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Applications of Metal Triflates and Assisted Acids as Catalysts for Organic
Transformations By
Mike Sbonelo Sibiya
Thesis submitted in fulfilment of the requirements for the degree
Philosophiae Doctor in
Chemistry in the
Faculty of Science of the
University of Johannesburg
Promoter: Prof. D.B.G. Williams
Co-supervisor: Dr. P.S. Van Heerden
September 2012
i
Acknowledgements
Thanks be to God for all the grace and strength and enabling me to execute this work.
First and foremost I would like to thank Professor D. Bradley G. Williams for his incredible
support, guidance and supervision. Thank you for the enthusiasm showed during our
consultation sessions. The time you took from your busy schedule to read the manuscript is
much appreciated. The skills and knowledge I have acquired during my studies have made me
a better scientist and researcher through your guidance.
I would like to thank Dr. Pieter S. Van Heerden, who has been my manager for quite a long time
at Sasol Technology R&D. Your support, guidance and co-supervision of the project will always
be appreciated. Thank you for introducing me to research and patiently mentoring me in the
organisation up to this stage.
I would also like to thank the following people:
Prof. Mike Green (Newcastle University) for all the support and encouragement while still at
Sasol Technology R&D.
Dr. Cathy Dwyer, for patiently allowing me to take some time and complete this work.
Mr. Petrus Makgoba and Mr Raymond Hunt for all the support and also for understanding if I
had to take leave to execute this manuscript.
Dr. Andile Mzinyati and Mr. Nceba Magqi for taking some time to proof-read and review the
document.
Dr. Mokgolela Mogorosi, Dr. Chris Maumela and Dr. Kenny Tenza for all the support and
scientific discussions on the project.
Dr. Sibusiso Mtongana and Dr. Rita Jordaan for assisting with the NMR analysis at Sasol
Technology Research and Development.
Dr. Megan Shaw, your assistance with NMR analysis at the University of Johannesburg is much
appreciated.
Dr. Michelle Lawton for assisting with the pH measurement instruments.
I would like to thank all my colleagues at Sasol Technology R&D who have sacrificed their time
and effort, to mention, but a few: Mrs. Mariam Abrahams, Dr. Norah Maithufi, Mr. Molladi
ii
Maseloane, Dr. Dave Morgan, Dr. Hendrik van der Westhuizen, Dr. Peter Bungu, Dr Irene
Kamara, Mr. John Smith and Dr. Esti van Ryneveld for support and encouragement.
I would also like to pass a word of thank you to the Acid and Base Catalysis team at Sasol
Technology R&D for all the support (Bongani Mdakane, Zibuyile Mncwabe and Dr. Daphne
Radebe).
To my family
I dedicate this work to my late Mother (Mrs. Minha Khonzaphi Sibiya), I will always remember
her as a supportive, loving and courageous person. “Noma ucashele amehlo ethu, kodwa
izinhliziyo ziyakuzwa nokho” siyabonga ngakho konke owasenzela kona, lala uphumule manje.
I would like to pass a word of thank you my father (Mr. Elphas M. Sibiya), my brothers
(Manzolwandle Tu, Phumlane Tile, Siyabonga Ndoda, Siyabonga Gede and Lethukuthula,
Mfana) bafethu nina niyikho konke kimi, amathemba ami ahlezi kunina kukhona konke. To my
sisters (Nokwazi Pita, Londi Lo, Philile Disco, maZakwe Sibiya, maNene Sibiya kanye no
Noxolo, Xolo) ngiyabonga kakhulu maGumede sengathi uThixo angangigcinela nina, niqhubeke
nokwenza okwamukelekile ngaso sonke isikhathi.
iii
Synopsis
The research contained in this thesis was aimed at the applications of Lewis acids (metal triflate
salts in particular) and Brønsted acids as catalysts for various organic synthesis reactions. The
ultimate objective was to prepare combinations of the Lewis and Brønsted acids to form
assisted acids. The assisted acids yield to the formation of highly acidic assisted acids which
exhibit high activity as compared to the individual Lewis and Brønsted acids. A detailed
literature study was undertaken, with emphasis on the applications of metal triflate salts as
catalysts for various organic reactions and the applications of assisted acids.
