Pd-Based Photocatalysts for Sonogashira C-C Cross-Coupling Reactions
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Pd-based Photocatalysts for Sonogashira C-C Cross-Coupling Reactions
Komadhie Charuka Dissanayake Eastern Illinois University
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Recommended Citation Dissanayake, Komadhie Charuka, "Pd-based Photocatalysts for Sonogashira C-C Cross-Coupling Reactions" (2018). Masters Theses. 4436. https://thekeep.eiu.edu/theses/4436
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Please submit in duplicate. Pd-based Photocatalysts for Sonogashira C-C Cross-Coupling Reactions
(TITLE)
BY
Komadhie Charuka Dissanayake
THESIS
SUBMITIED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF
Master of Science in Chemistry
IN THE GRADUATE SCHOOL, EASTERN ILLINOIS UNIVERSITY CHARLESTON, ILLINOIS
2018
YEAR
I HEREBY RECOMMEND THAT THIS THESIS BE ACCEPTED AS FULFILLING THIS PART OF THE GRADUATE DEGREE CITED ABOVE
S-/2�/IJ �1fl8 DATE DEPARTMENT/SCHOOL CHAIR DATE OR CHAIR'S DESIGNEE
lv<-1-Z-\."l.ol °" 6J'/:I- 3/..lolff • DATE DATE
0J/zLt/�ti DATE THESIS COMMITIEE MEMBER DATE Pd-based Photocatalysts for Sonogashira C-C Cross-coupling Reactions
KOMADHIE CHARUKA DISSANAYAKE
Research Advisor: Dr. Hongshan He
Eastern Illinois University
Department of Chemistry and Biochemistry TABLE OF CONTENTS
ABBREVIATIONS ...... v
ABSTRACT...... vii
ACKNOWLEDGMENTS...... ix
LIST OF FIGURES ...... x
LIST OF TABLES ...... xiv
1. Introduction ...... 1
1.1. Sonogashira reactions ...... 1
1.1.1. Transition metal catalyzed C-C bond formation ...... 1
1.1.2. Sonogashira reaction and its uses ...... 4
1.1.3. Mechanistic considerations ...... 7
1.1.4. Modified Sonogashira C-C coupling reactions ...... 10
1.2. Photocatalysts ...... 14
1.2.1. Photochemistryand photocatalysts ...... 14
1.2.2. Mechanisms of pho�ocatalysis ...... 17
1.2.2.1. Photo redox catalysis ...... 17
1.2.2.2. Energy transfer reactions ...... 20
1.3. BODIPY ...... 24
1.3.1. General characteristics ofBODIPY ...... 24 1.3.2. BODIPY in photo redox catalysis ...... 27
1.4. Motivation ...... 30
1.5. Objectives ...... 31
2. Experimental ...... 32
2.1 General information ...... 32
2.2 Synthesis...... 34
2.2.1 Synthesis of 4,7-diformyl-l ,l0-phenan throline (YHl) ...... 34
' ' 2.2.2 Synthesis of 4,7-di( 4',4 "-difluoro-1 ',3 ,5 ,7'-tetramethyl-4 '-bora-3 'a,4 'a-diaza-s-
indacene )-1, 1 0-phenanthroline (YH2) ...... 35
2.2.3 Synthesis of dichloro (4,7-di(4',4 "-difluoro-1 ',3 ',5',7'-tetramethyl-4'-bora-3 'a,4 'a-
diaza-s-indacene)-1 , 1 0-phenanthroline )palladium(II) (YH2-Pd) ...... 36
2.3 Sonogashira C-C cross coupling reactions ...... 37
2.4. Spectral and electrochemical measurements ...... 40
2.4.1. UV-Visible spectroscopic measurements ...... 40
Characterization ...... 40
Monitoring the reduction of Pd(JI) with UV-Visible spectroscopy ...... 40
2.4.2. Fluorescence spectra ...... 41
31 2.4.3. Monitoring the reduction of Pd(II) with P NMR studies ...... 41
Investigation of the system YH2-Pd, PPh3 and Et3N ...... 41
ii 2.4.4. Electrochemical procedure for cyclic voltammetry ...... 42
3. Results and discussion ...... 43
3.1. Synthesis and purification...... 43
1 3.1. Characterization with II NMR ...... 45
1 3.1.1. H NMR of YHl ...... 45
1 3.1.2. H NMR ofYH2 ...... 46
1 3.1.3. H NMR of YH2-Pd...... 47
3.2. Characterization with UV-VIS spectroscopy ...... 48
3.3. Characterization with fluorescence spectroscopy ...... 50
3.4. Cyclic voltammetry studies ...... 54
3.5. Sonogashira C-C cross-coupling reactions ...... 58
3.5.1. C-C cross-coupling between bromobenzene and phenylacetylene ...... 58
3.5.2. Coupling between iodobenzene and phenylacetylene- reaction optimization ...... 60
3.5.3. Substituent effect on Sonogashira C-C cross-coupling reaction between
iodobenzene and phenylacetylene ...... 62
3.6.4. Mixture of BODIPY and [Pd(phen)Ch] as a catalyst system ...... 65
3.6. Mechanism elucidation ...... 67
3 .6.1. UV-VIS spectroscopic studies ...... 67
1 3.6.2. 3 P NMR studies ...... 70
iii Investigation of the system YH2-Pd + 2 PPh3 ...... 70
Investigation of the system YH2-Pd + 10 PPhJ ...... 71
3.6.3. Cyclic voltammetry studies...... 73
3.7. Proposed n1echanisn1 ...... 75
4. Conclusion ...... 84
REFERENCES ...... 87
A. APPENDICES ...... A
Appendix A. BODIPY ...... A
Appendix B. Spectroscopic studies ...... D
Appendix C. GC-MS analysis ...... N
iv ABBREVIATIONS
1. C-C carbon-carbon
2. TON Turnovernumber
3. TOF Turnover frequency
4. EWG Electron withdrawing group
5. EDG Electron donating group
6. UV Ultraviolet
7. PET Photo induced electron transfer
8. SET Single electron transfer
9. MLCT Metal to ligand charge transfer
10. TIET Triplet to triplet energy transfer
11. BODIPY Dipyrrometheneboron difluoride
12. TIA Triplet to triplet annihilation
13. ISC Intersystem crossing
14. NMR Nuclear magnetic resonance
15. DCM Dichloromethane
16. CV Cyclic voltammetry
17. RBF Round bottom flask
18. DMF Dimethylformamide
19. ND Not detected
20. IL Illuminated
21. S Solvent
22. [Pd(phen)Ch] Dichloro(l,10 -phenanthroline)palladium(II)
v 23. DMSO Dimethyl sulfoxide
24. YHI 4,7-Diformyl-1,10-phenanthroline
25. YH2 4, 7-di(4 · ,4 · · -difluoro-1 · ,3 ',5 ', 7 '-tetramethyl-4 '-bora-3 'a,4 · a-diaza-s-indacene )-
1,1 0-phenanthroline
26. YH2-Pd dichloro(4,7-di(4',4" -difluoro- 1 ',3 ',5',7'-tetramethyl-4'-bora-3 'a,4 'a-diaza-s
indacene)- 1,I 0-phenanthroline)palladium(I I) (YH2-Pd)
27. rtRoom temperature
vi ABSTRACT
Sonogashira C-C cross-coupling reaction has been heavily used for its simplicity, flexibility and
value. Although the original Sonogashira C-C cross coupling reaction conditions entail the use of
0.5 mol% of Pd catalyst, 2 mol% of Cul as co-catalyst at room temperature, the experimental
conditions used in laboratories to prepare some compounds vary substantially, especially with
respect to the reaction time, temperature and loading amount of the catalysts. The most significant
drawback of the conventional Sonogashira reaction is the use of Cul as it leads to the formation of
homocoupling product when the reaction is exposed to air or oxidizing agents.
To address the above-mentioned shortcomings, we designed a photocatalyst based on
dipyrrometheneboron difluoride (BODIPY). The BODIPY based dichloro(4,7-di(4',4"-difluoro-
1 ',3 ',5 ',7 '-tetramethyl-4 '-bora-3 'a,4 'a-diaza-s-indacene )-1,10-phenanthroline)pal ladiurn(II)
(YH2-Pd) catalyst was synthesized and purified using column chromatography. The product and the intermediates were characterized using UV -Vis spectroscopy, 1 H NMR, fluorescence
spectroscopy and cyclic voltamrnetry.
Coupling reactions between iodobenzene and phenylacetylene were successfully catalyzed by the
YH2-Pd catalyst in the absence of Cu(I) co-catalyst at room temperature under inert conditions upon irradiation with 13W LED bulb (1050 Lumens). A yield of 94% was obtained via GC-MS after 24 hours with 0.5% loading of the catalyst. Substrate scope of the photoinduced Sonogashira reaction was investigated with various derivatives of iodobenzene and phenylacetylene. When para-substituted iodobenzenes were used, the desired cross-coupling product yields were lower than the model reaction, in contrast to for the phenylacetylene derivatives as the product yields were not significantly different from the model reaction.
VII With the intentions of simplifying the catalyst system, a mixture of BODIPY and dichloro(l, I 0- phenanthroline)palladium(ll) ([Pd(phen)Ch]) was used for the catalysis. A yield of 87% was obtained via GC-MS after 24 hours with 0.5% [Pd(phen)Ch] and 1 % BODIPY. Use of derivatives of iodobenzene resulted in the same patternof product yield observed for the YH2-Pd catalyst with low yields in general.
Mechanistic investigations were carried out using 31P NMR, UV-Visible spectroscopy and cyclic
3 voltammetry. 1P NMR and UV-Visible spectroscopies revealed the formation of the PPh3 ligated
complex upon reduction of Pd(Il) to Pd(O) and cyclic voltammetry studies provided the evidence, which indicates that the reduction is mediated by EtJN. Experimental studies with various aryl halides revealed the crucial role of BODIPY in the oxidative addition step in the catalytic cycle.
viii ACKNOWLEDGMENTS
I wish to express my sincere gratitude to Dr. Hongshan He for the guidance and instructions that have made this research possible. His patience and constant support have been invaluable to me during these graduate years at EasternIllinois University.
I'd like to thank Dr.Dan Sheeran for training me to use GC-MS instrument and continuous guidance and support throughout this research project, and Dr. Zhiqing Yan for helping and training in 31P NMR, Dr. Mark McGuire for all the help with electrochemical studies and suggestions during the research project and my other committee member Prof. Radu Semenuic for his advice and assistance throughout my graduate education.
I also wish to express thanks to the Department of Chemistry and Biochemistry at Eastern Illinois
University for their generous support.
Finally, I would like to express thanks to my family, without whose constant love and spiritual support this work would not have been possible.
ix LIST OF FIGURES
Figure 1-1. Some commonly used cross-coupling reactions and related reactions (Heck reaction and Buchwald-Hartwig coupling) (reproduced from reference 6) ...... 2
Figure 1-2. Sonogashira C-C coupling reaction conditions ...... 4
Figure 1-3. Use of Sonogashira cross-coupling reactions in molecular wires (reproduced from
reference 12) ...... 5
Figure 1-4 Synthesis of (Z)-tarnoxifenusing Sonogashira C-C coupling reaction (reproduced from reference 13) ...... 6
Figure 1-5. Proposed mechanism for Sonogashira C-C cross-coupling reaction ...... 7
Figure 1-6. Reduction of Pd (II) to Pd (0) by amines ...... 8
Figure 1-7. Formation ofhomocoupling product in the presence of oxygen and copper (1) ...... 10
Figure 1-8. Proposed mechanisms for copper-free Sonogashira reaction (reproduced from
reference 20) ...... 1 1
Figure 1-9. Proposed mechanism for anionic and cationic reaction pathways (reproduced from reference 20) ...... 12
Figure 1-10. Regioselective synthesis of raloxifene (reproduced from reference 30) ...... 16
2 Figure 1-11. [ 4+2] Cycloaddition upon exposure to visible light with [Ru(bpz)3] +(redrawn from reference 31) ...... 1 7
Figure 1-12. Key photochemical properties of [Ru(bpy)3)2+ ...... 19
Figure 1-13. Stephenson's dehalogenation of a-chloroester ...... 20
Figure 1-14. Triplet to triplet energy transfer (TIET) ...... 21
Figure 1-15. Dexter energy transfer process ...... 21
Figure 1-16. Trans to cis isomerization of 4-cyanostillbene (reproduced from reference 37) ..... 23
x Figure 1-17. BODIPY core and its numbering ...... 24
Figure 1-18. Jablonski diagram showing the excitation of the molecule to its, singlet excited states
(S 1. S2) from singlet ground state (So) after absorption (A) and decay through florescence (F) or
phosphorescence (P) after intersystem crossing (ISC) to its T 1 triplet excited state. Rate of A, F and P processes are given in the parentheses ...... 25
Figure 1-19. Synthesis of aminonaphthoquinone ...... 28
Figure 1-20. BODIPY-C o conjugates photocatalysts ...... 29 6 as
Figure 2-1. Reaction set up for Sonogashira reactions with 9 cm distance between the reaction
flask and the light source ...... 37
Figure 2-2. Reaction setup showing the three-electrode cell equipped with a stir bar under N2 conditions (a) general setup (b) setup for illumination ...... 42
Figure 3-1. Schematic diagram of the synthesis of catalyst YH2-Pd ...... 43
Figure 3-2. Absorption spectra for YH2 4.2 x I o·6 mol/L, YH2-Pd 2.1 x I o·6 mol/L and [Pd(1, 10- phen)Ch] (saturated solution) in DCM ...... 48
Figure 3-3 Fluorescence spectra for YH2 4 x I o-6 mol/L (a) and YH2-Pd 2.08 x I o-6 mol/L (b) in
DCM. YH2 with an excitation wavelength of 375.00 nm and emission wavelength at 620 nm and
YH2-Pd with an excitation wavelength of371.40 nm emission wavelength at 600 nm ...... 51
Figure 3-4. Comparison of emission spectra of YH2 and YH2-Pd (YH2 4 x 10·6 mol/L (a) and
YH2-Pd 2.08 x 10·6 mol/L (b) in DCM. YH2 with an excitation wavelength of 375.00 nm and
YH2-Pd with an excitation wavelength of 371.40 run) ...... 52
Figure 3-5. Cyclic voltamrnogram for YH2 in MeCN 0.1 M N-BU4PF , W: Pt disk, Aux: Pt I 6
wire, Ref: Ag wire, Scan rate = 100 m V /s ...... 54
xi Figure 3-6. Cyclic volt ammogram for YH2-Pd in MeCN I 0.1 M N-BU4PF6, W: Pt disk, Aux: Pt
wire, Ref: Ag wire, Scan rate= 100 mV/s ...... 55
Figure 3-7. Cyclic voltammogram for dichloro(l,10-phenanthroline) palladium(II) in MeCN I 0.1
M N-BU4PF6, W: Pt disk, Aux: Ptwire, Ref: Ag wire, Scan rate= l 00 mV/s ...... 55
Figure 3-8. Reaction progress with time monitored with GC-MS ...... 61
Figure 3-9. Monitoring the reaction with time upon addition of EtJN and PPh3 consecutively with
6 illuminating (IL) the reaction mixture with YH2-Pd-3.04x 1 o- mol/L in DMF ...... 68
Figure 3-10. Monitoring the formation of the unidentified species upon addition of EtJN and PPh3 6 with YH2-Pd-3.04x I0· mol/L in DMF ...... 69
Figure 3-11. 31 P NMR spectra for systems with different Pd/PPh3 molar ratios ...... 71
Figure 3-12. Cyclic voltammogram for YH2-Pd after four-hour irradiation in MeCN I 0.1 MN-
BU4PF6, W: Pt disk, Aux: Pt wire, Ref: Ag wire, Scan rate= 100 mV/s ...... 74
Figure 3-13. Proposed mechanism for YH2-Pd catalyst in Sonogashira C-C cross-coupling
reaction ...... 76
Figure 3-14. Ulman coupling ...... 80
Figure A-1. X-ray crystallographic structure of YH2-Pd showing the angle between BODIPY
plane and the phenanthroline plane ...... A
Figure A-2. Light intensity vs wavelength in 32 W regular lamp (blue) and 13 W LED (1050
Lumens) lamp (red) ...... B
Figure A-3. The 1H NMR spectrum for YHl ...... D
Figure A-4. The 11-1 NMR spectrum for YH2. The spectrum was collected in CDCh with TMS as the internalreference. S= solvent...... E
xii Figure A-5. The 1H NMR spectrum for YH2-Pd. The spectrum was collected in CDCb with TMS as the internal reference. S = solvent...... F
Figure A-6. 31P NMR spectrum forPd:PPh3 1 :2 system. The spectrum was collected in CDCb with
HJP04 as the refe rence ...... G
Figure A-7. 31P NMR spectrum for Pd:PPh3-l:23 system. The spectrum was collected in CDCh with HJP04 as the refe rence ...... H
Figure A-8. 31P NMR spectrum for Pd:PPh3 1:10 system. The spectrum was collected in CDCb
with H3P04 as the reference ...... I
Figure A-9. 31P NMR spectrum for Pd:PPh3 1 :10 + iodobenzene system. The spectrum was collected in CDCb with H3PQ4 as the reference ...... )
Figure A-10. Absorption spectra for the reaction mixture containing YH2-Pd, EtJN, PPh3 at
6 differenttime intervals after irradiation in a cuvette YH2-Pd-3.04x 10· mol/L in DMF ...... L
Figure A-1 1. Absorption spectra showing the difference in the reaction mixtures afterirradiating in the cuvette and the Schlenk flask YH2-Pd-3.04x10·6mol/L in DMF ...... M
Figure A-12. Calibration curve for diphenylacetylene ...... N
Figure A-13. Calibration curve for iodobenzene ...... N
Figure A-14. Calibration curve for phenylacetylene ...... 0
xiii LIST OF TABLES
Table 3-1: photophysical and electrochemical properties of the ligand (YH2) and the catalyst
(YH2-Pd)...... 57
Table 3-2. C-C cross-coupling between bromobenzene and phenylacetylene ...... 59
Table 3-3. C-C cross-coupling between iodobenzene and phenylacetylene ...... 60
Table 3-4. Substituent effect on Sonogashira C-C cross-coupling reaction between iodobenzene and phenylacetylene ...... 63
Table 3-5. Sonogashira C-C cross coupling reaction with a mixture ofBODIPY and (Pd(phen)Ch]
as a catalyst system ...... 65
Table 3-6. Comparison of irradiated and non irradiated samples with cyclic voltammetry ...... 73
Table A-1. Data and calculations for table 3-3 ...... Q
Table A-2. Data and calculations fortable 3-4 ...... T
Table A-3. Data and calculations for table 3-5 ...... 2
XIV CHAPTER 1
Introduction 1.1. Sonogashira reactions
1.1.1. Transition metal catalyzed C-C bond formation
Formation of C-C bond is an important reaction in the synthesis of many functional materials which are industrially important. Intensive research that have been conducted in past years have contributed numerous methods to the field of C-C bond formation. 1 About 50 years ago, the C-C bond was formed predominantly by reaction between reactive nucleophiles and electrophiles or via pericyclic reactions. Some of the most commonly used methods include Grignard reaction,
Wittig reaction, enolate alkylation, aldol reaction, Claisen condensation and Michael reaction.
