal conditions, achieving high conversion yields using potassium persulfate at 50 °C. The free-radical mechanism was elucidated with the identification of the key intermediate and radical species involved. Furthermore, additional experiments demonstrated the economic feasibility of scaling up this method for industrial applications by achieving methane functionalization under 1 atm conditions.
When various feedstocks were explored as sulfur sources, we discovered that not only H2SO4 and oleum, but also SO2 was able to produce TFAOSO3H to facilitate methane sulfonation. Accordingly, practical conditions for the utilization of SO2 to generate TFAOSO3H was developed which can perform methane sulfonation. Consequently, SO2, O2, and methane were successfully converted to MSA via a free-radical mechanism promoted by trifluoroperacetic acid. SO2 and CH4 were selectively converted to MSA in 74% and 95% yields, respectively, when they were employed as limiting reagents.
Secondly, metal-catalyzed C-H activation was investigated for oxidative functionalization of methane using Pd catalysts. The water-stable Pd complex containing N-heterocyclic carbene ligand was activated by removal of the chloride ligand and facilitated H/D exchange on methane, exhibiting a high deuterium conversion of 44% and an outstanding turnover number (TON) of 346 under mild conditions. Furthermore, spectral analysis confirmed a distinctive non-redox catalytic system derived from the amidate nitrogen on the catalyst. As the amidate nitrogen behaved as an internal base, facile protonation and deprotonation on the nitrogenwere observed. Consequently, the Pd metal center maintained its oxidation state during the H/D exchange reactions, resulting in unique non-redox catalysis.
Further studies on Pd complexes validated the successful conversion of methane to methyl trifluoroacetate (MeOTFA) with high a TON. As the background radical reaction and over-oxidation inhibited the desired metal-catalyzed methane oxidation, optimal reaction conditions were determined through comprehensive studies. Suppressing the background radical pathway corroborated higher productivity in Pd-catalyzed methane activation, resulting in a TON of 154.
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University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Kim, Sungah
(author)
Core Title
Studies on methane functionalization: efficient carbon-hydrogen bond activation via palladium and free radical catalyses
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Degree Conferral Date
2024-08
Publication Date
07/16/2024
Defense Date
06/27/2024
Publisher
Los Angeles, California
(original),
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
C-H activation,free-radical mechanism,H/D exchange,metal-catalyzed methane oxidation,methane,methane functionalization,methane sulfonation,Pd catalysis,radical-catalysis,sulfur dioxide,transition metal NHC complex
Format
theses
(aat)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Jung, Kyung Woon (
committee chair
), Comai, Lucio (
committee member
), Takahashi, Susumu (
committee member
), Zhang, Chao (
committee member
)
Creator Email
sungah815@gmail.com,sungahk@usc.edu
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-oUC113997P19
Unique identifier
UC113997P19
Identifier
etd-KimSungah-13240.pdf (filename)
Legacy Identifier
etd-KimSungah-13240
Document Type
Dissertation
Format
theses (aat)
Rights
Kim, Sungah
Internet Media Type
application/pdf
Type
texts
Source
20240716-usctheses-batch-1183
(batch),
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA
Repository Email
cisadmin@lib.usc.edu
Tags
C-H activation
free-radical mechanism
H/D exchange
metal-catalyzed methane oxidation
methane
methane functionalization
methane sulfonation
Pd catalysis
radical-catalysis
sulfur dioxide
transition metal NHC complex