The study was motivated by the fact that metal triflate Lewis acids are thermally stable, non
corrosive and water tolerant catalysts, hence can be used industrially to replace the corrosive,
moisture sensitive acids as catalysts. However, metal triflates have not yet been recognised and
utilised in the chemical industry. On the other hand, the active Brønsted acids such as triflic
acid, H2SO4 etc. are corrosive, which restricts the type of construction material to hastelloy.
However, the assisted acids composed of less corrosive Brønsted acids and metal triflate Lewis
acid is desirable to address the corrosion and safety challenges.
The metal triflate salts and Brønsted acids were evaluated as catalysts for etherification
reactions of alcohols and olefins, Friedel-Crafts alkylation reactions phenolic substrates with
isobutylene. The study showed that some dependence of the charge density to the activity, i.e.
metal triflate salts such as Al(OTf)3, Zr(OTf)4 and Sc(OTf)3 with relatively high charge density
were more effective in catalysing the reactions than those with relatively smaller charge density
such as lanthanides, which were virtually active. The activity of Brønsted acids showed a clear
dependence on the acid strength pKa, with H3PO4 giving the least activity.
The assisted acids formed via a combination of metal triflate salts with mineral Brønsted acids
showed a significant enhancement of the reaction rates as compared to the individual acids.
This set of new combined acids was proven to be excellent catalysts for the etherification
reactions, Friedel-Crafts alkylation reactions and also for the synthesis of biologically active
compounds called chromans. The assisted acids as well as Al(OTf)3, and Zr(OTf)4 could be
recycled at least four times without significant loss of activity. The study also showed that
assisted acids could be recycled for both etherification and Friedel-Crafts reactions.
iv
Abbreviations
H0 Hammett acidity function
HSAB Hard and soft acids and bases
PA Proton affinity
LAB Linear alkyl benzene
LA Lewis acid
Ln Lanthanide
ScCO2 Supercritical carbon dioxide
BMIM 1-butyl-3-methylimidazolium
EMIM 1-ethyl-3-methylimidazolium
TFA Triflic acid
NTF2 Triflimide
MTBE Methyl tertiary butyl ether
BHT Butylated hydroxyl toluene
S-ZrO2 Sulfated zirconia
TPA Tungstophosphoric acid
DPE Diphenylether
TAME Tertiary-amyl methyl ether
TAEE Tertiary-amyl ethyl ether
2M2B 2-methyl-2-butene
2M1B 2-methyl-1-butene
DM1B 2,3-dimethyl-1-butene
DM2B 2,3-dimethyl-2-butene
GC Gas chromatography
NMR Nuclear magnetic resonance
v
BLA Brønsted acid-assisted Lewis acid
LLA Lewis acid-assisted Lewis acid
LBA Lewis acid-assisted Brønsted acid
BBA Brønsted acid-assisted Brønsted acid
FID Flame ionisation detector
TOF Turn over frequency
SPA Solid phosphoric acid
2M2M3B 2-methoxy-2-methyl-3-butene
2,4DMB 2,4-dimethoxybutane
1M3M2B 1-methoxy-3-methyl-2-butene
MCP Methylenecyclopentane
UOP Inc. Universal Oil Products Incorporated
PC para-Cresol
MC meta-Cresol
DBPC 2,6-di-tert-butyl-para-cresol
MBPC Mono-butylated-para-cresol
DBMC 2,4-di-tert-butyl-meta-cresol
MBMC Mono-butylated-meta-cresol
HOTf Trifluoromethanesulfonic acid
GC-MS Gas Chromatography-Mass Spectroscopy
Bp Boiling point
Mp Melting point
HIV Human immunodeficiency virus
vi
Table of contents
CHAPTER 1: Literature Review
1.1 Introduction 1
1.1 Liquid phase Brønsted acid catalysts 3
1.2 Lewis acid catalysis: A focus on metal triflate salts 4
1.3 General applications of metal triflate as catalysts 6
1.3.1 Mukaiyama Reaction 6
1.3.2 Diels Alder Reactions 8