More regio- and stereo-selective formation of C-C bonds in a synthetically useful rate was achieved with the development of organometallic catalysis which mediates cross-coupling reactions.
C-C cross-coupling reactions link two dissimilar molecules to produce a new molecule by establishing a new C-C bond. Typically, a new bond is formed between (hetero) aryl or vinyl electrophiles and carbon nucleophiles with the help ofa transition metal catalyst. Transition metal catalyzed C-C cross coupling is used in the synthesis of majority of the pharmaceuticals,
agrochemicals and other industrially important compounds as they usually encompass aromatic and heteroaromatic unjts in their structures.1e As shown in Figure 1-1, several C-C cross-coupling
methods such as Suzuki- Miyura, Negishi, Sonogashira and related coupling reactions such as Heck have been developed over the years. Owing to the versatility of these reactions they have become useful tools for the synthesis in laboratory as well as in industries.
Cross-coupling
1 2 R -X + R -Y
X= halide, Y= -B(OR)z (Suzuki'),-SnR3 triOate, (Stille),-ZnR (Negishi),-MgX t.osilate.. (Kumada), -SnR3 (Hiyama), Cu (Sonogashira)...
Heck reaction + ")=
Buchwald-Hartwig coupling
1 R -X +
Figure 1-1. Some commonly used cross-coupling reactions and related reactions (Heck reaction
and Buchwald-Hartwig coupling) (reproduced from reference 6)
The rich history of C-C coupling reactions reveals the extensive efforts made by scientists to develop new and efficient methods to construct C-C bonds. The firstexample of a metal-catalyzed cross-coupling was reported by Kumada and Corriu independently in 1972 which included Pd and
Ni-catalyzed cross-coupling reaction for C-C bond forrnation. 1c Later in 1977 Negishi reported the use of nickel and palladium-catalyzed coupling of organozinc compounds with various halides.2
The Stille coupling is another C-C bond forming reaction between stannanes and halides or pseudohalides which was introduced in 1976.3 Followed by Suzuki-Miyaura coupling in 1979, in which boron is used as the co-catalyst.4 Heck and Cassar independently reported the coupling
2 between a halide and a terminal alkyne in the presence of palladium, which was later modified by
Sonogashira in 1975 by adding copper to make reactions occur under milder conditions. Extensive application of these coupling methods led to the attribution of the Nobel Prize in chemistry to R.
F. Heck, E. Negishi, and A. Suzuki in 2010.5
Many transition metals have been used for C-C cross-coupling reactions. Examples include Pd,
Ni, Fe, Cu, Co, and Au. However, due to the tunability, selectivity, and reactivity, palladium-based catalysts are known to be most useful for the C-C cross-coupling reactions. The ability of these reactions to proceed with a high turnover number (TON) and turnover frequency (TOF) allows the use of small amount of Pd. 6
Among other substrates used for C-C cross-coupling, alkynes, one type of useful starting materials, play a huge role as its reactions belong to the fu ndamentals of organic chemistry. Acetylenes, when combined with palladium catalysts, can be used to synthesize very useful building blocks and intermediates for the synthesis of many different products. Aromatics, heterocycles, alkenes, 1,3- diynes, ynones and allyl ethers are a few categories of products that are being synthesized using
alkynes as starting materials. 7
3 1.1.2. Sonogashira reaction and its uses
Among the leading reactions which use alkynes as starting materials, Sonogashira C-C coupling reaction ranks in the top due to its versatility, simplicity, and value. General reaction conditions for the Sonogashfra C-C coupling reaction are shown in Figure 1-2. The palladium-catalyzed sp2- sp coupling between a halides and terminal alkynes in the presence of copper (I) co-catalyst is one of the most important methods of preparing aryl alkynes and conjugated enynes which are either starting materials or intermediates to prepare natural products,8 pharmaceuticals,9 and molecular electronics.10•11
R1= aryl, hetaryJ. vinyl R2= aryl, hetaryl, alkenyl, alkyl, SiR3 X= I, Br, Cl, OTf
Figure 1-2. Sonogashira C-C coupling reaction conditions
Alkylation of arenes is a very useful approach to make carbo- or heterocyclic intermediates and acetylene-based highly conjugated systems. Highly conjugated structures are often used in molecular electronics and photonics. An example for the use of Sonogashira coupling to make a molecular wire is shown in Figure 1-3 which is an anthraquinone-based wire, designed to be used as redox-controlled switches in molecular electronic devices.12
4 SIMe3
t-B•• ·· t-BuS [Pd(PPb3)zCl1J,=------Cul -0- i·Pr1NH, THF 85% 2
SR 3 0
Br 3
Br [Pd(PPb3)zCl1J, Cul i-Pr2NH, THF 85% 0
0
RS
Figure 1-3. Use of Sonogashira cross-coupling reactions in molecular wires (reproduced from
reference 12)
Another example of synthesis of alkynylated arenes is shown below in Figure 1-4. (Z)-Tamoxifen is a medicine that blocks the actions of estrogen which is used in several breast cancer types.
Sonogashira coupling is used to synthesize the arylated acetylenic system in one of the steps in the synthesis process. 13
5 OH �___,/
[Pd(PPb3)2Cl2) (10 mol%), Cul(lO moWo), Et3N, THF, rt(83•!.)
OH
(Z)-Tamoxifen
Figure 1-4 Synthesis of (Z)-tamoxifen using Sonogashira C-C coupling reaction (reproduced
from reference 13)
6 1.1.3. Mechanistic considerations
The exact mechanism for the Sonogasnira C-C coupling is not completely understood yet due to the complexities arising from the use of two metals during the catalysis. The generally accepted mechanism for the copper co-catalyzed Sonogashira C-C coupling reaction is shown in Figure 1-
5.14 The proposed mechanism comprises of the elementary steps seen in transition metal based coupling reactions; oxidative addition, transmetallation and reductive elimination. The catalytic reaction takes place via two independent cycles, namely the palladium cycle (Cycle A) and the copper cycle (cycle B).
reductive elimination
L L
L-PdI ---- R2 R1 - PdI -X I R1 Cycle A I trans-metalation
Cu ----- R2
' ' L= phosphene, base or • · solvent cu x
Figure J-5. Proposed mechanism for Sonogashira C-C cross-coupling reaction
7 Initiation
The catalytic cycle starts with the palladium cycle (cycle A). Palladium(Il) is reduced to [Pd(O)Li]
which is known to be the active catalytic species. This reduction is promoted by amines through
sigma- complexation, dehydropalladation and reductive elimination as shown in Figure 1-6.
/'--... � xe �·· :NEt3 XHNEt3 ___ .. . .. [Pd(O)) \ N (Pd(ll))X HIPd(D)JX ., " dehydropalladadon) reductiveu elimlnadon MekH- . H
Figure 1-6. Reduction of Pd (II) to Pd (0) by amines
Step I- Oxidative Addition
In the next step oxidative addition of the aryl or vinyl halide to the low ligated Pd(O) takes place.
Oxidative addition increases the oxidation number of the Pd from 0 to +2. Thisis considered to be the rate-limiting step of the reaction and is facilitated by electron withdrawing groups in the halide.
Four mechanisms are proposed for the oxidative addition step, namely concerted, SN2, radical and ionic mechanisms. The oxidative addition could occur via either one of the mechanisms or a
combination depending on the nature of the reagent, properties of the solvent, metal-bound ligands and added additives.15
Step 2- Trans-metalation
Hereafter the palladium cycle connects with the copper cycle. Formation of a n- alkyne-Cu complex is necessary to increase the acidity of the terminal H in the alkyne, which allows amines to deprotonate the alkyne to generate the anionic nucleophile that forms the copper acetylide.
Trans-metalation occurs from the formed copper acetylide where the alkyne group is transferred
8 from the Cu center to the Pd center. Trans metalation reactions could take place via redox mechanism, metal exchange mechanism or "ate" complex mechanism. This step is followed by cis-trans isomerization which then undergoes reductive elimination to give off the product.15
Step 3- Reductive elimination
Reductive elimination is the reverse process of oxidative addition. Two metal-ligand bonds are broken, and one new ligand -ligand bond is formed. Palladium center is reduced to its 0-oxidation state after the reductive elimination by which the catalytic cycle reach completion. The generally accepted mechanism for the elimination is known to be a concerted mechanism.
9 1.1.4. Modified Sonogashira C-C coupling reactions
Addition of copper to the catalytic system as a co-catalyst increased the reactivity of the system, which allowed the reaction to take place in much milder conditions with an increased rate.
However, in the presence of oxygen, copper acetylide undergoes homocoupling and generate butadiyne products as shown in Figure 1-7.16 Although acetylene homocoupling reactions are generally used in organic synthesis, formation of the homocoupling product while targeting the cross-coupling product is undesirable because formation of the dimer decreases the product yield.
Therefore, a large excess of the alkyne must be employed. Also, the removal of the diyne from the desired product might be difficult.
2Cu (I)+ 1/2 02 + H20 ____, .,_ 2Cu(II) + 20H
R -- R ------R 2 + 2Cu(II) ----1- + 2H+ +2Cu(I)
Figure 1-7. Formation of homocoupling product in the presence of oxygen and copper (I)
Over the years, the reaction conditions have been modifiedto avoid homocoupling. Slow addition of alkyne was suggested by Thorand et al, 17 which keeps the alkyne concentration low in the medium thereby minimizing the formation of the homocoupling product. Elangovan et al 18 introduced a method which uses an atmosphere of hydrogen gas diluted with nitrogen and argon to minimize the homocoupling. Several copper-free versions of Sonogashira coupling have been also developed to minimize the undesired homocoupling product. One of the most recent studies on eliminating copper was reported in Lipshutz et al, 19 where they have shown that
(HandaPhos)Pd complex catalyzes Sonogashira reaction at the ppm level of metal in water between room temperature and 45 °C without copper as a co catalyst. The monodentate cyclic
10 phosphenes form micelles in aqueous medium, which gives the benefit of increased concentration of catalyst and the reagents inside the inner core. which allows the use of ppm level catalysts.
The mechanism for the copper-free Sonogashira reaction has been studied experimentally and theoretically.20 Two mechanisms have been proposed, namely deprotonation and carbopalladation mechanisms which are shown in Figure 1-8.
H-Base• + x· Pd R Pdl R' l2 �R' -X :�� 2 x
Ly R' \ R1 r � I L -Pd- R1-Pd-L / x L2Pd/' 1 . L Pd R, Deproton�t1on 2 1 R2�L Carbopalladation 11 'x H :J: \ R2 ::=:H R2I Mechamsm Mechanism R2 ::=:H L H- Base + � L L tLx x· L ��-�dI -X R1-PdI -X L 2 + R1-Pd-X H R2 L H.>'=\ 2 --- -1- + -1- R2 R � H 2 Figure 1-8. Proposed mechanisms for copper-free Sonogashira reaction (reproduced from
reference 20)
1 Both mechanisms undergo the initial oxidative addition of the halide R -X to the (PdL2(0)] complex giving the intermediate 1, and then one ligand (L) is substituted by the alkyne resulting complex 2. These two mechanisms take different routes in the next step. ln deprotonation mechanism shown in the leftcycle in Figure 1-8, the deprotonation of the alkyne takes place along with the coordination of the ligand L resulting Pd complex with the two organic groups in cis position to each other. This step is followedby the reductive elimination of the product. In contrast, in the carbopalladation mechanism, the terminal alkyne with R2 group is coordinated to the Pd
11 center before deprotonation which is followed by the coordination of L and base mediated reductive elimination.
The carbopalladation mechanism was ruled out by Martensson et al21 by experimental studies which was later confirmed using theoretical studies by Melchor et al. 20 Martensson also proposed two alternativeroutes for the deprotonation pathway: anionic and cationic mechanisms are shown in Figure 1-9.
Pdl + R1 R2 Pdl R1 R2 2 ::=:: 2 + ::=::
Reductive Reductive I Elimination IL Elimination R1-Pd� -L R1-PdI -L L R1-Pdr -X R1-Pd-I X I H _J_R2 111 H-L R2 II2 (Cationic Mechanism) (Anionic Mechanism) R 2 R2 2 H-Base• L Base L R'-tt . R,_�d-X H-Base• � H -1- R2 x·� /; Ill 1-A:,
Figure 1-9. Proposed mechanism for anionic and cationic reaction pathways (reproduced from
reference 20)
The two mechanisms differ by a negatively or positively charged intermediate. In the cationic mechanism, substitution of L to the complex 2 gives positively charged intermediate by which then deprotonation takes place. In contrast, in the anionic mechanism, deprotonation occurs from the complex 2. which gives rise to the anionic intermediate which is followed by ligand substitution and reductive elimination. According to the authors, the cationic and anionic mechanisms can be favored depending on the electronic nature of the substituents directly attached to the terminal
12 alk:ynes. Alkynes bearing electron withdrawing groups (EWG) may favor the anionic mechanism whereas alkynes bearing electron donating groups (EOG) may favor the cationic pathway.21
Another approach to address the drawbacks associated with Sonogashira reaction is to develop photocatalysts. Over the last few years, several studies reported the use of visible light to catalyze
Sonogashira reaction. Albini et al22 proposed a metal-free protocol for alkynylation of aromatic compounds substituted with electron donating groups. The reaction takes place via phenyl cation formed from photo heterolysis. However, the use of phosphor coated lamps with emission at 310
or 254 run, which are in the UV region, have prevented the use of aromatic alkynes as starting material as they absorb the incident light and undergo undesired coupling reactions. Akita et al23 reported a mixed catalyst system of [Pd(CH3CN)2Ch]/P(t-Bu)3/[Ru(2,2-bi pyridine )3] · 2PF6, which catalyzes copper-free Sonogashira coupling reaction of aryl bromides at room temperature under irradiation of visible light. Nevertheless, the use of another metal (Ru) instead of Cu increases the metal loading and the cost as well.
Several heterogenous catalyst systems have also been reported. Use of palladium and gold alloy nanopartic1es for the cross-coupling reactions under copper-free Sonogashira conditions at 45°C was introduced by Xiao et al.24 These alloy nanopartic1es absorb light, and their conduction electrons gain energy which becomes available on the palladium surface. These light excited electrons get transferred to the substrates which are adsorbed onto the metal surface and get activated. Bhalla et al25 introduced an in situ generated supramolecular ensembles of oxidized CuO nanopartic1es which shows catalytic properties induced by visible light. Photoexcited electrons are believed to activate C-H bond in the terminal alkyne and CuO-phenylacetylide is formed which acts as a photo sensitizer. This is followed by radical reaction with the aryl halide and formation of the product.
13 1.2. Photocatalysts
1.2.1. Photochemistry and photocatalysts
Inspired by the photosynthesis, scientists were interested in using solar energy as an energy source
for chemical reactions. The interest of using sunlight as an energy source is mainly due to sunlight
being inexpensive, nonpolluting, abundant and an endlessly renewable source. One of the earliest
mention of the idea of using solar energy for environmental sustainability can be found in a lecture
presented by a pioneering chemist, Giacomo Ciamician in 1912. In his "The photochemistry of
the Future" titled article, Ciamician stated ·'The photochemistry of the futureshould not, however, be postponed to such distant times; I believe that industry will do well in using from this very day
all the energies that nature puts at its disposal. So far, human civilization has made use almost
exclusively of fossil solar energy. Would it not be advantageous to make better use of radiant energy?" .26 Numerous studies have been conducted over the years in search of methods to utilize the energy from sunlight for the advancement of industries. Solar energy is most commonly used in photovoltaics and solar fuel addressing the issues concerning environmental pollution and the depletion of fossil energy sources. Also, use of solar energy to affect chemical changes to facilitate synthesis of chemical compounds has also been recognized as a promising approach.
Nevertheless, use of photochemical synthesis in industrial scale is limited due to the inability of most organic molecules in interest to absorb energy in the visible range wavelengths. Instead, highly re active intermediates are generated by absorption of energy from the UV region, which increases the cost as well as the environmental apprehensions compared to the direct use of visible light. In addition to that, short wavelengths in UV contain high energy photons which can cause uncontrolled photodecomposition. To address these drawbacks, photocatalysts have been
14 developed.27 A photocatalyst is a specifically designed photon absorbing molecule which after
getting excited, can induce another reagent, substrate or catalyst to participate in a unique pathway.