1.3.3 General Friedel-Crafts alkylation reactions 17
1.3.4 Friedel-Crafts alkylation of phenolic compounds 22
1.3.4.1 Friedel-Crafts alkylation of cresols 22
1.3.4.2 Friedel-Crafts alkylation of anisole 32
1.3.4.3 Friedel-Crafts alkylation of diphenylether (DPE) 35
1.4 Etherification of alcohols and olefins 38
1.5 Condensation of phenols with dienes 45
1.6 The concept of combined acid systems 49
1.7 Summary 50
CHAPTER 2: Hydroalkoxylation of alcohols
2.1 Introduction 52
2.2 Screening of Lewis acids 55
vii
2.3 Screening of Brønsted acids 56
2.4 Optimisation of reaction conditions 58
2.4.1 The influence of varying the alcohol to olefin mole ratio. 58
2.4.2 The influence of changing catalyst concentration 59
2.4.3 The influence of changing the reaction temperature 60
2.5 Recycling of Al(OTf)3 and Zr(OTf)4 61
2.6 The evaluation of Lewis assisted Brønsted acids 63
2.7 The influence of varying La(OTf)3/H3PO4 concentration 68
2.8 The influence of varying temperature on La(OTf)3/H3PO4 catalysed reactions 69
2.9 Effect of varying the catalyst composition 71
2.10 Recycling of La(OTf)3/H3PO4 assisted acids 72
2.11 Solid phosphoric acid (SPA) catalysis 73
2.12 Comparison of activity of Amberlyst 15 and La(OTf)3/H3PO4 75
2.13 The reactivity of other olefins with methanol 76
2.13.1 The reactivity of isoprene with methanol 76
2.13.2 Etherification of styrene with methanol 79
2.13.3 Etherifcation of methylenecyclopentane (MCP) with methanol 81
2.14 Etherification of tertiary olefins in the presence of other olefins 87
2.15 Etherification of other alcohols with 2-methyl-2-butene 89
2.16 Conclusions 91
CHAPTER 3: Friedel-Crafts alkylation
viii
3.1 Introduction 93
3.2 Alkylation of cresol 95
3.3 Evaluation of metal triflate Lewis acids as catalysts for the butylation of cresol 100
3.3.1 Catalyst recycling studies 108
3.3.2 The influence of catalyst concentration 110
3.3.3 The influence of varying stirring speed 112
3.4 Screening of Brønsted acids 114
3.5 Evaluation of assisted acids 115
3.6 Evaluation of La(OTf)3/SPA assisted acid 120
3.7 Friedel-Crafts alkylation of anisole 124
3.7.1 Evaluation of individual Lewis and Brønsted acids 126
3.7.2 The evaluation of assisted acids as catalysts for the butylation of anisole 130
3.8 Alkylation of diphenylether (DPE) 133
3.9 Conclusions 140
CHAPTER 4: Synthesis of chromans
4.1 Introduction 142
4.2 Reaction of phenol with 2-methyl-1,3-butadiene (isoprene) 143
4.3 Reaction of phenols with 2,3-dimethyl-1,3-butadiene 149
4.4 Conclusions 153
ix
CHAPTER 5: Experimental protocol
5.1 General protocol for preparation of ethers 154
5.2 General protocol for alkylation of phenolic compounds 162
5.3 General protocol for synthesis of chromans 168
REFRENCES 181
APPENDIX 193
x
List of schemes
Scheme 1.1: Yb(OTf)3 catalysed Mukaiyama reactions 6
Scheme 1.2: Lanthanide triflate catalysed aldol reactions of silyl enolates with aldehydes
and acetals 7
Scheme 1.3: Michael addition reaction catalysed by Yb(OTf)3 8
Scheme 1.4: Diels-Alder reaction of methyl vinyl ketone with isoprene in the presence of
Sc(OTf)3 8
Scheme 1.5: Sc(OTf)3 catalysed Diels-Alder reaction in aqueous medium 10
Scheme 1.6: Diels-Alder reaction in water catalysed by polymer supported Sc(OTf)3 10
Scheme 1.7: Ionic liquids used in the investigation 11
Scheme 1.8: Diels-Alder reactions catalysed by ionic liquids and metal triflates 11
Scheme 1.9: Diels-Alder reactions catalysed by Yb(OTf)3 at 0˚C 13
Scheme 1.10: Reaction catalysed by Yb(OTf)3-H2O under high pressure. 13
Scheme 1.11: Intramolecular Diels-Alder reaction of oxazole-olefin 14
Scheme 1.12: Preparation of chiral rare-earth M(OTf)3 catalyst 15
Scheme 1.13: Diels-Alder reaction catalysed by “chiral Yb triflate.” 15
Scheme 1.14: Preparation of tetrahydropyridines in the presence of Sc(OTf)3 17
Scheme 1.15: Friedel-Crafts alkylation of benzene with benzyl alcohol. 17
Scheme 1.16: Friedel-Crafts alkylation of toluene with alkyl halides 19
Scheme 1.17: Friedel-Crafts alkylation of furan with α-chloro-α-(ethylthio)acetate 20
Scheme 1.18: Friedel-Crafts alkylation in ionic liquids 20
Scheme 1.19: Alkylation of indoles with aldehydes and ketones using Dy(OTf)3 21
xi
Scheme 1.20: Dehydration of tert-butanol and butylation of p-cresol 23
Scheme 1.21: Alkylation of p-cresol with tert-butanol in the presence of TPA/ZrO2 26
Scheme 1.22: tert-Butylation of phenol 27
Scheme 1.23: Butylation of cresols with tert-Butanol using K10-Fe-120 at 80 °C 28
Scheme 1.24: Butylation of p-cresol with MTBE 29
Scheme 1.25: Alkylation of m-cresol with isopropanol 30
Scheme 1.26: Butylation of anisole with isobutylene 33
Scheme 1.27: Etherification reaction of methanol and isoamylene 38
Scheme 1.28: Zeolites catalysed etherification of methanol with isobutylene 42
Scheme 1.29: Etherification of isopropanol with isobutylnene 43
Scheme 1.30: Mechanism for synthesis of 2,2-dimethylchromane 45
Scheme 1.31: Products from the reaction of phenol and isoprene 46
Scheme 1.32: Production of chromans and chromenes catalysed by Amberlyt 15 46
Scheme 1.33: [(acac)2Mo(SbF6)2]-catalysed preparation of chroman 47
Scheme 1.34: Products for the reaction of isoprene with phenol in the presence of
Al(OPh)3. 47
Scheme 1.35: Ag(OTf) catalysed reaction of isoprene with 4-methoxy phenol 48
Scheme 2.1: Etherification of alcohols with 2M2B 53
Scheme 2.2: Lewis acid catalysed etherification 54
Scheme 2.3: Another possible mechanism for a Lewis acid catalysed etherification 54
Scheme 2.4: Hydration reaction of 2M2B 56
xii
Scheme 2.5: Brønsted acid catalysed etherification reaction of methanol and 2M2B 57
Scheme 2.6: Addition of HCl to 2M2B 58
Scheme 2.7: Proposed reaction of Brønsted and Lewis acid 65
Scheme 2.8: Other olefins used for etherification with methanol 76
Scheme 2.9: Products distribution during etherification of isoprene 77
Scheme 2.10: Reaction of styrene with methanol 79
Scheme 2.11: Etherification and isomerisation of methylenecyclopentane 81
Scheme 2.12: Etherification of ethanol with 2M2B 89
Scheme 3.1: Alkylation of phenol and o-cresol in the presence of sulfonic acids 96
Scheme 3.2: Aryl sulfonic acid catalysts 97
Scheme 3.3: Rearrangement of 2-tert-butylphenol to 4-tert-butylphenol 97
Scheme 3.4: De-alkylation 2,4-di-tert-butylphenol 98
Scheme 3.5: The acid catalysed Friedel-Crafts alkylation of p-cresol 99
Scheme 3.6: Alkylation of m-cresol with isobutylene 100
Scheme 3.7: Dimerisation of isobutylene under acidic conditions 101
Scheme 3.8: Formation of a complex via combination of La(OTf)3/H3PO4 116
Scheme 3.9: Alkylation of anisole with isobutylene 124
Scheme 3.10: Generation of isobutylene from tert-BuOH and MTBE 125
Scheme 3.11: Alkylation of DPE with 1-decene 135
Scheme 4.1: Addition of 1,3-diene to a phenol derivative. 142
xiii
Scheme 4.2: Proposed mechanism for AgOTf catalysed synthesis of chromans. 143
Scheme 4.3: Preparation of 2,2,6-trimethylchroman catalysed by La(OTf)3/H3PO4 144
Scheme 4.4: Reaction of isoprene with hydroquinone in the presence of La(OTf)3/H3PO4 146
Scheme 4.5: Products obtained from the reaction of phenol and isoprene. 146
Scheme 4.6: Brønsted acid catalysed preparation of chroman. 147