The ability of many inorganic and organometallic compounds to absorb energy from the visible
region has inspired the interest in photocatalysts. The energy absorbed by these compounds from
the visible region of the spectrum can be used to catalyze important organic reactions.27a, 28 This
ability to utilize visible light to catalyze reactions comes with certain advantages. Neither solvents
nor common organic reagents will typically absorb in the visible region which results in selectivity.
Also, ability to undergo oxidation as well as reduction in the excited state improves the
applicability in diverse reactions. Many of the reactions use small amount of catalysts and results
in regio- and stereo-selective products. 27a,2 7b
Photocatalysts can be categorized into organic photocatalysts and metal complexes. Transition
metal catalysts-based catalysts which are capable of absorbing light are used widely such as
ruthenium and iridium polypyridyl complexes. In addition, several organic chromophores are
known to engage in photo induced electron transfer process (PET) which acts as photocatalysts.
Some common organic photocatalysts includes cyanoarenes, benzophenones, quinones, and xanthenes. 29
One example of an organic photocatalyst was reported by Konig group. They suggested a method to obtain benzothiophene (an estrogen receptor modulator) in one regio-isomer by reductive alkyne annulation of diazonium salt which is shown in Figure 1-10. The conventional synthetic routes had the drawback of moderate regioselectivity. However, using eosin Y as a photocatalyst with a green LED illumination for 14 hours, a yield of 70 % of raloxifene was obtained as the only isomer, which is a key intermediate in the synthesis of benzothiophene.30
15 S molo/o eosin Y
OMS0, 20 °C LED 530 nm
Br
0
Br Br
Figure 1-10. Regioselective synthesis of raloxifene (reproduced from reference 30)
Natural products have complex structures. There are numerous studjes conducted on natural products using inorganic photo redox catalysts. One example in natural product synthesis was demonstrated by Yoon and co-workers. Heitziamide A is a natural cytotoxic product which is shown in Figure 1-11. Use of photo redox catalysis allowed the formation of the intermediate which is otherwise thermally disfavored. Electron-rich ruenophile and the corresponding diene undergoes [4+2] cycloaddition upon exposure to visible light with [Ru(bpz)3]2+, as the photocatalyst. Tills results in an intermediate with regioselectivity, which will then be converted to the natural product after four more steps. 31
16 200 °c MeO no reaction 24 h
+ Meo Me 0.5%( Ru(bpz)312+ air, light electron.lcally mismatched I h Diels-Alder cycloaddltion�-·
Me
98�. yield
2 Figure 1-11. [4+2] Cycloaddition upon exposure to visible light with [Ru(bpz)3] +(redrawn from
reference 3 l)
1.2.2. Mechanisms of photocatalysis
32 Four main mechanisms have been proposed for photocatalytic reactions. Namely energy transfer, organometallic excitation, light-induced atom transfer and photo redox catalysis. Among them, photo redox catalysis has a wide range of applications including organic synthesis. Some of the other applications include water splitting, novel solar cell material and C02 reduction to methane, photo voltaic cells,33 and energy storage,33b organic light emitting diodes34 and photo dynamic therapy.35
1.2.2.1. Photo redox catalysis
The excited photo redox catalysts can involve in a single electron transfer (SET) process with organic substrates. When the catalysts are irradiated with visible light, stable and long-lived excited states are generated. Lifetime of these excited species is long enough to transfer electrons
17 to another molecule. Although these complexes are weak oxidants and reductants in their ground state, in their excited state they become very potent electron transfer agents.
Ruthenium and iridium metal complexes rank as the most extensively used photo redox complexes for synthetic applications among a wide variety of transition metal complexes. As an example, Ru photochemistry is described here. [Ru(bpy)3)2+ complex (bpy stands for2,2'-bipyridine) exhibits a strong, broad absorbance in the visible range (A.max = 452 nm)that results in the production of a relatively long-lived excited state (t � 0.9 µs). Figure 1-12 summarizes the key photochemical properties of [Ru(bpy)3)2+ complex as a photo-redox catalyst. When [Ru(bpy)3]2+ absorbs a photon from the visible range, one electron in the hg orbital get excited to a ligand centered n* orbital.
This is a metal to ligand charge transfer (MLCT) and results in oxidation of the metal center (Ru
Ill). This excited state undergoes intersystem crossing to give rise to the lowest energy triplet state which is the long-lived photo excited species that engage in electron transfer process.
[Ru*(bpy)3]2+ can act as an oxidant as well as reductant which allows it to engage in redox reactions based on the substrates availability. The property of being more potent reductant and an oxidant can be demonstrated using standard electron potentials.
[Ru(bpy) 3 + e Ru(bpy)3]2+ (E112 -0.81 V vs SCE) 3] + - ._ [* IIV*II =
[Ru(bpy) 3 e [Ru(bpy) (E11 = l .29V SCE) 3] + + - ---+ 3]2+ 2 II VII + VS
18 eg •
Oxidant --- 1 n•
===
e • 1� s t * ig [Ru(bpyh]•
1 eg • n• n• ---. MLCT + ISC � 1� 1 Reductant t2g ti g 1 Ground state Excited state tig [Ru(b [Ru(bpyhJ3• pyhJ1• •[Ru(bpyhJ2I
Figure 1-12. Key photochemical properties of (Ru(bpy)3]2+
These potential energies signify thatthe excited-state *[Ru(bpy)3]2+ is a much more potent electron
donor than ground-state. ln the meantime, the reduction potential of the excited state (E112 *II/I =
+0.77 V vs. SCE) indicates that this species is a much stronger oxidant than the ground state (E112
11/I = -1.33 V vs. SCE). This phenomenon can be explained using the molecular orbital diagram, as depicted in Figure 1-12. The generated higher energy electron from photoexcitation of the
[Ru(bpy)3]2+ can be donated easily to a LUMO of another molecule and act as a reductant and oxidize to [Ru(bpy)3]3+, whereas the hole generated in the lower tig level can accept electrons and act as an oxidant and reduce to [Ru(bpy)3] 1+.
An example of Ru based complexes acing as photoredox catalysts is found in Stephenson's photo redox reductive dehalogenation method which is illustrated in Figure 1-13. This method involves
19 2 a single electron oxidation of the amine by *[Ru(bpy)3] + which resulted in an aminium radical cation and [Ru(bpy)3]3+. While reducing Ru (Ill) complex to Ru (JI), a-chloroester is oxidized to the a-carbonyl radical. Oxidation of the amine lowers the bond strength of C-H thus facilitatesthe
3 abstraction of the H by the a-carbonyl radical to result in the dehalogenated product. 6
.l.0 /Ph RO"' I H
Figure 1-13. Stephenson's dehalogenation of a-chloroester
1.2.2.2. Energy transfer reactions
Photoexcited molecules can decay in several pathways. One of them is by transfer of energy to another molecule. Figure 1-14 illustrates the energy transfer process using [Ru(bpy)3]2+ as an example. Irradiation of the photocatalyst will excite the molecule to its lowest singlet excited state
(St) followed by intersystem crossing, which generates the long-lived lowest energy triplet state
(T1). This triplet state decay by transferring energy to another molecule A, promoting the excitation of molecule A from the growid state to its triplet state. This process is known as Triplet to Triplet
Energy Transfer (TTET). Several mechanisms have been proposed to explain the energy transfer from photo-excited molecule to another substrate.
20 *1Ru(bpy)Jl2+ A (So) s, s,
T _ _/ - , •A(T ) s IRu(bpi·hl , 0 l )mc_T,--=-T =-T TESo ( x _1Ru(bpy)JJ 2+ -_A Figure 1-1.t. Triplet to triplet energy transfer (TTET)
The most common mechanism is Dexter energy transfer which is illustrated in Figure 1-15. Decay
of the excited donor and the excitation of the acceptor takes place by a bilateral electron exchange.
For an efficient transfer of energy, the excited state should have a reasonable life time thus giving
enough time for energy transfer. In addition, the energy transfer between the donor and acceptor
should be thermodynamically feasible. There is no net change in number of electrons thus no redox
chemistry. To determine the fe asibility of the energy transfer process, electrochemical potentials
cannot be used, instead the triplet energy states of the both molecules must be considered.
Ll'\10 +�-- Donor Acceptor I 110\10 • �. � �
Figure 1-15. Dexter energy transfer process
21 Photoexcitation by energy transfer have several benefits compared to direct excitation of the substrate. Direct excitation of most of the substrates do not undergo ISC to result in long-lived triplet states. Instead, they tend to relax rapidly to the ground state which diminish the ability to engage in an energy transfer process. On the other hand, photocatalyst s undergo rapid ISC to generate triplet excited states which provides a more efficient pathway for energy transfer. In addition, direct photoexcitation of most of the organic compounds requires high energy UV radiation, which is not compatible with other functional groups like organohalides and nitrates. In contrast, the photocatalysts are capable of absorbing in the visible range, thus longer wavelengths which doesn't have an impact on other functional groups.
Photocatalysts which undergo triplet-triplet energy transfer are not widely utilized compared to photo-redox catalysts. Photoexcited substrates have several relaxation pathways including vibrational relaxation and unimolecular emission to reach the ground state. These pathways reduce the probability of another catalyst to interact with the electronically excited substrate. However, there are several studies that reports several dual catalyst systems that use energy transfer to catalyze the reactions. 27b
Osawa and co-workers merged photocatalysis with transition metal catalysis where they use a complex containing Ru, which is denoted as Pru. It acts as the "light harvesting ligand" to another metal center as shown in Figure 1-16. Pru is indirectly attached to the second metal center through a phenanthroline ligand with a diphenylphosphine group at position-3. This Ru catalyst catalyze trans to cis isomerization of 4-cyanostillbene. First, the acetonitrile ligand is displaced with the stilbene substrate. TIET takes place from Pru ligand to the stilbene substrate which promotes the isomerization. 37
22 �
,.. R l'--..P N CN �O /'' CN Me
Ph Visible light
8S% cts
Figure 1-16. Trans to cis isomerization of 4-cyanostillbene (reproduced from reference 37)
In addition to the Ru based photocatalyst mentioned above, there are other photocatalyst s in use.
Both organic and inorganic compounds are being used as photocatalysts. Some of the organic
compounds that are being used as photocatalysts are benzophenones, quinones, xanthene dyes and
rhodamines and some of the metal complexes include [Cu(dap)2t and [Ir (ppy)3).
23 1.3. BODIPY
1.3 .1. General characteristics of BODIPY
4,4' -Difluoro-4-bora-3a,4a-diaza-s-indacene abbreviated as BODIPY dyes are a class of bright fluorophores that were firstdiscovered by Treibs and Kreuzer in 1968. Characteristics of BODIPY led to its huge popularity and wide applicability in different fields. These chromophores tend to have high molar absorption coefficients (40000-110000 M·1cm·1 at 500 nm) and fluorescence quantum yields leading to the high brightness. They have narrow emission bandwidths with high peak intensities, robustness toward light and chemicals, resistance toward self-aggregation in solution, fluorescence life times in the nanosecond range, and excitation-emission wavelengths in the visible spectral range, tunability of the spectroscopic/photophysical properties by changing the substituents at suitable positions of the BODIPY core.38 All these characteristics led BODIPY to
be widely used in different fields. Such as optical engineering (organic light-emitting diodes, dye- sensitized solar cells), biological labeling for in vivo imaging and molecular sensors,39 sensitizers of singlet oxygen production for photodynamic therapy ,40 as a photosensitizer for artificial photosynthetic systems,41 solar cells,42 and photocatalysis.43
6
Figure 1-17. BODIPY core and its numbering
24 At room temperature, most molecules occupy the lowest vibrational level of the ground electronic
state So, and on absorption of light, they are elevated to produce excited states. The simplified
diagram below shows absorption by molecules to produce either the first, S1 or second S2, excited
state which is illustrated in Figure 1-18. The molecule rapidly loses its excess of vibrational energy
by collision and falls to the lowest vibrational level of the excited state, S 1.
______v A : absorption (1o-16s)
F : fluorescence (10-12-1 o-6s) -- ISC ---- P : phosphorescence (1 o-6-1 Os) '
A F p .... Inter-System Crossing (ISC)
· -- Vibrational relaxation �------So
Figure 1-18. Jablonski diagram showing the e:-.citation of the molecule to its. singlet excited states
(S1 S2) from singlet ground state (So) after absorption (A) and decay through
florescence (F) or phosphorescence ( P) after inlersystem crossing (lSC) lo its T1 triplet
excited state. Rate of A. F and P processes are given in the parentheses
From this S1 level, the molecule could cross to an excited vibrational level of T1. which is known
as intersystem crossing (lSC). After non-radiative vibrational relaxation, molecule reaches the
lowest energy in T1 state. A molecule could relax from S1 or T1 to So by emitting a photon.
Transitions from S1-+Sois called florescence whereas, T1-+So is called phosphorescence.
In photochemistry triplet state is important, and its applications include electroluminescence,
photocatalysts, photo dynamic therapy. photovoltaics, luminescence bio imaging and sensing.
25 BODIPY has been extensively studied for its singlet state related applications such as fluorescent molecular probes, molecular logic gates, dye-sensitized solar cells. However, some studies are focused on the triplet state of the BODIPY, which mainly consists of photocatalysis, and photodynarnic therapy. 43b
Triplet photosensitizers are compounds that produce triplet excitation state efficiently upon excitation. One of the methods for generating triplet excited state is facilitating ISC which will lead to the quenching of the fluorescence. The quenching by heavy atoms was first identified by
F. Perrin in 1926.44 Spin-orbit coupling explains the intersystem crossing of the organic molecules from singlet states to triplet states which is otherwise spin forbidden. Magnitude of the spin-orbit coupling is dependent on the atomic number.45 Introducing a heavy atom to the fluorophore is known to strengthen the spin-orbit coupling and facilitates the ISC which can be observed by quenching of the fluorescence. The heavy atom effect can be internal or external. Internal heavy atom effect is when the heavy atom is a part of the chromophore whereas external heavy atom effect is when the heavy atom is external to the chromophore. The external process requires close contact between the heavy atom and the chromophore. 46 However an efficient of ISC can be
observed when the heavy atom is either attached directly to the BODIPY or attached to a n conjugated unit which bridges the BODIPY and the heavy atom. In addition to the ISC, processes
3 such as charge recombination have also been reported to produce triplet state in BODIPY.4 b
26 1.3 .2. BODIPY in photo redox catalysis
BODIPY has been used as a photocatalyst in several occasions. Compared to the commonly used triplet photosensitizers, BODIPY has several advantages. Transition metal complexes like
[Ru(bpy)3C}i] and [Ir(ppy)3] show only moderate or weak absorption in the visible spectra range
(s< 20 000 M-1 cm-1) compared to the high absorption of BODIPY (40 000-110 000 M"1cm"1).
Also, the absorption maximum of metal complexes is <500 nmwhereas 500 run range in BODIPY.
The triplet state lifetimes of these complexes are short (less than 5 ms),28 and the redox properties of these photosensitizers are not readily tunable.
Jianzhang Zhao group used diiodo-BODIPY derivatives as organic catalysts for photo redox catalytic reactions which is illustrated in Figure 1-19. They reported one-pot reaction to prepare aryl-2-amino-1 ,4-naphthoquinones by aerobic oxidative coupling of amines and the photooxidation of hydroxynaphthalene which was mediated by singlet oxygen (102), and subsequent addition of amines to the naphthoquinones.
27 OH
···-Q� R 0
HO 1.H �R
Figure 1 -1 9. Synthesis of aminonaphthoquinone
The same group introduced C6o-styryl-BODIPY conjugates which show strong absorption of
t 1 visible light (e = 65 000M- cm- at 650 run),and a long-lived triplet excited state (life time = 120 ms) which found to have tenfold that of the conventional Ru(II)/Jr (III) photocatalyst. Preparation of bioactive pyrrolo[2,1 -a] isoquinoline is shown in Figure 1-20. The synthesis was carried out with BODIPY-C6o conjugates and a much higher catalytic efficiency was reported. When photocatalyst [Ru(bpy)3CJi] was used, a yield of 37% was obtained in four hours, compared to when BODIPY-C6o dyads were used as photocatalysts, 91 % of the product was obtained within an hour.47
28 COOEt I � 6 BOOlPY-C60 Visibl)l,:ght NBS.AO #)) -1 . ·1� -� Q
!SC ·1& ltv � [PS]•
0
N
'0-.. -·-
BOD!PY C60 conjugate
Figure 1-20. BODIPY-C6o conjugates as photocatalysts
29 1.4. Motivation
Since its discovery in 1975, Sonogashira coupling reaction has been heavily used for its broad
applications, which led Sonogashira C-C coupling reactions to be ranked third among the most
heavily used Pd-catalyzed reactions over the past decades. 19 Although the original Sonogashira
coupling entails the use of 0.5 mo1% of Pd catalyst, 2 mo1% of Cul as the co-catalyst at room
temperature, 14 the experimental conditions used in laboratories to prepare some compounds vary substantially, especially concerning reaction time, te mperature and loading amount of the catalysts. Also, the most significant drawback of the conventional Sonogashira re action is the use of Cu as a co-catalyst as it leads to the formation of homocoupling product when the reaction exposed to air or oxidizing agents. Therefore, large amount of alkyne must be used and the separation of the homocoupling product from the desired cross-coupling product may also be difficult.
To overcome the drawbacks mentioned above, numerous studies have been reported in literature over the past years including the use of copper-free versions, reactions in aqueous media, palladium free catalysis, heterogenous catalysis, and photocatalysis.
Despite of the incessant availability of the energy source, photo catalytic approaches have been used scarcely. Most of the photocatalytic systems reported are heterogenous catalysts systems, whjch are known to exhibit lower activities than the homogenous catalysts.48
It remains a great challenge to develop a methodology to catalyze the Sonogashira C-C coupling
under the following conditions: (a) without using copper asa cocatalyst, (b) that is able to catalyze the reaction under visible light (c) at room temperature, and (b) without using large amounts of expensive Pd metal.
30 1.5. Objectives
Objectives of this research project was to:
1. Synthesize the BODIPY based YH2-Pd catalyst.
2. Characterize the product and intermediates using UV-Vis spectroscopy, 1H NMR,
fluorescence spectroscopy and cyclic voltammetry.
3. Use the catalyst for Sonogashira coupling reactions.
4. Study the effect of substituted starting materials on product yield.
5. Use a mixture of BODIPY and [Pd(phen)Ch] as a catalyst system.
6. Mechanism elucidation using 31P NMR, UV-Visible spectroscopy, and cyclic
voltammetry.
31 CHAPTER 2
Experimental
2.1 General information
Commercial reagents chloroform (CHCb), dichloromethane (DCM), methanol (MeOH), hexanes
and triethylamjne (EtJN) from Fisher Scientific, 2,3-ilichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) from Biosynth International Inc., tetrahydrofuran (THF), dimethylformamide (DMF),
deuterated chloroform (CDCb), bromobenzene, l-chloro-4-iodobenzene, 4-iodobenzonitrile,
ethyl-4-iodobenzoate, 4-iodoanisole, methyl 4-iodobenzoate, diphenylacetylene, N,N
dimethylformamidefrom Acros organics, 4-iododbenzonitrile, 4-(phenylethynyl)acetophenone, 3- ethynylbenzonitrile from Alfa Aser, dichloro( l,10 -phenantbroline)palladium (II), 4-ethynyl-N,N dimethylamine, o-tolunitrile from Sigma Aldrich and iodobenzene from Eastman, 48% boron
trifluoride diethyl etherate (Bf3 · O(C2Hs)2) 2,4 dimethylpyrrole from TCI were used without further purification unless otherwise stated.
DCM was dried with CaH2 under nitrogen and distilled prior to use. A Heidolph WB eco rotary evaporator with a water bath was used to remove solvent. Chromatographlc purification of products was done under gravity on silica gel (70-230 mesh Silica gel). Thin-layer chromatography
(TLC) was performed on Silica plated aluminium backed TLC plates. Visualization of the developed TLC plates was performed using Mineralight UVG-1 1 short wave UV lamp. 1H NMR spectra were recorded on 400 MHz Bruker Avance II- NMR spectrometer and were internally referenced to CDCb (o 7.26 ppm). Data for 1H NMR are reported as follows: chemical shift (o
32 ppm), multiplicity (s = singlet, d =doublet, t =triplet, q = quartet, m = multiplet, dd =doublet of doublets, dt = doublet of triplets, br = broad), coupling constant (Hz), and integration. 31P NMR spectra were recorded on 400 MHz Bruker Avance II- NMR spectrometer. UV- VIS spectra were recorded on a Cary 100 Series UV-VIS Dual Beam Spectrophotometer over a range of 200-800
nm. Fluorescence spectra were collected on a Spectro fluorometer FS5 from Edinburgh
Instruments Inc.
Sonogashira reactions were carried out under inert atmosphere with the use of standard Schlenk techniques. Great vlue LED dirnrnable Par38 (E26) light bulb, 13W (1050 Lumens) and 32W incandescent lamp were used as light sources when appropriate. The yields of products were analyzed by GC-MS.
GC-MS: Shimadzu GC-MS-QP 2010 SE equipped with a SHRXI-5MS 30 m column, 0.25 um ID.
GC-MS method: Sample injection: 1 µL. Split ratio, 30-1, although another split ratio of 5: 1 was
used as appropriate. Temperature program: 75 °C for 2 minutes then ramped at 20 °C per minute to 140 °C then ramped 50 °C per minute to 300 °C and held at 300 °C for 4 minutes. Solvent cut time varied depending on the split ratio used 2.4 minutes to 3.5 minutes.
Cyclic voltarnmetry experiments were carried out with a Potentiostat/Galvanostat Model 263 A from Princeton Applied research.
USB 2000 CCD array spectrometer from oceanoptics, equipped with a fiber optic cable was used for intensity measurements of the light sources.
33 2.2 Synthesis
2.2.1 Synthesis of 4,7-diformyl-1,10-phenanthroline (YHl)
YBJ
Ligand YHl was synthesized according to the literature method42b with the following modifications. 4,7-Dimethyl-1,10- phenanthroline (1.50 g, 7 mmol) was dissolved in dioxane containing 4% v/v water (100 mL) in a 250 mL round bottom flask and Se02 (3. 75 g, 34 mmol) was added. The mixture was refluxed for 2 hours at 90 °C and it was filtered while hot. The filtrate was allowed to cool down to room temperature. The yellow solid was filtered out fromthe solution.
Recrystallization from 1,4-dioxane provided the title compound (0.4725 g, 30% yield) as light yellow powder.
1H NMR (400 MHz, CDCb) o 10.54 (s, 2H), 9.54 (d, JH-H = 4.32 Hz, 2H), 9.23 (s, 2H), 8.09 (d,
J11-H =4.32 Hz, 2H)
34 2.2.2 Synthesis of 4,7-di(4 ',4 "-difluoro-1 ',3 ',5 ', 7'-tetramethyl-4 '-bora-3 'a,4 'a
diaza-s-indacene)- 1,1 0-phenanthroline (YH2)
H
H
0 YHI YH2
Ligand YH2 was synthesized as follows. Compound YHl (0.476 g, 1.79 mmol) was added to
distilled DCM under Ni, followed by 2,4-dimethylpyrrole (0.856 g, 9.03 mmol) and two drops of
trifluoroacetic acid. The mixture was stirred overnight at room temperature. 2,3-Dichloro-5,6-
dicyano-l,4-benzoquinone (0.915 g, 4.00 mmol) was dissolved in 15 mL of DCM and was slowly added to the reaction mixture. Afterstirring the mixture for one-hour triethylamine (8.0 mL, 57
mmol) was added. Stirring was continued for 30 min and afterwards 48 % Bf3 · O(C2Hs)2 (8.0 mL,
31 mmol) was added to the mixture, and a strong green fluorescence was immediately observed
under flash light. The reaction mixture was stirred for 3 hours at room temperature before removing
the solvent under vacuum. The crude product was purified via column chromatography with
DCM/MeOH (v:v, 200:5) and CHCb/MeOH (v:v, 100:1). The product containing fraction which showed green fluorescence was subjected to vacuum to remove the solvent and the recrystallization of the resultant solid with MeOH provided the title compound (0.175 g, 15% yield) as orange solid.
1H NMR (400 MHz, CDCb) o 9.36 (d, J=4.44 Hz, 2H), 7.84 (s, 2H), 7.695 (d, J=4.44 Hz 2H),
5.97 (s, 2H), 2.58 (s, 3H), 1.09 (s, 3H)
35 2.2.3 Synthesis of dichloro( 4, 7-di(4 ',4 "-difluoro-1 ',3 ',5 ', 7'-tetr amethyl-4 '-bora-
3 'a,4 'a-diaza-s-indacene )-1,1 0-phenanthroline)palladium(I I) (YH2-Pd)
YB2 YH2-Pd
Catalyst YH2-Pd was synthesized as follows. Bis(benzonitrile)dichloropalladium(II) (0.844 mg,
2.20 mmol) was dissolved in CHCb in a 250 mL RBF. Ligand YH2 (0.138 g, 2.01 mmol) was added to the mixture. The mixture was stirred at room temperature under dark for 3 hours. Upon completion of the reaction, the solvent was removed under vacuum. The crude product was purified via column chromatography with DCM/MeOH (v:v, 200:5). The product containing fraction was subjected to vacuum to remove the solvent and the recrystallization of the resultant solid with MeOH provided the title compound (0.155 g, 91 % yield) as an orange solid.
1H NMR (400 MHz, CDCh) o 9.865 (d, J= 5.36 Hz, 2H), 7.98 (s, 2H), 7.97 (s,2H), 6.01 (s, 2H),
2.57 (s, 3H), 1.07 (s, 3H)
36 2.3 Sonogashira C-C cross coupling reactions
Representative procedure for coupling of phenylacetylene and iodobenzene (Table 3-3 entry 5)
I . Reaction setup
Catalyst YH2-Pd (4.2 mg, 0.005 mmol) was added to a Schlenk flask (50 mL) wi th a rubber stopper. The vessel was degassed and filled with Ni for 5 times followed by the addition of dry
DMF (4 mL). Then iodobenzene (0.111 mL, I mmol), Et3N (I rnL, 7 mmol), PPh3 (0.5 mL of a
0.01 M solution in DMF, 0.05 mmol) and phenylacetylene (0. 130 mL, 1.2 mmol) were added via syringes sequentially to the stirred reaction mixture. Irradiation with visible light was carried out using a 13W LED lamp. The reaction setup is shown in Figure 2-1.
Figure 2-l. Reaction set up for Sonogashira reactions with 9 cm distance between the reaction
flask and the light source
37 2. Sample preparation for GC-MS analysis
Analysis of the products in 4, 17 and 24 hours were carried out using GC-MS. At each time interval two samples were prepared by mixing l 0 µL of the reaction mixture in a 50-ppm solution of benzonitrile in DCM (1.5 mL) in a GC-MS vial.
3. GC-MS analysis
a. Preparation of calibration curves for GC-MS analysis
Calibration curves were prepared according to the equation given below using 2- methylbenzonitrile as the standard. A solution series of 10, 20, 30, 40, 50 ppm iodobenzene, phenylacetylene and diphenylacetylene were prepared in 50 ppm 2-methylbenzonitrile. Area of standard signal/concentration of the standard vs plotted against the area of analyte signal/concentration of analyte to diphenylacetylene, iodobenzene and phenylacetylene to give the below equations (Figure A-12, A-13 and A-14)
Area of the analyte signal Area of the standard signal ------Concentration of the analyte = F x Concentration of the standard
Equation 1 Relationship between the analyte signal and the standard signal where Fis response factor b. Calculations
Three methods were used to calculate yield % from GC-MS analysis.
Method 1
Regression line from the calibration curve fordiphenyl acetylene was used determine yield %.
0 - y = 4.5651x 2 x 101
Equation 2. Regression line from the diphenyl acetylene calibration curve
38 Method 2
Calibration curves prepared for the starting materials (iodobenzene (2a) and phenylacetylene(2b)
) was used to calculate % yield.
y = 0.9114x + 6 x 108
Equation 3. Regression line from the iodobenzene calibration curve
y = 0.5377x + 108
Equation 4. Regression line from the phenyl acetylene calibration curve
Where y = Area of analyte signal/concentration of analyte
x = Area of standard signal/concentration of the standard
Method 3
A direct relationship between the standard area/ standard concentration to product area/ product concentration was used instead of calibration curves.
All the calculations are shown in Appendix C. Calibration curve for the diphenylacetylene
(method 1) and calibration curve forthe iodobenzene (method 2a) were used to determine the yield from coupling of the phenylacetylene and its derivatives with iodobenzene. Calibration curve for phenylacetylene (method 2b) and method 3 were used for reactions coupling iodobenzene derivatives with phenylacetylene. Two samples were analyzed and the average of the results from two samples were taken.
39 2.4. Spectral and electrochemical measurements
2.4.1. UV-Visible spectroscopic measurements
Characterization
Solutions of YH2 (4x 10-6 mol/L), YH2-Pd (5x 10-6 mol/L) and a supernatant of a saturated solution of a dichloro( 1,10 -phenantbroline) palladium (ll) in DCM were used to obtain UV-VIS spectra for the preceding compounds.
Monitoringthe reduction of Pd OJ) with UV-Visible spectroscopy
Catalyst YH2-Pd (4.2 mg, 0.005 mmol, 0.005 equiv) was added to a Schlenk flask (50 mL) fitted with a rubber stopper. The vessel was degassed and filled with N2. All the manipulations hereafter was carried under Ar conditions inside the glove box. DMF (4 mL) was added to the flask followed by EtJN (1 mL, 7.11 mrnol, 7.11 equiv) and PPh3 (0.5 mL of a 0.01 M solution in DMF, 0.05 mrnol,
0.05 equiv). The stirred mixture was irradiated using a 13 W LED lamp.
UV-VIS spectra were obtained in 0, 10, 60, 120, 240 min time intervals after irradiation. Samples for UV-VIS were prepared by diluting 15 µL of the reaction mixture in a 2.5 mL DCM solution in a quartz cuvette at each time interval.
40 2.4.2. Fluorescence spectra
Emission and excitation spectra for ligand YH2 and catalyst YH2-Pd were recorded.
Stock solutions ofligand YH2 (1.74 xl 0-4 mol/L) and catalyst YH2-Pd (1.00 xI0-4mol/L) were prepared and 60 µL and 50 µL from the stock solutions were diluted in 2.5 mL DCM to give 4.00
x l 0-6 mol/L and 2.08 xI0-6 mol/L, respectively.
Ligand YH2 emission spectra was recorded at a fixedexcitation wavelength of 375.00 nmwhile
scanning from 400.00 nmto 700.00 nm . Excitation spectrum was recorded with a fixed emission wavelength at 620 nmwhile scanning in 350-600 nmrange.
Catalyst YH2-Pd emission spectrum was recorded at a fixed excitation wavelength of 3 71.40 nm while scanning from 400 nmto 750 run Excitation spectrum was recorded with a fixed emission wavelength at 600 nmwhile scanning in 350-585 nmrange.
2.4.3. Monitoring the reduction of Pd(II) with 31P NMR studies
Investigation of the system YH2-Pd, PPh3 and Et3N
Catalyst YH2-Pd (8.5 mg, 0.025 rnmol, 0.025 equiv) was added to a Schlenk flask (50 mL) fitted with a rubber stopper. The vessel was degassed and filled with N2 followed by the addition of
DMF (4 mL). Then EtJN (1 mL, 7.11 mmol, 7.11 equiv) and PPh3 (x=2, 4.0 mg, 0.05 mmol, 0.05 equiv) were added respectively via syringes to the stirred reaction mixture under N2 conditions.
Afterirradiating the sample for four hours CDCb (-0.5 mL) was added to the reaction mixture in the glove box and the NMR tube was prepared.
41 2.4.4. Electrochemical procedure for cyclic voltammetry
Experiments were carried out in a three-electrode cell with Pt working electrode, Ag wire reference electrode at room temperature connected to a Ni supply as shown in Figure 2-2 (a). AJI three compartments were filled with nBll4NBf4 (0.1 M) in acetonitrile followed by purging N1 for 20 minutes. To the working electrode containing compartment, the compound of interest (- 4mg) and
1 ferrocene were introduced. Cyclic voltammetry was performed at 100 m Vs· •
For the mechanistic studies the sample was irradiated for 4 hours before performing cyclic voltammetry as shown in Figure 2-2 (b).
(a) (b)
Figure 2-2. Reaction setup shov. ing the three-electrode cell equipped \\ ith a stir bar under Ni
conditions (a) general setup (b) setup for illumination
42 CHAPTER 3
Results and discussion
3 .1. Synthesis and purification
The synthesis of the Palladium complex YH2-Pd followedthe steps shown in Figure 3-1.
H
sc0, Dlo:une, reflui: fY
(Pd(PbCN)zCI,)
Figure 3-1. Schematic diagram of the synthesis of catalyst YH2-Pd
43 Oxidizing 4,7-dimethyl-1, 10- phenanthroline with Se02 furnished the dialdehyde product, YHl
as a yellow solid with 30% yield. Compound YHl was reacted with 2,4-dimethylpyrrole in
distilled DCM followed by the addition of two drops of TF A. DDQ was added to the reaction
mixture to oxidize the carbon connecting two 2,4-dirnethylpyrrole and the phenanthroline moiety.
This was followed by addition ofBf3·Q(C2Hs)2 resulting the coordination of the two N atoms from
the pyrrole rings to BF2 units in the presence of in the presence of EtJN. A green florescence was
observed upon irradiation with a flashlight which confirmedthe formation ofBODIPY. The ligand
(YH2), was purified with successive column chromatography with DCM/MeOH (v:v, 200:5) and
CHCb/MeOH (v:v, 100: 1) as the eluent systems to give a bright orange solid with 15% yield. The catalyst (YH2-Pd) was prepared by reacting the ligand with [Pd(PhCN)2Ch] in CHCb, which
resulted in a brownish red solid with 91 % yield after purification with column chromatography
DCM/MeOH (v:v, 200:5) as the solvent system. Compounds YHl, YH2, and YH2-Pd were
characterized with 1H NMR, UV-VIS, fluorescence spectroscopies and cyclic voltammetry.
44 3.1. Characterization with 1H NMR
3.1.1. 1H NMR ofYHl
l H H 1
1H NMR (400 MHz, CDCb) o 10.54 (s, 2H), 9.54 (d, J= 4.32 Hz, 2H), 9.23 (s, 2H), 8.09 (d, J
=4.32 Hz, 2H)
IHNMR of compound YHl is illustrated in Figure A-3. Due to the two-fold symmetry of the YHl, only four major peaks were observed. The protons in the aldehydes labeled as 1 H resulted in the most de-shielded singlet peak at 10.54 ppm. The compound was identified by the aldehyde H which is not present in the starting material. The aromatic proton next to the nitrogen is the next most de-shielded proton which appears as a doublet at 9.54 ppm with a coupling constant of 4.32
Hz. A singlet was observed at 9 .23 ppm corresponding to the aromatic protons labeled as 3H. The aromatic proton labeled as 4H appears at 8.09 ppm as a doublet with a coupling constant of 4.32
Hz confirmingthe coupling between protons labeled as 2H and 4H.
Several residues of the solvents used in the synthesis and purification process were observed in the spectrum, which were identified to be DCM at o 5.32 ppm, dioxane at o 3.72ppm, acetone at o
2.19 ppm, H20 at o 1.66 ppm, and methanol at o 1.27 ppm.