Scheme 4.6: Brønsted acid catalysed preparation of chroman. 151
xiv
List of figures
Figure 2.1: Influence of varying the methanol to olefin mole ratio using 1.5 mol% Al(OTf)3 59
Figure 2.2: The influence of changing the catalyst concentration 60
Figure 2.3: Influence of changing the reaction temperature 61
Figure 2.4: Recycling of Al(OTf)3 during etherification reactions. 62
Figure 2.5: Recycling of Zr(OTf)4 during etherification reactions. 63
Figure 2.6: Etherification reactions catalysed by La(OTf)3/H3PO4 assisted acid 64
Figure 2.7: Activity of metal triflates/H3PO4 acid combinations 66
Figure 2.8: Comparison of metal triflate/mineral acids activity. 67
Figure 2.9: Comparison of metal triflates/ organic acids for etherification 68
Figure 2.10: Effect of increasing La(OTf)3/H3PO4 concentration 69
Figure 2.11: Effect of changing the reaction temperature 70
Figure 2.12: The effect of varying the catalyst composition 72
Figure 2.13: Recycling of La(OTf)3/H3PO4 73
Figure 2.14: The activity of La(OTf)3/SPA during etherification 74
Figure 2.15: Comparison of La(OTf)3/H3PO4 and Amberlyst 15 for etherification reactions 75
Figure 2.16: Etherification of isoprene with methanol in the presence of Zr(OTf)4 78
Figure 2.17: Reaction of isoprene with methanol catalysed by La(OTf)4/H3PO4 79
Figure 2.18: Results for etherification of styrene with methanol 80
Figure 2.19: Etherification of MCP with methanol in presence of Al(OTf)3 83
Figure 2.20: Products distribution afforded by various acids 84
xv
Figure 2.21: Etherification of MCP with methanol catalysed by La(OTf)3/H3PO4 85
Figure 2.22: Etherification MCP with methanol catalysed by La(OTf)3/H2SO4 86
Figure 2.23: GC trace for selective etherification of 2M2B 88
Figure 2.24: Reactivity of methanol with 2M2B in the presence of 1-hexene and
cyclohexene 89
Figure 2.25: The activity of various acids during etherification of ethanol and 2M2B 90
Figure 2.26: Reaction catalysed by assisted acids 91
Figure 3.1: Butylation of m/p-cresol in the presence of Zr(OTf)4 (0.05wt%) at 70 °C 104
Figure 3.2: Summary of reaction rates for various assisted acids 124
Figure 3.3: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by 1.46
mmol Zr(OTf)4 at 70 ˚C, and stirred at 1000 rpm. 126
Figure 3.4: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by
Zr(OTf)4 (1.46 mmol ) at 100 ˚C, and stirred at 1000 rpm. 127
Figure 3.5: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by HOTf
(0.2 mol%) at 100 ˚C, and stirred at 1000 rpm. 129
Figure 3.6: The activity of 2.0 mol% H3PO4 during alkylation of anisole. 130
Figure 3.7: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by
La(OTf)3/H3PO4 (0.8 mol%) at 100 ˚C, and stirred at 1000 rpm 131
Figure 3.8: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by
Al(OTf)3/H3PO4 (0.8 mol%; 0.8 mol%) at 100 ˚C, and stirred at 1000 rpm 132
Figure 3.9: Alkylation of anisole (560.01mmol) with 1.5 bar isobutylene catalysed by
Gd(OTf)3/H3PO4 (0.8 wt%; 0.2 mol%) at 100 ˚C, and stirred at 1000 rpm 133
xvi
Figure 5.1: Reactor set-up used during etherification of alcohols and olefins 155
Figure 5.2: Experimental set-up for the purification of ethers 157
Figure 5.3: The experimental set-up for the butylation of phenolic compounds 162
Figure 5.4: Kugelrhor Distillation setup used during purification of chromanes 169
xvii
List of tables
Table 1.1: The super acids with their Hammet constants 2
Table 1.2: Diels-Alder reaction of 1 or 4 with 5 12
Table 1.3: Metal triflates catalysed intramolecular reaction of oxazole olefin 14
Table 1.4: Enantioselective Diels-Alder reactions catalysed by chiral rare-earth metal
triflates 15
Table 1.5: Lewis acid-catalysed benzylation with benzyl alcohola 18
Table 1.6: Dy(OTf)3 catalysed alkylation of indoles with aldehydes and ketones 21
Table 1.7: The products afforded by Nafion® resin/silica and Amberlyst 15. 25
Table 1.8: Butylation of phenol with tert-butanol using K10 catalysts at 80 °C 27
Table 1.9: Activity of various acids for butylation of p-cresol with MTBE 29
Table 1.10: Comparison of various solid acid catalysts during etherification of DM1B with
methanol. 41
Table 2.1: Reaction of methanol with 2M2B and correlation to ionic radiia 55
Table 2.2: Catalytic activity of Brønsted acids during etherification reaction 57
Table 2.3: Turn over frequencies over a period of 15 minutes. 70
Table 2.4: Comparison of activity of various catalysts for etherification of MCP and
methanol 87
Table 3.1: Results for butylation of p-cresol in the presence of Zr(OTf)4 103
xviii
Table 3.2: Butylation of m/p-cresol in the presence of Al(OTf)3 (0.05 wt%), at 70 ˚C 105
Table 3.3: Butylation of m/p-cresol in the presence of 0.05 wt% Sc(OTf)3, at 70 ˚C 106
Table 3.4: Comparison of activity of the triflate salts of Zr, Al and Sc. 107
Table 3.5: Recycling of Al(OTf)3 (0.09 wt%) during butylation of m/p-cresol at 70 °C,
stirring at 1200 rpm and using 1.1 bar of isobutylene 109
Table 3.6: The influence of catalyst concentration during butylation of m/p-cresol in the
presence of Al(OTf)3 at 70 °C, 1.1 bar isobutylene pressure and stirring at
1200 rpm 110
Table 3.7: Influence of stirring speed on butylation of m/p-cresol in the presence of 0.09
wt% Al(OTf)3 at 70 °C 113
Table 3.8: Butylation of the m/p-cresol in the presence of H2SO4 114
Table 3.9: Butylation of m/p-cresol in the presence of [La(OTf)3/H3PO4] 117
Table 3.10: Butylation of m/p-cresol in the presence of [Gd(OTf)3/H3PO4] 118
Table 3.11: Butylation of m/p-cresol catalysed by Al(OTf)3/H3PO4 119
Table 3.12: Butylation of m/p-cresol in the presence of La(OTf)3/SPA. 120
Table 3.13: Comparison of cresols conversions and product selectivities afforded by
La(OTf)3/H3PO4 and La(OTf)3/SPA after 120 minutes
121
Table 3.14: The results obtained during recycling of La(OTf)3/SPA. 123
Table 3.15: Comparison of the acid strengths of H3PO4 and HOTf 128
Table 3.16: Properties of the products obtained during alkylation of diphenylether 137
Table 3.17: The variation of reaction parameters during butylation of DPE (0.36mol) in
the presence of Zr(OTf)4 138
Table 3.18: The results obtained during evaluation of other catalysts for butylation of
DPE (0.57 mol%). 139
xix
Table 3.19: Results obtained during the evaluation of assisted acids for the butylation of
DPE 140
Table 4.1: Reaction of various phenols (2.1 mmol) with isoprene (7.0 mmol) in the
presence of assisted acid La(OTf)3/H3PO4 148
Table 4.2: Reaction of substituted phenols with 2,3-dimethyl-1,3-butadiene. 152
Table 5.1: Reagents used during etherification reaction of olefins and alcohols 156
Table 5.2: GC operating conditions during analysis of the etherification reaction mixture. 158
Table 5.3: Reagents used during alkylation or butylation of phenolic compounds 163
Table 5.4: Analysis conditions of the butylated compounds 164
1
CHAPTER 1
Literature Review This chapter entails the literature review on Lewis and Brønsted acid catalysis with high
emphasis on Friedel-Crafts alkylation reaction of aromatic compounds, etherification of olefins
and alcohols and condensation reactions of phenols with dienes.