45 3.1.2. 1H NMR ofYH2
5
YH2
1H NMR (400 MHz, CDCb) 0 9.36 (d, JH-H =4.44 Hz, 2H), 7.84 (s, 2H), 7.695 (d, 11-1-H =4.44 Hz
2H), 5.97 (s, 2H), 2.58 (s, 3H), 1.09 (s, 3H)
IH NMR of for compound YH2 is illustrated in Figure A-4. All the peaks corresponding to the product were observed. The proton attached to the carbon next to the nitrogen was observed as the most de-shielded proton which was at 9.36 ppm with a coupling constant of 4.4 Hz. The proton
2 labeled as H appeared as a singlet at 7.84 ppm. At 7.695 ppm a doublet was observed with a coupling constant of 4.44 Hz corresponding to the proton labeled as 3H. Protons in the dimethyl pyrrole was observed at 5.97 ppm as a singlet. Methyl groups attached to pyrrole appeared at 2.58 and 1.09 labeled as sH and 6H respectively as singlets. Despite being methyl groups attached to pyrrole, the protons labeled as sH are more de-shielded than 6H due to its proximity to nitrogen in the pyrrole ring.
Several residues of the solvents used in the synthesis and purification process were observed in the spectrum, which were identifiedto be DCM at o 5.32 ppm, acetone at o 2.17 ppm, and H20 at o 1.57 ppm.
46 3.1.3. 1H NMR ofYH2-Pd
5
1H NMR (400 MHz, CDCb) o 9.865 (d, J = 5.36 Hz, 2H), 7.98 (s, 2H), 7.97 (2H), 6.01 (s, 2H),
2.57 (s, 3H), 1.07 (s, 3H)
The 1H NMR of compound YH2-Pd is illustrated in Figure A-5. All the peaks corresponding to the ligand (YH2) were observed, except for that the two hydrogens ( 1H, 2H and 3H) have shifted more downfield than the hydrogens in the ligand YH2 which is due to the attachment of the electrophilic Pd (II). The shift of 3H is higher than shift of 2H, which had resulted in overlapping
3 the signals corresponding to the 3H and 2H. Due to the overlapping, coupling constant for H could not be determined.
Several residues of the solvents used in the synthesis and purification process were observed in the spectrum, which were identified to be DCM at o 5.32 ppm, acetone at o 2.19 ppm, and H20 at o 1.66 ppm, and methanol at o 1.27 ppm.
47 3.2. Characterization with UV-VIS spectroscopy
BODIPY dyes are strongly colored solids which form intensely colored solutions with bright
fluorescence when irradiated.
0.6 An..= 503 nm An..= 509nm
0.5
0.4
-� � 0.3 � c:
0.2 - YH2-Pd
- YH2 - Pd( 1,10-phen)Cl2 0.1
420 440 460 480 500 520 540 560 580 600 Wavelength (nm)
Figure 3-2. Absorption spectra for YH2 4.2 x 1 o·6 mol/L. YH2-Pd 2.1 x l o·6 mol/Land [Pd( 1.10-
phen)Ch] (saturated solution) in DCM
As shown in Figure 3-2, Both the YH2 and YH2-Pd shows typical absorption features of
BODIPY. Both exhibit absorption bands in visible region, assigned to 7t77t* (So7S ) transition 1
with maximum /1.abs at 503 nm (s = l.38x 105 M"1cm-1) and 509 run (s = 1.14 x 105 M"1cm"1)
respectively. Key observations to note are that upon attaching the PdCh to the ligand YH2 the
So7S 1 transition of BODIPY moiety doesn't significantly shift in energy nor in the position and
48 absorption of the reference compound dichloro( I,10 -phenanthroline) palladium (Il) is negligible when compared to the absorption of BODIPY.
As the name states, photo-induced reactions begin with the absorption of photons by a photocatalyst, to generate a high energy photoexcited state of the catalyst. Thus, energy absorbed
by the catalyst is the main driving force of the reaction and one of the most vital characteristics of a successful photocatalyst. The absorption in the visible range ( 400-700 nm) is essential for a photocatalyst as it allows to absorb the maximum energy from photons by avoiding the direct excitation of the organic substrates. Also, the high absorption coefficient in the catalyst is an
indicator of the amount of energy that can be transferred to induce the reaction. Strong absorption of the visible light will ensure that the most of the photocatalysts will be in their excited state, which will enable efficient energy transfer or electron transfer from the fluorophore. Owing to general photophysical characteristics ofBODIPY, YH2-Pd catalyst shows strong absorption in the visible range with maximum absorption at 509 nm which indicates characteristics of a promising photocatalyst.
49 3.3. Characterization with fluorescence spectroscopy
Emission and excitation spectra for YH2 and YH2-Pd are presented in Figure 3-3 (a) and (b), and the spectral data are summarized in Table 3-1.
6e+5
5e+5
4e+5 - ::J co - � 3e+5 ·v; c Q) - c 2e+5
�.=500 rvn
- E.xcrtatioo spectrum 1e+5 - Emission spectrum
0
450 500 550 600 650 700 Wavelength(nm)
(a)
50 A,,..=506nm 40000
30000
...... ::J
-cu ->- 20000 'iii c -Q) c
10000 "--=602nm - Excltaboo speclrum - Emission spectrum
450 500 550 600 650 700 750 Wavelength (nm)
(b)
Figure 3-3 Fluorescence spectra for YH2 -l x 0·0I mol/L (a) and YH2-Pd 2.08 x 10"6 mol/L (b) in
DCM. YI 12 \·\ith an excitation ..,,a,clcngth of 375.00 nm and emission wavelength at
620 nm and YI 12-Pd with an excitation wa\'elength of 371.40 nm emission v;avelength
at 600 nm
The singlet fluorescenceof YH2 is observed at A.cmat 525 nm. Excitation spectrum closely mimics the absorption profile with maximum excitation at 500 nm. Fluorescence of YH2-Pd is centered around 602 nm, and the maximum excitation is observed at 506 nm.
51 6e+5 �ex=525 nm
5e+5
4e+5 - � ('O - >- - 3e+5 ·v; c -Q) c 2e+5
- YH2-Pd - YH2 1e+5
0
450 500 550 600 650 700 Wavelength (nm)
Figure 3-4. Comparison of emission spectra of YH2 and YH2-Pd (YH2 4 x 1 o-6 mol/L (a) and
YH2-Pd 2.08 x 1 0-6 mol/L (b) in DCM. YH2 with an excitation wavelength of375.00
run and YH2-Pd with an excitation wavelength of 371.40 run)
Comparison of YH2 and YH2-Pd emission spectra as in Figure 3-4 shows that upon formation of
the catalyst by attaching the Pd to the ligand YH2, florescence intensity has been drastically
reduced from 600000 to I 0000 a.u. Fluorescence can be quenched in several ways, which includes
energy or electron transfer from the excited molecule to another molecule, heavy atom effect or
charge recombination process.
In the YH2-Pd catalyst, Pd is not directly attached to the BODIPY. Also, BODIPY molecules are
perpendicular to the phenanthroline moiety which is connected to the Pd center. Because of this
alignment of the units in the catalyst, the effect of the heavy atom (Pd) to the BODIPY is inefficient
52 as there is no electronic interaction between the BODIPY and the Pd connected phenanthroline.
However, several studies have suggested the charge separation and charge recombination process to explain the quenching of the florescence in similar BODIPYs which are not directly connected to the heavy atom.43b Further information about the quenching of fluorescence and formation of triplet state in BODIPY can be found in reference 43b.
Rationales behind a successful photocatalyst are to have strong absorption in visible light, high triplet state quantum yield, long-lived triplet excited state and tunability of the structure.43a
Coordination of the YH2 ligand to the Pd center significantly quenches the fluorescence which could an indication of high triplet state quantum yield as required by a successful catalyst.
However, the quantum yield, life-time measurements must be done to explain the successfulness of the proposed catalyst.
53 3.4. Cyclic voltammetry studies
The electrochemical properties ofYH2 and YH2-Pd were measured in acetonitrile, and the results
are summarized in Table 3-1, presented in V versus Fc+/Fc (Fc-Ferrocene).
15 Epc=-1.498 V
10
s
� 0 ...., c -5 ....QJ ::I u ' -10 E a=·l.378 V p E112=1.44 V (120 mV) -15
-20
-25 - 1.5 1 0.5 -0. -1 ·1.5 -2 2.5 0 S Volts vs. Fc+/Fc
Figure 3-5. Cyclic 'oltammogram for YH2 in MeCN I 0.1 M N-Bu�rr,,. W: Pt disk. Aux: Pt
\.\ire. Ref: Ag v.ire. Scan rate - 100 mV/s
The cyclic voltarnmogram of ligand (YH2) in Figure 3-5 displays one reversible reductive wave at Ep.c = -1 .498 V and an irreversible oxidative wave at 0.982 with a shoulder at 0.822 V. Reduction and oxidative wave separation was found to be 2.3 V which is in close range for the characteristic value of 2.5 V for the compounds with green fluorescence as reported by Bard et al.49
54 10
5
0
.., c Epa=-1.303 V �-S- .... � E112=1.33 V (73 mV) ::I ::I U-
-10
-15
-20 1.5 1 05 0 -0.S -1 ·1.5 -2 ·2.5 Volts VS. Fc•/Fc
Figure 3-6. C) clic 'oltammogram for Y I12-Pd in MeCN I 0. 1 M N-Bu-1PF". \\.': Pt disk. Aux: Pt
\\ire. Ref: Ag '"'ire. can rate = 100 m V/s
10.00
Epc = 0.378 V
5.00 Epc = -1.256 V
� 0.00 ::I .., c QI t ·5.00 ::I u
-10.00 V E112 = 0.402
Epa = 0.425 V -15.00 1.5 1 0.5 0 -0.5 ·1 1 - .5 Volts vs. Ag
Figure 3-7. Cyclic voltammogram for c.lic hloro( I.I 0-phenanthrolinc) palladium( II) in MeCN I 0. 1
M N-Bu-1PF,,. W: Pt disk. Aux: Pt \\ ire. Ref: Ag '"'ire. Scan rate = JOO mV/s
55 Presence of these redox waves in YH2 and YH2-Pd shown in Figure 3-6 and absence of these in dichloro( 1,10 -phenanthroline) palladium(II) illustrated in Figure 3-7 confirmed that the oxidative and reductive waves correspond to the BODIPY units in YH2 and YH2-Pd. Peale separation of the reductive pealc is 420 mV which is higher than the 57 m V expected for an electrochemically
reversible one-electron redox process. so BODTPY oxidation appears to be electrochemically irreversible at 1 OOmV /s rate. Electrochemical properties ofthe BODIPY dyes depend on the nature
of the substitution in the meso, alpha and beta positions. Bard et al. 2012 st states that absence of substitution at positions of2,3,5 or 6 causes formation of unstable radical cations upon oxidation,
which explains the irreversible oxidative waves as 2 and 6 positions are not substituted in YH2 or
YH2-Pd.
Both the ligand and the catalyst (YH2 and YH2-Pd) consist of two BODIPY units per each molecule. According to the crystal structure Figure A-1 these two BODIPY molecules are in
78.25° to the plane of the phenanthroline molecule which explains the single oxidative and reductive waves. If these two BODTPY units can communicate with each other, two one electron waves should be observed. Electrochemical studies of the BODIPY containing YH2 and YH2-Pd show the presence of one-electron reduction and oxidation waves suggesting the lack of communication between the two BODIPY units.
56 Table 3-1: photophysical and electrochemical properties of the ligand ( YH2) and the catalyst
(YI-12-Pd)
E112 (Fe/Fe+) Compound A.max(ab)/nm c*/ 105LmoJ·1em·1 A.max(fl)/nm AJA- AJA+
YH2 503 1.38615 525 -1.44 0.88
YH2-Pd 509 1.13808 602 -1.33 0.89
57 3.5. Sonogashira C-C cross-coupling reactions
3.5.1. C-C cross-coupling between bromobenzene and phenylacetylene
Table 3-2 summarizes the results for the coupling between bromobenzene and phenylacetylene
using YH2-Pd.
0-···< ) A review of the literature provided the most common conditions used in Sonogashira reaction,
which comprises of DMF as the solvent, either Et3N or PPh3 or both as the electron donor, under
inert conditions and varying temperatures from room temperature (RT) to 120 °C. Therefore, for
the experimental purposes, Et3N and PPh3 as bases, DMF as the solvent and RT were selected as
the preliminary reaction conditions. Entries 1-4 served as controls, and in entry 5 all the reagents
mentioned above, and the conditions were used. However, no product was detected by GC-MS analysis. In the following entries, a different light source (13 W LED), longer period of reaction
time, higher loading of the catalyst, and higher temperature were used. However, considerable
activity of the catalyst was not observed. Several possibilities were considered for the
unproductiveness of the reaction. Inability to obliterate oxygen completely from the system,
incapability of YH2 to act as a photocatalyst and underactivity of the substrates. As most of the
Sonogashira coupling reactions were performed with iodobenzene including the original work, it
was speculated that using a halide which has a lesser bond stn:mgth than C-Br bond will be
beneficial. Based on that, the next set of experiments were conducted with iodobenzene as the
substrate, which is summarized in Table 3-3.
58 Table 3-2. C-C cross-coupling between bromobenzene and phenylacetylene
Entry Catalyst System Conditions GC-MS yield Mol Light EbN PPhJ N2 Time/h Temp (%) 0/o cat source/W 32 + 3 rt ND
2 + 32 + 3 rt ND
3 + 32 + 3 rt ND
4 YH2-Pd 0.5 32 + 3 rt ND
5 YH2-Pd 0.5 + + 32 + 3 rt ND
6 YH2-Pd 0.5 + + 13* + 4 rt ND
7 YH2-Pd 0.5 + + 13* 4 rt ND
8 YH2-Pd 0.5 + + 13* + 4 40 ND
9 YH2-Pd 0.5 + + 13* 4 40 ND
Pd(PPh3}2Ch, 10 5 + + + 17 rt Small Cul
* 11 YH2-Pd 5 + + 13 + 16 rt 0.6
* 12 YH2-Pd 5 + + 13 12 rt ND
13 YH2-Pd 5 + + + 12 rt 0.1
14 YH2-Pd, Cul 5 17 rt 0. 2
15 YH2-Pd 5 + + 13* + 17 60 0.7
* Notes: 13 W LED; +: provided; -: not provided; and ND, not determined
59 3.5.2. Coupling between iodobenzene and phenylacetylene- reaction optimization
A screen of palladium-catalyzed Sonogashira coupling reaction conditions revealed that coupling of iodobenzene to the phenylacetylene could be best affected using Pd(II) catalyst, Et3N, and PPh3 in DMF or THF medium. Following that several reaction conditions were tested as shown in the
Table 3-3.
Q-1+( ) - Table 3-3. C-C cross-coupling between iodobenzene and phenylacetylene
Entry Catalyst system Conditions GC-MS yield (%) Mol Light % EbN PPhJ source Ni 4h 17 h 24 b cat LED/ W YH2-Pd 0.5 13 + ND ND ND
2 YH2-Pd 0.5 + 13 + 6 14 18
3 YH2-Pd 0.5 + 13 + 0.06 3 5
4 YH2-Pd 0.5 + + + 5 22 25
5 YH2-Pd 0.5 + + 13 + 28 86 94
6 + + 13 + ND ND ND
7 + + + ND ND ND
8 (Pd( 1, 1 0-phen )Ch] 0.5 + + 13 + 3 13 17
Notes: +: provided; -: not provided; ND; not determined
Among the entries, entry 5 indicates the highest yield, when YH2-Pd catalyst, Et3N, PPh3, light and inert conditions were used. The same coupling reaction when carried out without the above- mentioned reagents (entries 1 to 5), demonstrated that, for the C-C coupling with the new catalyst
60 (YH2-Pd) the following reagents and conditions; Et3N, PPh3 and light are essential. Out of Et3N,
PPh3 and light EtJN seems to be the most crucial reagent as it gave the lowest yield which is 6%.
With all the conditions present 92% GC-MS yield was obtained for the cross-coupling product
without any evidence for the homocoupling product. When THF was used as the solvent, no
product fonnation was observed. These results confirmed the catalyst system of YH2-Pd 0.5
mol%, EtJN, PPh3 and light under the inert condition in DMF reports the best results for the
coupling of iodobenzene and phenylacetylene. Comparison of the entries 4 and 5, indicates the
importance of light whereas entries 5 and 8 depict the involvement of BODIPY in the reaction.
These results establish the photo-catalytic property of the YH2-Pd.
After establishing the conditions, the reaction was monitored for 24 hours in 4-hour intervals.
According to the results depicted in Figure 3-8, reaction progresses up to 17 hours and then the
rate decreases, which may be due to either the depletion of starting material or the degradation of
the catalyst.
120
100
"C 80 Qi � '#. 60 (/) ::2 0 C> 40
20
0 0 5 10 15 20 25 Time/h
Figure 3-8. Reaction progress with time monitored with GC-MS
61 3.5.3. Substituent effect on Sonogashira C-C cross-coupling reaction between
iodobenzene and phenylacetylene
To probe the substrate scope of the photocatalyzed Sonogashira C-C cross-couplings reactions, a variety of para-substituted derivatives of iodobenzene and phenylacetylene were used. Table 3-4
summarizes the results for the Sonogashira coupling reactions with substituted starting materials.
0.005 mmol 1.2 mmol 1.0 mmol
Entries 11-14 show that substitution at the para position of the phenylacetylene has a minimal effect on the product yield. However, the entries 1-10 depict the opposite with the iodobenzene derivatives. Substituent groups were varied from electron donating to electron withdrawing groups. Regardless of the nature of the substituent, product yield was lower than the model reaction.
A similar observation has been reported by Kobayashi52 for the visible light mediated Ullmann type C-N coupling reactions. Where they have observed a reduction in product yield with iodobenzene derivatives. This study exploits the use TTET in a dual catalyst system which will be discussed in detail in section 3.8.
62 Table 3-4. Substituent effect on Sonogashira C-C cross-coupling reaction between iodobenzcnc
and phenylacetylene
GC-MS yield (%) Entry R1 Ri 4h 17 h 24 h H OCH3 7 18 36
2 H NH2 ND ND Very low 3 H CH3 27 74 83 4 H H 23 86 92 5 H Cl 15 43 50 6 H COO Me 11 20 23 7 H COOEt 12 38 40 8 H CHO 2 8 9 9 H CN 8 15 33
10 H N02 ND 8 18 11 CH3 H 17 91 98
12 N(CH3)2 H 44 82 87 13 N02 H 40 63 64 14 CN H 66 86 88
Notes: ND; not determined
The exact mechanism of the Pd catalyzed Sonogashira C-C cross-coupling reaction is not well understood due to the complications arising with the use of two metals. Several studies of thermal alternatives for Sonogashira reaction have presented few general rules regarding the factors influencingthe reactivity of individual substrates. Among them includes that oxidative addition of aryl halide is promoted by electron withdrawing groups at the aryl halide. 53 In contrast to the thermal methods, photochemical methods have shown the opposite substituent effect. Albini et a122 report that the photolysis of aryl halides is supported by electron donating groups at the aryl halide as the photolysis goes through a phenyl cation.22 From the results summarized in Table 3-
63 4, it's evident that the substitution at the para position negatively affects the product yield. This could be due to several reasons such as steric effects in transition states, electronic effects changing the rate of the reaction and YH2-Pd following a distinct mechanistic pathway.
However, further investigations are required to explain the results effectively. Kinetic analysis of
Sonogashira reaction with the YH2-Pd catalyst system will provide the evidence to support or reject the electronic effect. Besides, computational studies for the mechanism will help to identify the intermediates and transition states which might give an insight in to the mechanism. However, both are out of the scope of this thesis project.
64 3.6.4. Mixture ofBODIPY and [Pd(phen)Ch] as a catalyst system
To investigate the possibility of using the mixture of BODIPY and [Pd(phen)Ch] as a catalyst system, BODIPY termed AH7 was added to the reaction mixture containing [Pd(phen)Ch] in 2: 1 molar ratio of AH7: [Pd(phen)Ch]. Results for the coupling between iodobenzene derivatives and phenylacetylene are compiled in Table 3-5.
+ I R, R2 j Ugh• N,. rt R1 ( ) -o- [Pd(phen)Cli] 0.005 mmol l.2 mmol l.O mmol AH7 0.01 mmol
Table 3-5. Sonogashira C-C cross coupling reaction with a mixture of BODIPY and [Pd(phen)Ch] as a catalyst system
Entry R1 GC-MS yield (%) 4h 17 h 24 h H H 15 84 87
2 H OCH3 3 20 21
3 H CH3 9 9
4 H N02 0.6 3 3
65 Under BODIPY and (Pd(phen)Ch] catalytic manifold, highest yield was reported in the entry 1, when the hydrogen substituted starting material was used. The highest yield being 87% is still less than the yield when YH2-Pd was used as the catalyst which was 94%. Substitutions at the para position in the iodobenzene gave a similar pattern of yields as the YH2-Pd catalytic system. This led to speculate that both catalytic manifolds may follow the same mechanism which will be discussed under the proposed mechanism in section 3.7.
66 3.6. Mechanism elucidation
3.6.1. UV-VIS spectroscopic studies
Mechanistic investigations were carried out using UV-VIS spectroscopy. According to the proposed mechanism for the conventional Sonogashira coupling reaction, ditforent palladium based complexes are being formed at each stage which might be able to be observed by UV-VIS spectroscopy. To probe the changes in UV-VIS spectra upon addition of each substrate, several attempts of reaction monitoring with UV-VIS spectroscopy were carried out. In the fust two trials, after addition of each reagent, a sample was taken out from the original reaction mixture, and it was diluted in the cuvette. The prepared sample in the cuvette was subjected to irradiation and
UV-VIS spectra were obtained in specific time intervals. However, in this method, the only noticeable observation was the disappearing of the BODIPY absorption peak with no changes in peak position illustrated in Figure A-10. Comparison of a fresh sample from the original reaction mixture with the irradiated cuvette sample revealed that absorptiondue to BODlPY was remaining which is shown in Figure A-11. This difference may be due to the ability of the glass to filterUV rays out while when quartz is used (cuvette), it allows UV rays to pass through. Another possible reason is that, due to the presence of oxygen in the solvents might have affected the stability of the complexes.
These observations led to irradiate the original reaction mixture in the glove box and take samples out when necessary. With this modification in the procedure, EtJN and PPhJ were introduced consecutively to the reaction mixture and reaction was monitored after addition of each reagent and the results are shown in Figure 3-9.
67 0.6
min IL Q) - YH2-Pd+Et3N 0 g 0.4 min IL co - YH2-Pd+Et3N 60 .0 .... YH2-Pd+Et3N+PPh3 60 min IL 0 - en .0 �
0.2 t
440 460 480 500 520 540 560 580 600
Wavelength (nm)
Figure 3-9. Monitoring the reaction with time upon addition of EtJN and PPhJ consecutively with
illuminating (IL) the reaction mixture with YH2-Pd-3.04x 1 o-<> mol/L in DMF
The characteristic BODIPY absorption peak was observed in all three steps. However, upon
addition of PPhJ to the reaction mixture resulted in an unidentified absorption peak centered around
540 nm. This Jed to monitor the formation of the unidentified absorption peak. For this EtJN, PPhJ
were combined with the catalyst and it was monitored with time. Figure 3-10 shows that afterone
hour the new species was fanned.
68 0.5
0.4
- Q) 0.3 OminlL 0 - c 10 minlL nJ -- 60min IL .0 -- � 120 minIL 0 en - 240 minIL .0 0.2 <( 0.1 I
0.0
440 460 480 500 520 540 560 580 600 Wavelength (nm)
Figure 3-10. Monitoring the fom1ation of the unidentified species upon addition ofEtJN and PPh3
with YH2-Pd-3.04x 10-6 mol/L in DMF
69 3 .6.2. 3 'P NMR studies
Investigation of the system YH2-Pd + 2 PPh3
As an attempt to characterize the peak observed in the UV-Vis reaction mechanism monitoring
3 (section 3.3.1.) 1P NMR was employed. A mixture of YH2-Pd (0.025 mmol), EtJN, and PPh3
(0.05 mmol) in DMFwas irradiated for four hours before samples were taken out for NMR study.
The active catalytic species in Pd catalyzed coupling reactions is known to be the reduced Pd complexes in (0) or (+I) oxidation states. Based on the YH2-Pd catalyst structure, the possibilities of binding of PPh3 to the neutral Pd complex or Pd(I) complex is either two or one. Binding of
PPh3 to the reduced Pd center should shiftthe signal forphosphorus from its free formto the bound
3-11. form. Results are summarized in Figure
A-6, In the NMR spectrum illustrated in Figure two peaks, shorter peak at 01 = 27.55 ppm and a
stronger peak at 02 = 26.91 ppm were observed. However, the characteristic signal for the free
PPh3 (o -4. 75 ppm) was not observed. Both signals disappeared upon the addition of a large excess of PPh3 (-23 equivalents), and two new peaks were observed as shown in Figure A-7. The peak
at OJ = 28.33 was smaller compared to the signal observed at 04 = -4.65 ppm which could be reasonably assigned to the free PPh3 comparing to the reported value in the literature (o -4.75 ppm)54 and the relative strength of the peak. Literature indicates the signal for the [Pd(PPh3)4] at o
4 = 29.8 ppm.5 8J peak is in close range forthe [Pd(PPh3)4]. The added excess of PPh3 might have displaced the YH2 ligand from the YH2-Pd catalyst resulting [Pd(PPh3)4]. 01 and 0i remained unassigned at this stage.
70 -4.65 28.33
27.46
·4.90
24.79 '1 YH2-Pd:PPh_ I: I 0 + Phi � I L
27.49 I YH2-Pd:PPh3 l:I 0 1.18 ... ---- II 11 YH2-Pd:PPh3 -l :23 ! I _.)11 '--
27.55 26.91 YH2-Pd:PPh. I :2
:c pp:'"!
Figure 3-1 1. 31 P NMR spectra forsystems with different Pd/PPh3 molar rat ios
Investigation of the system YH2-Pd + I 0 PPh3
Further investigations were carried out following the same procedure as above except for adding
10 equivalents of PPhJ instead of 2 equivalents and the results are illustrated in the Figure A-8.
Interestingly the NMR showed one sharp signal at 04 = 26. 76 and a broad signal at Os = 1.18 ppm.
04 is differing from 01 only by I ppm which suggests that both signals could represent the same
compound. The broad peak suggests an equilibrium. In 1992 Amatore reported a broad peak in 31P
NMR when 10 equivalents of PPh3 was added. They identified this peak to be an average signal
71 of zerovalent palladium species which are in fast equilibrium with each other, [Pd0(PPh3)3),
[Pd0(PPh3)2] and PPhJ.
Addition of iodobenzene to the reaction mixture resulted in the disappearance of the broad peak os = 1.18 ppm and appearance of a new peak at 06 = 24. 79 ppm which is illustrated in Figure A-
9. 06 = 24.79 ppm could be benzene and iodine substituted Pd complexes. These results led to speculate that the 01 = 27.55 ppm and 02 = 26.94 ppm to be the PPh3 substituted YH2-Pd. When
Pd:PPh3 was 1 :2 it could result in the complex (a) at 01 = 27.55 ppm where one PPh3 is coordinated to the Pd center while a solvent molecule(s) or Et3N is coordinated to the other vacant site whereas when PPhJ was added in l 0 equivalent, both coordination sites can get coordinated with PPh3 which results in the complex bat Oi = 26.91 ppm. These findings are in compliance with the first step in the catalytic mechanism reported for any coupling reaction where the Pd(II) is reduced to its Pd(O) oxidation state to generate the active catalytic species in-situ.
72 3.6.3. Cyclic voltammetry studies
Cyclic voltammetry experiments could offer insight as to whether any electronic changes take place. Shiftin wave positions will indicate any changes in oxidation states of the species involved.
The two primary mechanisms by which a photocatalyst operates is either by a single electron transfer (SET) process or energy transfer process. SET consists a redox reaction which will change
the redox waves in the voltammogram. To investigate whether an electron transfer process is involved with the photocatalyst, a solution of YH2-Pd was irradiated for four hours before cyclic voltammogram was taken. The results are summarized in the table 3-6 and the resultant voltammogram is shown in Figure 3-12. Values are presented in V versus Fc+/Fc (Fc-Ferrocene).
Table 3-6. Comparison of irradiated and non irradiated samples with cyclic voltammetry
Compound E112 (Ferrocene) - AJA A/A + Pd YH2-Pd -1.33 0.89 -1.24
YH2-Pd-irradiated -1.31 0.91 -1.23
73 YH2-Pd in MeCN- Irradiated Epe=-1.356 v 15 EPC=-1.2t0 V ' 10
5
� 0 .....,c Cl) � 5 � / ::I u Epa=-1.262 V ·10 El/2=-1.309 V (94 mV)
·15
-20 � �=0.905 V -25 -2 1.5 1 0.5 0 -0.5 ·1 ·1.5 -2.5 Volts vs. Fc+/Fc
Figure 3-12. Cyclic ' oltammogram for YH2-Pd after four-hour irradiation in McCN I 0.1 MN-
Bu..iPF,,. W: Pt disk. Au:\: Pt '' ire. Ref: Ag "' ire. Scan rate 100 mV s
A 0.02 V difference in the redox waves corresponding to the BODIPY between the irradiated
sample and the sample under dark was observed, whereas the reductive peak for the Pd(II) only
changes from 0.01 V. These differences could be within the experimental error which led to
speculate that there is no intramolecular electron transfer involved.
74 3.7. Proposed mechanism
Exact mechanism for the copper co-catalyzed Sonogashira or copper-free Sonogashira is not fully understood yet. However, generally accepted mechanism for a palladium-catalyzed cross-coupling reaction consists of oxidative addition, transmetallation and reductive elimination as the elementary steps.21 Mechanistic suggestions for copper-free Sonogashira is scarcely reported yet alone for the photocatalyzed Sonogashira. Combining the experimental evidence and the information available a mechanism is proposed for the catalytic activity of YH2-Pd. A full outline of the proposed mechanism is illustrated in Figure 3-13.
75 Ill 0 $• Solvent
b N...... _ ,....N- ri\
Figure 3-13. Proposed mechanism for YH2-Pd catal)st in Sonogashira C-C cross-coupling
reaction.
76 Initiation
Reaction initiation entails the reduction of Pd(II) to Pd(O). As the neutral Pd is generated PPhJ is
coordinated to the Pd to satisfy the coordination (intermediate 1, Figure 3-13). There are several
other possibilities for the neutral complex as Pd could be coordinated by the solvent used; DMF
or the base; EtJN as well. However, based on previous literature reports 15, 55 and previous work in
our group (which has not been published yet), coordination with PPh3 is proposed. The
unidentified peak at 540 nm in UV-Vis reaction monitoring, and the NMR peak 02 = 26.94, led to
speculate the formation of the intermediate 1.
Oxidative addition
The catalytic cycle commences with the oxidative addition of the iodobenzene. Oxidative addition
0 to a low valent (14 electrons), electron-rich metal (Pd ) involves breaking of a substrate a bond
and formation of 1 or 2 new M-L a bonds. This process is accompanied by an increase in metal's
coordination number by I or 2 units respectively. Oxidative addition with aryl halides are known
to undergo either by dissociative or associative mechanisms. Dissociative mechanisms are favored
by the presence of bulky ligands, whereas an associative mechanism is followed by complexes
with less bulky ligands. Hartwig and coworkers were able to isolate tri coordinated Pd(II)
complexes which indicated the oxidative addition through dissociative pathway.56
Addition of the iodobenzene to the Pd center will mediate through dissociation pathway as the
oxidative addition requires a low valent metal center. The decrease of the intensity of the peak 8i
= 26.94 ppm and the emergence of free PPh3 afteraddition of iodobenzene to the reaction mixture containing YH2-Pd, EtJN, and PPhJ, support the idea of dissociation of PPh3 to from the Pd(O) to
77 form the low valent YH2-Pd(O) intermediate to which iodobenzene will be added oxidatively to form the intermediate 2.
Deprotonation
In the next step, acetylene is coordinated by the Pd center accompanied by the removal of the iodide. Slightly different mechanisms have been proposed for copper co-catalyzed and copper-free
Sonogashira. In the copper co-catalyzed Sonogashira reaction, acetylene interacts with copper through T12 bond, which facilitates the deprotonation of the terminal H from the alkyne by increasing the acidity of the terminal H. Deprotonated alkyne which is coordinated to copper will be transferred to the palladium center. However, in the absence of copper, two competing mechanisms based on the order of the deprotonation and the substitution, have been proposed.
Adapting these mechanisms to explain the YH2-Pd catalytic cycle is challenging.20-21, 57 In the design of the YH2-Pd, use of phenanthroline serves the purpose of the elimination of the cis-trans isomerization step which is required in the conventional catalyst system. Therefore, the formation of the intermediate which gives rise to the anionic pathway cannot be related (Chapter 1, section
1.1.4.). However, after the oxidative addition step, iodine will be substituted by the phenylacetylene which will result in a cationic intermediate and this could be related to the cationic pathway.
Reductive elimination
In the reductive elimination step, C-Pd-C angle get decreased and a new bond is formed between the carbon atoms which were attached to the Pd center, and the product is eliminated via the reductive elimination by generating the Pd (0) complex to complete the catalytic cycle.
78 Role of BODIPY
Although Sonogashira coupling reaction can operate in the absence of BODIPY (Table 3-3, entry
8), reactions in which it is present gives high product yield (Table 3-3, entry 5). In addition to that, the fact that visible light has an impact on the product yield (Table 3-3, entry 4) confirmed that
BODIPY is playing a crucial role in the catalysis.
A photocatalyst is a molecule which absorbs energy from the visible region and induces a chemical change in another species. The activation of another molecule could be affected by electron transfer, atom transfer or by energy transfer.27 Among them, photo-redox catalysis has been studied extensively due to its wide applications in organic synthesis. On the other hand, triplet triplet energy transfer has been employed scarcely in the field of photocatalysts. One of the early studies that report TTET is by Kutal and his coworkers in 1985 the study of the conversion of norbornadiene to quadricyclane with [Ru(bpy)3)2+ as the photocatalyst. In their study they report the quenching of the phosphorescence upon addition of the norbomadiene with no change in fluorescence, which indicates the selective energy transfer from the triplet state. In addition to that, to support their findings, authors show that an electron transfer is not possible as both oxidation and reduction of the [Ru(bpy)3]2+* is not favored.28· 58
Yoon and his coworkers performed [2+2] cycloaddition for styrene using
[Ir[df (CF 3)ppy ]2(dtbbpy)t ([4,4'-bis(tert-bu tyl)-2,2'-bipyridine ]bis[3,5-difluoro-2-[5-
(trifluoromethyl)-2-pyridinyl]phenyl]iridium(Ill)) as the photocatalyst which mediates through
TTET. The reaction between styrene and the [Ir(dF(Cf3)ppy]2(dtbbpy) t* via electron transfer is not feasible as Iridium catalyst (E112*llVll = + 1.21 V vs SCE) is not capable of oxidizing styrene (E l/2red = + 1.42 v vs SCE).
79 Another approach that utilizes TIET process is reported in dual catalyst systems where the energy transferring photocatalyst is in conjunction with a second transition metal, Bronsted acid or an organic co-catalyst. Many of these reactions involve the photochemical generation of singlet oxygen via energy transfer process, which then interacts with substrates to yield activated substrate which reacts with the co-catalyst to give the desired product.27b
In addition to these preceding examples, use of photocatalyst to directly interact with a second catalytic transition metal have been proposed by Kobayashi to explain the acceleration of Ulman coupling in the presence of [lr(ppy)3] and visible light which is shown in Figure 3-14.