1.1 Introduction The concept of acidity was established by S.A. Arrhenius 1 in 1903. This Nobel Prize winner
described an acid as any hydrogen containing species able to release protons and base as any
species able to release hydroxide ions. This concept was modified by J.M. Brønsted2 and T.M.
Lowry3 independently in 1923. According to these pioneers, a base is any species that is able to
combine with protons. In this view, equilibrium exchange of a proton from an acid to a base,
which could also be a solvent, generates a conjugate base and conjugate acid. In the same
year (1923), G. N. Lewis4 proposed a different approach. He described an acid as any species
that can accept an electron pair (octet rule of electron configuration), thus forming a dative or
coordinative bond. Conversely, a base is any species bearing a non-bonding electron pair which
can be donated to form a dative bond.
The acid strength in water is determined by the acid dissociation constant (Ka), which is
promoted by the solvation of the protons by water molecules forming hydronium ions (H3O+).
The extent of dissociation of pure anhydrous acids is far lower than for the corresponding water
solutions, i.e. the dissociation constants (Ka) for sulfuric acid and hydrofluoric acids in water are
> 102 and 10-3, respectively, but they decrease to 10-4 and 10-10 respectively in the absence of
water.5 The acidity of the highly concentrated or anhydrous acids is described according to the
Hammett acidity function (H0), proposed by Hammett in the 1930s.6
H0 = pKBH++ log [B]/[BH+]
Where B is a basic indicator and pKBH+ is the pKa of its conjugate acid. The obtained value of H0
is almost independent of the indicator base B. The H0 values for anhydrous H2SO4 and HF are -
12 and -15, respectively. One of the strongest acids known is SbF6/HSO3F called “magic’ acid,
which is a composed of Lewis acid component (SbF6) and Brønsted acid component (HSO3F).
2
The Hammett number of this complex is between -23/-26, and the 1:1 complex of SbF6/HF gives
H0 = -28. These highly acidic liquids are called super acids, a term first used by Conant in 1972
to describe very strong acids.7 This very term was also used by Gillespie to indicate acids that
are stronger than 100% sulfuric acid the 1960’s.8 This field of superacid catalysis has been
widely explored by Olah and co-workers. 9 A list of super acids is reported in Table 1.1. The
carborane acids of the formula HCB11H11-xXx, where X = Cl, Br or I, have been developed by
Reed and co-workers.10 These acid systems are strong yet gentle solid acids and are able to
protonate extremely weakly basic substrates such as olefins and aromatics.
Table 1.1: The super acids with their Hammet constants11
Acid Name Molecular formula H0
Hydrogen fluoride/Antimony fluoride HF/SbF6 -28
Antimony fluoride (“magic acid”) SbF6/HSO3F -23/-26
Hydrogen fluoride HF (anhydrous) -15
Fluorinated sulfuric acid HSO3F -15
Disulfuric acid H2S2O7 -15
Hydrogen chloride/aluminium chloride HCl/AlCl3 -15/-14
Hydrogen fluoride/trifluoroborane HF/BF3 -15/-14
Water / trifluoroborane H2O/BF3 -15/-14
Triflic acid CF3SO3H -14.1
Sulfuric acid H2SO4 (100%) -11.9
In 1963, Pearson12 and co-workers introduced the concept of hard and soft acid and bases
(HSAB). According to this theory, hard acids are defined as highly positively charged, small
sized and not easily polarisable electron acceptors: hard acids prefer to associate with hard
3
bases. Hard bases are substances that hold their electron pair tightly due to high
electronegativity, low polarisability and difficulty of oxidation of their donor atoms. Furthermore,
soft acids prefer to associate with soft bases. According to this Pearson theory, the proton is a
hard acid and metal cations may have different hardness properties. The acid and base
properties may be evaluated experimentally or estimated by theory. The enthalpy of
deprotonation of the conjugate acid in the gas phase leads to an acidity or basicity scale on
proton affinity (PA):
PA = -ΔHprotonation
1.1 Liquid phase Brønsted acid catalysts
A wide range of liquid acids has been evaluated as catalysts for hydrocarbon conversion both in
the industry and academic research projects. The advantages associated with liquid acids
include their activity and selectivity under mild conditions as compared to solid acids. The
drawback associated with liquid acids is separation of catalyst from the products, loss of
catalysts and environmental factors. A common liquid acid used in hydrocarbon chemistry is
sulfuric acid (H2SO4). H2SO4 is a strong diprotic acid with H0 ranging between -3.5 and -11.9,
depending on the extent of dilution. There are several industrial processes that are still based
on H2SO4 e.g. Friedel-Crafts alkylation reactions, hydration of olefins and oligomerisation of
reactions.