Cul(10mo1%) _ Phooca1 ta1ys1 (2 mo-tl%�•) QD-=\_ r # LiO'Bu, Solvent, LED � N 1s N n. b I H a __ _ Ph 38 Q-Dla 2 __ __
'BuOH
la+ LiO'Bu
la --��cul+(cbz) Li01Bu A
a 3a
LiCu2+(cbz)i D
Ph JPh-1r 2a' Tc
Figure 3-14. Ulman coupling
80 In this system Cul is used as the transition metal catalyst and (Ir (ppy)3] as the photocatalyst. Under
strong basic conditions, Cul forms the Cul amide complex (B) which then be excited from energy
transfer from the Ir based photocatalyst. The formed excited Cu complex then undergoes SET
process with iodobenzene to generate the radical anion 2a', which will be dissociated to give rise
to the phenyl radical which get coordinated to the oxidized Cu center to produce the product 3a.
Authors eliminate the alternative approach that could be used to rationalize the influence of the
photocatalyst by taking the electrochemical properties of the compounds into consideration. The
SET process between the [Ir(ppy)3)* and the copper amide complexes is unfavorable as [Ir(ppy)3)*
•111111 = may not be a sufficientlystrong enough oxidant (E112 -0.3 V vs Fe/Fe+) to oxidize the copper
amide complexes. 52
There are two possible mechanisms by which the Pd center could be reduced to it's Pd(O) state.
One of them being reduced by the excited BODIPY through a SET process. And the other being
reduced by EtJN. Photoexcited BODIPY (BODIPY*) is capable of undergoing electron transfers
in the presence of a suitable acceptor or donor. 59 In the present study, electrochemical studies show
similarity in the voltarnmograrns of the catalyst YH2-Pd under dark and irradiation conditions.
This indicates that upon irradiation there's no intramolecular electron transfer, which supports to
exclude the idea of single electron transfer process (SET) to reduce the Pd. If SET were to happen
so that Pd could be reduced, the redox waves should be shifted after irradiation. This suggests that
Pd was reduced by EtJN. EbN being a crucial reagent (Table 3-3, entry 3) support the mechanism where EtJN is responsible for reducing Pd(II).
In addition, in the present study when bromobenzene was used as the halide for the Sonogashira
reaction, the product was not observed with 0.5 mol% catalyst loading. Even with a 5 mol%
81 catalyst loading less than 1 % yield was obtained (Table 3-2) compared to when iodobenzene was used, 92% yield was obtained with 0.5 mol% of catalyst. Which could be explained using the difference in the bond energies in both halides (C-Br bond energy (285 kJ/mol) is higher than that of the C-I bond (213 kJ/ mol)). Also, when a variety of iodobenzene derivatives were used, irrespective of the nature of the substituent, product yields within 24 hours were decreased compared to the non-substituted iodobenzene. These experimental observations suggest that the effect of BODIPY and light can be related to the oxidative addition step.
Two mechanisms have been used to explain the photoinduced Aryl-halide (ArX) bond dissociation. 60
1. In the absence of a metal, base or a nucleophile which could be excited using UV light can
transfer an electron to ArX to generate ArX radical anion which will dissociate to give the
x· and aryl radical. The radical will couple with the nucleophile to give the target
compound.
2. In the presence of a metal catalyst, visible light will excite the catalyst which will then
undergo an electron transfer to generate the aryl radical which subsequently will give the
desired product.
Inspired by these two mechanisms, three mechanisms can be proposed to explain the effect of
BODIPY in the oxidative addition step.
1. An energy transfer from the excited BODIPY* to the Pd(O) will excite the electron rich
Pd(O). The excited Pd (0) can engage in a single electron transfer process with the
iodobenzene to result in a radical iodobenzene anion which will dissociate to result the
iodide and the phenyl radical which will interact with the Pd radical.
82 2. An electron transfer from the excited BODIPY* to the C-1 bond to from the radical anion
of the halide. The formed BODIPY+* can be reduced with the excess Et3N present in the
medium. The formed (ArX]--, will further dissociate to give the halide anion and the phenyl
radical react with the Pd.
3. An energy transfer from BODIPY* to the C-X bond, which will result in breaking the C
X bond to result in the oxidative addition.
83 CHAPTER 4
Conclusion
Palladium-catalyzed Sonogashira C-C cross-coupling reaction is a fundamentally important
reaction for the formation of C-C bonds. Despite being rank as the third most widely used Pd
catalyzed coupling reaction, the conventional Sonogashira C-C coupling reaction has its own flaws
which includes undesired homo coupling product in the presence oxygen, higher temperatures,
longer duration, higher loading of metals.
To overcome the above-mentioned drawbacks, numerous studies have been reported in literature
over the past years including the use ofcopper free versions, reactions in aqueous media, palladium
free catalysis, heterogenous catalysis and photocatalysis.
Despite the incessant availability of the energy source, photocatalytic approaches have been used
scarcely. Most of the photocatalytic systems reported are heterogenous catalysts systems, which
are known to exhibit lower activities than the homogenous catalysts.48 Homogenous photo
catalytic system reported by Akita for Sonogashira C-C cross-coupling reaction uses ([Ru(2,2 ' -
bipyridine)3]2+) as an energy transfer agent. By using the Ru based photocatalyst, they avoided the
use of Cu as a co catalyst. However, Ru is an expensive metal and it also increases the total metal
loading as the catalyst system. To address the above-mentioned shortcomings a photocatalyst
based on BODIPY was developed. The high absorption coefficients compared to the commonly used Ru and Ir based complexes, absorption in the visible region, efficient triplet state production,
84 long lived triplet states, and ability to modify the structure make BODIPY a suitable candidate as
a component in a photocatalytic system.
The BODIPY based YH2-Pd catalyst was synthesized and purified using column chromatography.
Product and the intermediates were characterized using UV- Vis spectroscopy, 1 H NMR,
fluorescence spectroscopy and cyclic voltamrnetry.
Catalyst was used for the C-C cross-coupling reaction where coupling between iodobenzene and
phenylacetylene was used as the model reaction. YH2-Pd catalyst successfully cross coupled
iodobenzene and phenylacetylene in the absence of Cu(I) co-catalyst at room temperature under
inert conditions upon irradiation with 13W LED bulb. 94% GC-MS yield was obtained after 24
hours with 0.5% loading of the catalyst. To investigate the substrate scope of the photoinduced
Sonogashira reaction various derivatives of iodobenzene and phenylacetylene were used. When
para- substituted iodobenzene were used, desired cross-coupling product yield was lower than the
model reaction, which was true forthe phenylacetylene derivatives as well. However, the deviation
of the product yield from the model reaction was not large for the phenylacetylene derivatives.
With intentions of simplifying the catalyst system a mixture of BODIPY and [Pd(phen)Ch] was
used as the catalyst system. 87% GC-MS yield was obtained after 24 hours with 0.5%
[Pd(phen)Ch] and 1 % BODIPY. Use of derivatives of iodobenzene resulted in the same pattern of
product yield observed forthe YH2-Pd catalyst with low yields in general.
31 As an attempt to get an insight to the mechanism of the YH2-Pd catalyst, several studies using P
NMR, UV-Visible spectroscopy and cyclic voltammetry were carried out. Changes in UV-VIS
spectra upon addition of each reagent showed appearance of a new peak at 540 nm after the
1 addition of PPh3 to a mixture of EtJN and YH2-Pd. Further studies with 3 P NMR revealed the
85 formation of the PPh3 ligated complex upon reduction of Pd (II) to Pd(O) by EtJN and PPh3. To determine the role of BODIPY cyclic voltamrnetry was employed. Irradiation of YH2-Pd in DMF for fourhours did not resulted in any shiftsin the redox waves of the catalyst indicating no electron transfer processes taking place in Pd center and BODIPY upon irradiation. With the aid of these studies, and the evidence from literature the YH2-Pd catalyst is speculated to engage in an energy transfer process during the catalytic cycle.
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95 APPENDICES Appendix A. BODIPY
F2
Figure A-1. X-ra: crystallograpruc structure of Yl l2-Pd '" ith 50% thermal probabilit) sho\\ing
the angle between BODJPY plane and the phenanthrolinc plane.
A 1�
O&-
Ot\- \
or,
Olh-���.-;:=.;...���-.-���--...��..--�.;;;::=---.-���---.�� m 500 100
Figure A-2. Light intensity vs waveJength in 32 W regular lamp (blue) and 13 W LED (1050
Lumens) lamp (red).
B Appendix B. Spectroscopic studies
..... "' -- .,.. - ..,,. if"'\ ...-., "' co- ..... °' 0 •D \0 U'l ""T --...,_ ti) ,..., ,.... -00 "'w ....r- ""' "' "� N 0- ... .,.; ...; "' ; - �°'°' oo an v I v I I s l I 0 0 \ �J 3 3 'Y---H
1 3
2 4
j-- l 1.. l._____ .. I •.,-. -���-, • ...... 1 O 5 1 0 0 9 5 9 0 8 5 8 O ppm CH Ch s s s
1 O 9 8 7 6 5 4 3 2 1 ppm ® �� �
Figure A-3. I he 111 NMR spectrum for YI 11. I he spectrum \\as collected in CDCh v.ith TMS as the internal reference. s=solvent. � ,..., Q) co ,... ,... ,... ,... ,_ \D ,.., °' Q) \D ,_ w ,.., ,..., Q) \D \D °' Ill 0
f1\ °' ,... r-· ,... .n N .... I I s s v \ \/ CH Ch
6 s
5
2 4
1 3
s
l'''''''''l'''''''''l'''''''''l'''''''''l'''''''''l'''''''''l'''''''''l'''''''''l' 'r•• � 1 O 9 8 7 6 5 4 3 2 ppm � �I� �I (�1 �1 Figure A-4. The 111 NMR spectrum for YI 12. The spectrum was collected in CDCI � with TMS as the internal reference. S solvent.
E ... r- ... .,...... , ... "' Q) '° 0 .., .., Q) 00 "' C1\ 0 "' 0 a-°' r- r- .., "' .... s CH Cb s s
v v I I I I I s
s
6 5
4
2 I 1 3
10 9 8 7 6 5 4 3 2 ppm � f� I� (;] ( � Figure A-5. fhc 1 H NMR spectrum for YI 12-Pd. The spectrum was collected in CDCh \vi th TMS as the internal reference. S =solvent.
F ... - "'? � ...... I I a
b a
b
I'" " " " I' "" " " I" " ' ' "I "' " ' 'I "' " " 'I' "" " 'I " " " " 'I " " " "' I" "' "" I' " " " " I' " " " " I '" " " " I' " " .. " I' .. '' " " I.. " .. " 'I " "" "., " " .. "'I "" " " �Tnnrnn .... 29 28 27 2625 24 23 22 21 20 19 18 17 16 15 14 13 12 ppm
31 Figure A-6. P NMR spectrum for Pd:PPh3 I :2 system. The spectrum was collected in CDCb with H3PO� as the reference.
G ...., "' .., �
..,. .;,r1 . I PPh1
Ph3P'- PPh3 '-Pd/ Ph3P/" PPh3
· _jJ \A....�--�..,>...��--�--'���--��--
• --• --� -r------·- .- -. T I r I 30 25 20 1 5 1 o s o -5 ppm
Figure A-7. 31 P NMR spectrum forPd:PPh3 - l :23 system. The spectrum was collected in CDCb "ith I hP0-1 as the reference.
H "' - .., ..... "' - I
b
(Pd0(PPb3)J) (Pd0(PPb3)i] PPh3
I I I - -�-- I ---- 30 25 20 15 10 5 0 -5 ppm
Figure A-8. lip NMR spectrum for Pd:PPhJ I :JO system. The spectrum was collected in CDCIJ with H.iP01 as the rclcrcncc. "' � ... �
,.. .. I ...... I I
�� ...... ���- ·"�������w�����·_.... ,,..lll""l ���"'"���w...-.-...1'·��� �J�-....����� ·4t1· ...... ,...... ,, ..� l ....,. ,. � y- -� � ..-���� �����-.-��� ------����. ..-,. --.--.--��. .-���� �����J---.- �� 30 25 20 15 1 o 5 o -5 ppm
A-9. CDCb Figure '1 P NMR spectrum f'or Pd:PPh1 I:I0 + iodobenzcnc system. The spectrum was collected in with I hP01 as the reference. 0.6
0.5
0.4
(l,) 0 c 0.3 co J::>.... 0 IJ) J::> 0.2 �
0.1
0.0
-0.1 100 200 300 400 500 600 700 800 900 Wavelength (nm)
-- Omin -- 10 min -- 20min -- 30min -- 40 min -- SO min -- 60min
Figure A-10. Absorption spectra for the reaction mi"Xture containing YI 12-Pd. Et�N. PPhJ at di flercnt time in ten als after irradiation in a cuvette. YH2-Pd-3.04x 10-6 mol/L in DMF
L 4
3
Q) 0 c (1J -e 2 0 II) .0 <(
1
200 300 400 500 600 Wavelength (nm)
-- flask -- cuvette
Figure A-11. Absorption spectra showing the difference in the reaction mixtures after irradiating in the cuvctte and the Schlenk nask. YH2-Pd-3.04x l0-6 mol/L in DMF
M Appendix C. GC-MS analysis
9e+9
8e+9
7e+9
6e+9 'ii' Q. :!:!. "' Se+9 Q. "ti Ill !!! < 4e+9
3e+9
10 2e+9 y = 3.922.x - 2 r 2 = 0.9827
1e+9 4.6e+9 4.8e+9 5.0e+9 5.2e+9 5.4e+9 5.6e+9 5.8e+9 6.0e+9 6.2e+9 6.4e+9 6.6e+9
Area s/[s)
Figure A-12. Calibration curve for diphenylacetylene
6.6e+9
6.4e+9
6.2e+9
• 6.0e+9
5.8e+9 :0 � 5.6e+9 Ill Cl> � 5.4e+9
5.2e+9
8 5.0e+9 y = 0.9114x + 6 x 10 r2 = 0.9225 4.8e+9 •
4.6e+9 +-�-.-�-...��...-�-.-�---.��..-�-r-�--.-��..--�� 4.6e+9 4.8e+9 5.0e+9 5.2e+9 5.4e+9 5.6e+9 5.8e+9 6.0e+9 6.2e+9 6.4e+9 6.6e+9
Area s/[s)
Figure A-13. Calibration curve for iodobenzene
N 5.0e+9
4.8e+9
4.6e+9 •
'ii' 4.4e+9 s - .. a. Ill 4.2e+9 � <
4.0e+9 0.5377x+1c>8 y= 0.9213 r2= 3.8e+9 •
3.6e+9 4.6e+9 4.8e+9 5.0e+9 52e+9 5.4e+9 5.6e+9 5.8e+9 6.0e+9 6.2e+9 6.4e+9 6.6e+9
Area sJ(s)
Figure A-14. Calibration curve for phenylacetylene Calculations:
Limiting reagent - iodobenzene or iodobenzene derivative
Method 1: Using product (diphenylacetylene calibration curve) Ap y = [p]
As x=- [s]
Ap = area of the product As = area of the standard
[p] = concentration of the of the product (mol/L) [s] = concentration of the of the standard (mol/L)
[p] x V1 x Vt yield % % = 100 V2 x mo l L.b
0 V 1 = volume after diluting forGC-MS analysis
V2 = volume taken from the reaction mixture
V1 = total volume of reaction mixture
Method 2: Using starting material (phenylacetylene (pa) and iodobenzene (ib) calibration curves)
R =pa or ib
AR y = [R]
As x = [s]
AR = area of the reactant Apa or Aib
As = area of the standard
[R] = concentration of the of the reactant [pa]or[ib]
[ s] = concentration of the of the standard R mol R - ([ ] x Vi x Vi) V2 % yield = 100% mol ib
Method 3: Using percent area of the product (p) and standard (s)
%Ap %As [p] [s]
] . - [p x Vi x Vt o oVo yield - 100 Vo V2 x mo l L.b
p Table A-1. Data and calculations for table 3-3
YH2-Pd
Et3N, rt, 0-1+< ) Light, N2,
V1 Vt (reaction Method of Entry Hour s mol/L As x Ap mol/L pmol Yield % Average I ) IP) sample/mL mixture)/mL calculation
2 4 0.000423 3J03473 7344207427 946725 0.000107462 I.OJ 5.241 5.6884 J E-05 5.69 4 0.000423 2910410 6887333880 737469 0.000105088 1.01 5.241 5.56274E-05 5.56 5.63 17 0.000423 3124067 7392942057 2367974 0.000263078 1.01 5.241 0.000139258 13.93 J7 0.000423 3223887 7629160895 2443 190 0.000246099 1.01 5.241 0.00013027 13.03 13.48 24 0.000297 J 907547 6413286956 1806496 0.000350229 1.01 5.24J 0.000185391 18.54 24 0.00033 2134931 647J0538J8 16940J5 0.000314601 1.01 5.241 0.000166531 16.65 17.60
YH2-Pd
• PPh3 0-··<) Light, N2, rt Vt (reaction Method of Entry Hour (sl mol/L As Ap mol/L V1 sample/mL p mol Yield % x IP) mixture)/mL calculation 3 4 0.000305 2026483 6636J25094 6977 1.15663E-06 1.01 4.741 5.5384 1 E-07 0.06 17 0.000305 2893649 9475834113 1087727 6.33438E-05 I.OJ 4.74J 3.033J6E-05 3.03 24 0.000305 2234279 7316594779 83557J 9.60257E-05 I.OJ 4.74J 4.5981E-05 4.60
Q YH2-Pd
Et3N, PPh3 0-1+( ) N2, rt \ V1 Vt (reaction Method of Entry Hour (s( mol/L As x Ap IPI mol/L p mot Yield % Average sample/mL mixture)/mL calculation 4 4 0.000191 1787846 9371032477 1423467 8.49289E-05 1.01 5.741 4.92453£-05 4.92
4 0.000191 1695230 8885583762 1092678 7 .35495E-05 1.01 5.741 4.2647E-05 4.26 4.59
17 0.000423 3235440 7656500469 3808972 0.000379572 1.01 5.741 0.000220091 22.01
17 0.000423 3330179 7880695384 4103475 0.000375969 1.01 5.741 0.000218002 21.80 21.90
24 0.000423 3176669 7517421954 3686082 0.000388444 1.01 5.741 0.000225236 22.52
24 0.000423 2937617 6951717830 3480520 0.000478738 1.01 5.741 0.000277592 27.76 25.14
YH2-Pd
0-1+( ) Light, N2, rt,
(st V1 Vt (reaction Yield Method of Entry Hour As x Ap mol/L [ibJ mol/L ib mot pmol Average mol/L IPI sample/mL mixture)/mL % calculation
5 4 0.000214 1320102 6182684202 1621363 0.000381 189 1.01 5.741 0.000221029 22.10
4 0.000207 1274269 6156827922 1597532 0.000384762 1.01 5.741 0.000223 10 I 22.31 22.21 17 0.000191 1578989 8276304111 2390450 0.000293558 1.01 5.741 0.0001702 17 0.000829783 82.98 2a
20 0.000191 1614646 8463201028 1659980 0.000199676 1.01 5.741 0.00011578 0.00088422 88.42 2a
20 0.000191 1624524 8514976773 1706379 0.000204099 1.01 5.741 0.0001 18345 0.000881655 88.17 88.29 2a
24 0.000191 1663866 8721 188695 906190 0.000106006 1.01 5.741 6.14665E-05 0.000938533 93.85 2a
24 0.000191 1452506 7613340802 855522 0.0001 13483 1.01 5.741 6.58018E-05 0.000934198 93.42 93.64 2a
R [Pd(phen)C12] ,_ 0-I+o-==\ j == Et3 N, PPh3 \ Light, N2, rt, Vt (reaction Method of Entry Hour Isl mol/L As x Ap mol/L v. pmol Yield % Average IPI sample/mL mixture)/mL calculation
8 4 0.000423 3066097 7255759067 468933 5.54105E-05 1.01 5.74J 3.2J293E-05 3.2J
4 0.000423 3J66J64 74925624 J8 44980J 4.78928E-05 I.OJ 5.74J 2.77702£-05 2.78 2.99
J7 0.000423 2862296 6773474602 J554496 0.00023657 I.OJ 5.74J 0.000J37173 J3.72
17 0.000423 3133938 74J6301265 2018859 0.000222032 I.OJ 5.741 0.000 J 28743 J2.87 J3.30
24 0.000423 3 J896J J 7548048524 3J68257 0.00032970 J I.OJ 5.741 0.00019J 174 J9.J2
24 0.000423 3572287 845363 J373 3498717 0.00026582 J I.OJ 5.741 0.000 J 54 134 15.4 J 17.27
s Table A-2. Data and calculations for table 3-4
YH2-Pd + H,co 1 1 -- 1 0CH3 Et3N, PPh3 ,, ) ,, )-- ) Light, N2, ( ) ( rt (pl or (ib) Vt (reaction yield Method of Entry Hour (s( mol/L As %As x Aib %Ap v. ib mol p mol mol/l sample/ml mixture)/ml % calculation 4 0.000429 14.33 2.81 8.4055E-05 1.51 5.63 7.15E-05 7.15 3 17 0.000429 15.78 7.89 0.0002 1433 1.51 5.63 0.000182 18.22 3 24 0.000425 1394343 3280233925 2732224 0.00098858 1.51 5.63 0.000840423 0.00036 35.96 2b
YH2-Pd H3C CH3 + I , 1 -- 1)-- -0- Et3N, PPh3 , ) � ( Light, N2, ) rt V1 Vt (reaction yield Method of Entry Hour (s) mol/l As x Apa (pal mol/l pa mol p mol Average sample/ml mixture)/ml •1. calculation 3 4 0.000425 1195464 2812365085 2746465 0.00109325 1.51 5.63 0.000929402 0.00027 1 27.06 2b 17 0.000425 1476374 3473214325 1512488 0.00052745 1.51 5.63 0.000448401 0.000752 75.16 2b 17 0.000425 1337556 3146640797 337995 0.00012556 6.61 5.63 0.000467254 0.000733 73.27 74.22 2b 24 0.000425 1463198 3442217388 1251578 0.00043901 1.51 5.63 0.000373219 0.000827 82.68 2b
T YH2-Pd -- + Cl 1 (\. 1) (\ ,}--ct Et3N, PPh3 -0- Light, N2, ( ) rt Vt (reaction Method of Entry Hour Isl mol/L o/oAs %Ap moVL V1 sample/mL pmol yield % Average IPI mixture)/mL calculation 5 4 0.000727 27.94 6.67 0.0001735 1.51 5.63 0.000147 14.75 3 4 0.000722 28.34 7.1 0.00018087 1.51 S.63 O.OOOIS4 IS.38 IS.06 3 17 0.0004 11 17.51 22.38 0.00052S03 1.51 S.63 0.000446 44.63 3 17 0.00042 17.8 20.75 0.00048926 1.51 S.63 0.000416 4 l.S9 43.1 1 3 24 0.000403 17.S7 2S.4S O.OOOS8387 I.SI S.63 0.000496 49.64 3 24 0.000409 17.67 25.2 0.00058326 1.51 5.63 0.000496 49.59 49.61 3
YH2-Pd -- + Mci>JC I (\. 1) (\. 1}--COOMe Et3N, PPh3 ( Light, N2, ( ) ) rt Vt (reaction Method of Entry Hour Isl moVL %As %Ap fp) moVL V1 sample/mL p mol yield % Average mixture)/mL calculation 6 4 0.0004 17.58 5.71 0.0001299S 1.51 5.63 0.0001 1 11.05 3 4 0.0004 11 18.1 S.52 0.00012533 l.S I S.63 0.000107 10.65 I0.8S 3 17 0.000354 2S.6S 15.8S 0.000218S7 1.51 S.63 0.000186 18.S8 3 17 0.00033S 23.32 17.67 0.0002S3S3 l.S I 5.63 0.0002 16 21.SS 20.07 3 24 0.000333 2S.37 20.9S 0.00027499 l.S I S.63 0.000234 23.38 3 24 0.00034 1 2S.64 19.51 0.0002S9SI l.S I S.63 0.000221 22.06 22.72 3
u YH2-Pd -- +EtOOC }--COOEt (, ;) (, ; Et3N, PPh3 <)I Light, N2, < ) rt Vt (reaction Method of Entry Hour Isl mol/L %As o/tAp [p[ mol/L V1 sample/mL pmol yield 0/o Average mixture)/mL calculation 7 4 0.000393 17.87 6.76 0.00014882 1.51 5.63 0.000127 12.65 3
4 0.000393 18.63 6.51 0.00013747 1.51 5.63 0.000117 11.69 12.17 3
17 0.000274 21.59 35. I 0.00044571 1.51 5.63 0.000379 37.89 3
17 0.000274 21.52 35.36 0.00045047 1.51 5.63 0.000383 38.30 38.09 3
24 0.000274 21.53 37.65 0.00047942 1.51 5.63 0.000408 40.76 3
24 0.000274 21.6 37.06 0.00047038 1.51 5.63 0.0004 39.99 40.37 3
YH2-Pd + OHC 1 .. CHO Et3N, PPh3 ) \) Light, N2, < rt
Vt (reaction Method of Entry Hour Isl mol/L 0/o As %Ap {pl mol/L V1 sample/mL pmol yield % Average mixture)/mL calculation
8 4 0.000328 17.81 1.56 2.8761 E-05 1.51 5.63 2.45E-05 2.45 3 4 0.000328 17.94 1.47 2.6905E-05 1.51 5.63 2.29E-05 2.29 2.37 3
17 0.000274 16.32 5 8.3993E-05 1.51 5.63 7.14E-05 7.14 3
17 0.000274 16.15 6.32 0.00010728 1.51 5.63 9.12E-05 9.12 8.13 3
24 0.000274 16.59 6.27 0.00010361 1.51 5.63 8.81E-05 8.81 3 24 0.000274 15.98 6.59 0.000 11306 1.51 5.63 9.61E-05 9.61 9.21 3
v YH2-Pd -- + NC I (\ 1) (\ 1}---CN Et3N, PPh3 ) ( Light, N2, ( ) rt Vt (reaction Method of Entry Hour Is) mol/L %As %Ap mol/L V1 sample/mL p mol yield % Average IPI mixture)/mL calculation
9 4 0.000843 20.59 l.94 7.9467£-05 1.51 5.63 6.76E-05 6.76 3
4 0.000364 17.39 5.54 0.00011593 1.51 5.63 9.86E-05 9.86 8.31 3
17 0.000364 21.66 10.5 0.00017641 1.51 5.63 0.00015 15.00 3
17 0.000364 21.82 10.85 0.00018095 1.51 5.63 0.000154 15.38 15.19 3
24 0.000393 21.53 20.67 0.00037768 1.51 5.63 0.000321 32.11 3
24 0.000393 20.47 21.1 0.0004055 1.51 5.63 0.000345 34.47 33.29 3
YH2-Pd + o2N I N02 Et3N, PPh3 ( ) ( ) Light, N2, rt
(reaction Method of Entry Hour fsl mol/L %As 0/oAp (pl mol/L V sample/mL Vt pmol yield % Average 1 mixture)/mL calculation
10 17 0.000429 29.25 6.86 0.00010053 1.51 5.63 8.55E-05 8.55 3
24 0.000429 24.62 12.03 0.00020945 1.51 5.63 0.000178 17.81 3
w YH2-Pd H3C + H3C Et3N, PPh3 ( ) 0-1Light, N2, rt libl Vt (reaction yield Method of Entry Hour Is) mol/L As x Aib v. ib mol pmol Average mol/L sample/mL mixture)/mL O/o calculation 11 4 0.000429 2190112 SI 11113186 S028339 0.00095627 l.S I S.763 0.000832161 0.000168 16.78 2a 17 0.000429 271S293 6336739790 67S682 0.000IOS98 1.51 5.763 9.22289E-05 0.000908 90.78 2a 17 0.000429 2445227 S706480747 SS9010 9.6366E-OS I.SI S.763 8.38S92E-OS 0.000916 91.61 91.20 2a 24 0.000423 2171947 Sl39799602 104313 l.974E-OS I.SI S.763 l.71778E-OS 0.000983 98.28 2a 24 0.000423 1913767 4S28830061 90674 l.918E-OS l.Sl S.763 1.6690SE-OS 0.000983 98.33 98.31 2a
YH2-Pd (H3CJ2N + (H3C)iN Et3N, PPb3
( ) 0-1Light, N2, rt [ibl Vt (reaction yield Method of Entry Hour Is) mol/L As x Aib v. ib mol p mol Average mol/L sample/mL mixture)/mL % calculation 12 4 4.29E-04 2323S74 5422576429 3629396 0.0006S487 l.S I S.611 O.OOOSS4848 0.00044S 44.S2 2a 17 3.99E-04 2419234 6060986242 1262430 0.000206 1S l.S I S.61 1 0.000 I 746S9 0.00082S 82.S3 2a 24 4.29E-04 2068704 4827780630 80476S 0.0001609S 1.5 I 5.611 0.000136368 0.000864 86.36 2a 24 4.29E-04 2130161 4971204201 74S934 0.00014S38 1.51 S.611 0.000123179 0.000877 87.68 87.02 2a
x YH2-Pd 02N 02N + Et3N, h3 0-I ; () Light, N2, rt Vt (reaction yield Method of Entry Hour Isl mol/L As x Aib fibl mol/L v. ib mol p mot Average sample/mL mixture)/mL % calculation
13 4 4.23E-04 2820223 667391 1036 4740266 0.00070934 1.51 5.611 0.000601 0.000399 39.90 2a
4 4.23E-04 2555282 604694 1940 4297910 0.00070329 1.51 5.61 1 0.000595867 0.000404 40.41 40.16 2a
17 4.23E-04 3099358 7334469494 3099704 0.00042551 1.51 5.611 0.00036052 0.000639 63.95 2a
17 4.23E-04 2463 161 5828942385 2587396 0.00043761 1.51 5.611 0.000370774 0.000629 62.92 63.44 2a
24 4.23E-04 3378375 7994748711 3322701 0.00042132 1.51 5.611 0.000356968 0.000643 64.30 2a
24 4.23E-04 2350395 5562087512 2466 129 0.000435 1.51 5.611 0.000368557 0.00063 1 63.14 63.72 2a
-Pd NC YH2 NC + Et3N, PPh3 0-1Light, N2, ( ) rt Vt (reaction yield Method of Entry Hour Isl mol/L As x Aib libl mol/L v. ib mot p mot Average sample/mL mixture)/mL % calculation
14 4 4. J OE-04 2696470 6574511 143 2650808 0.000402 12 1.51 5.611 0.000340704 0.000659 65.93 2a
4 4. IOE-04 2408 190 5871629200 2440175 0.00041002 1.51 5.611 0.000347391 0.000653 65.26 65.60 2a
17 4.23E-04 2344888 5549055483 924856 0.00016348 1.51 5.611 0.000138508 0.000861 86.15 2a
17 4.23E-04 2584510 6116108482 1053784 0.00017067 1.51 5.611 0.000144606 0.000855 85.54 85.84 2a
24 4.23E-04 2520667 5965027343 844882 0.00013996 1.51 5.611 0.000118584 0.000881 88.14 2a
24 4.23E-04 2247 118 5317687863 794801 0.00014593 1.51 5.611 0.000123639 0.000876 87.64 87.89 2a
y Table A-3. Data and calculations for table 3-5
[Pd(phen)Cl2] + AH7 + Q-1 Et3N, PPh3 \ ( ) Light, N2, rt x Vt Entry v, (reaction yield Hour Isl mol/L As (IX Ap or Aib IPI mol/L lib! mol/L sample mixture) ib mol p mol % Average Method 109) /mL /mL 4 4.86E-04 3225602 6.64 1048228 0.000173254 1.5 I S.741 0.000ISO1922 15.02 17 0.000423 3581220 8.47 1566581 0.0001882 1.51 5.741 0.00016315 0.0008368488 83.68 2a 17 0.000423 3606535 8.53 1612919 0.00019251 1.5I S.741 0.00016688 0.000833 1176 83.31 83.50 2a 24 0.000423 3441621 8.14 1404699 0.00017509 1.51 S.741 0.00015178 0.0008482179 84.82 2a 24 0.000423 3437144 8.13 1080340 0.00013482 1.5I S.741 0.00011687 0.000883 1252 88.31 86.57 2a
[Pd(phen)Cl2] + AH7 OCH3 +H,co • -- , ;,>-- () () Et3N, PPh3 \ 1) , Light, N2, rt Vt (reaction Entry Hour Is) mol!L %As %Ap (pl mol/L Vi sample mixture) pmol yield % Average Method /mL /mL 2 4 0.000538 25.25 1.7 3.61932E-OS 1.51 S.63 0.0000307689 3.08 3 4 0.000526 24.93 1.7 3.S834SE-OS I.SI S.63 0.0000304640 3.05 3.06 3 17 0.000487 30.54 12.47 0.00019905 1.5I S.63 0.0001692185 16.92 3 17 0.000476 30.16 14.79 0.000233372 l.S1 S.63 0.0001983970 19.84 19.84 3 24 0.000439 33.04 17.59 0.000233734 1.5 I 5.63 0.0001987043 19.87 3 24 0.00044 32.51 18.85 0.00025507 1.5 I 5.63 0.0002168431 21.68 20.78 3
z [Pd(pben)C12] + AH? CH3 + H C • 1 -- 1 , I , , -- ( ) Et3N, PPh3 , ) , ) ( ) Light, N1, rt --Vt (reaction Entry Hour Isl mol/L %As %Ap mol/L Vt sample mixture) pmol yield % Average Method IPI /mL /mL
3 4 0.000573 24.91 0.73 I .68027E-05 1.51 5.63 0.0000142845 1.43 3
4 0.000591 24.57 0.62 1.49102E-05 1.51 5.63 0.0000126756 1.27 1.27 3
17 0.000679 26.5 3.86 9.89301 E-05 1.51 5.63 0.0000841034 8.41 3
17 0.000698 27 4 0.000103412 1.51 5.63 0.0000879 134 8.79 8.60 3
24 0.000696 28.24 4.51 0.000111097 1.51 S.63 0.0000944467 9.44 3
[Pd(phen)Cl2] + AH? + 02N 1 -- 1 N02 I ) )-- ) ( ) Et3N, PPh3 \ � ( Light, N2, rt Vt (re.action Ent Vt sample ry Hour s) mol/L %As �o Ap moVL mixture) p mol yield % Average Method I IPI /mL /mL 4 4 0.000384 44.23 0.75 6.5070 I E-06 1.51 5.63 0.00000553 18 0.55 3 4 0.000384 42.35 0.74 6. 70526E-06 1.51 5.63 0.0000057003 0.57 0.56 3
17 0.000384 49.45 4.1 3. 8 67E-05 1.51 5.63 0.0000270483 2.70 3 l l 17 0.000384 49.7 4.46 3.44362E-05 1.51 S.63 0.0000292753 2.93 2.82 3
24 0.000384 51.4 5.33 3.97925E-05 1.51 5.63 0.0000338288 3.38 3
24 0.000384 52.17 5.53 4.06763E-05 1.51 5.63 0.0000345801 3.46 3.42 3
AA