Sulfur trioxide (SO3) is soluble in H2SO4, resulting in the formation of disulfuric acid (H2S2O7)
also known as “oleum”. Oleum is a liquid super acid with H0 = -15. This super acid is mostly
used for sulfonation reactions. However, the main drawback associated with usage of strong
sulfuric acid is related to the difficulty of its regeneration, purification and concentration.
Furthermore, H2SO4 is capable of oxidising paraffins which results in the formation of SO2 and
alkyl sulfates. An additional disadvantage associated with H2SO4 includes its corrosive nature,
which imposes usage of specialised material for construction of reactors and distillation towers.
It is also essential that spent catalyst is carefully disposed of in a safe manner.
Hydrofluoric acid (HF) is a super acid with H0 = -15 in pure liquid form and H0 = -11 in the
presence of small amounts of water. In water solution HF is a weak acid [Ka = 2-7 x10-4]. Its
acidity increases as a function of an increase in concentration, due to increase in stabilisation of
F- anion when its surroundings become more ionic. The acidity of HF is further increased by
combination with a Lewis acid such as SbF5, and this acid combination HF/SbF5 is the strongest
known acid system with H0 = -28. Literature suggests that the acidity is increases by the
4
formation of (H2F)+ ions [H2F+(HF)n] and of solvated ions such as (Sb2F11)- and Sb3F15..13 HF has
been widely used as a catalyst for the isobutene or isobutylene alkylation process.14 HF has
also been reportedly used for benzene alkylation processes such as the synthesis of linear alkyl
benzene (LAB), and cumene.15 During the synthesis of LAB, the feed contains approximately
79% HF. The reaction temperature ranges between 0 and 10 °C at ambient pressure with a
large excess of benzene (4-10 mol benzene/olefin).16 The advantage associated with HF over
H2SO4 is in the ease of catalyst separation and purification by means of distillation, due to the
high volatility of HF, and hence the loss of this substance is reduced. The main drawback
associated with HF is related to its toxicity together with its volatility, which promote the
formation of toxic aerosol clouds, thereby posing a high safety hazard. However, the use of
suppressants such as nitrogen-donor bases as additives limits the shortcoming to some extent
e.g. pyridinium poly-(hydrogen fluoride), also known as Olah’s reagent.17 It is indicated in the
literature that amine poly-(hydrogen fluoride) complexes are active catalysts and are associated
with lowered HF vapour pressure.18 The UOP process for the production of cumene via
alkylation of benzene with propene shows that the suppression additives can mitigate the risk of
HF release by 90%.19
The aluminium trichloride Lewis acid, was discovered in the 19th century by C. Friedel and J.M.
Crafts and applied specifically to alkylation reactions. The solid has a melting point of 193 ˚C
and can form the dimer complex Al2Cl6. It also produces other low temperature complexes with
other metal chlorides and gives rise to liquid complexes with hydrocarbons20 and ionic liquid
precursors.21 In solution this Lewis acid produces ionic liquid species such as AlCl4-, Al2Cl7-. Al in
the monomeric complex is coordinatively unsaturated and is only saturated in the polymeric
anions by weak nucleophile such as the Cl- anions.
1.2 Lewis acid catalysis: A focus on metal triflate salts
The Lewis acid (LA) catalysts are of great importance and interest in organic chemistry,
especially during carbon-carbon bond formation and because of their unique activities and
selectivities under mild reaction conditions.22 A variety of Lewis acid-catalysed reactions have
been investigated and these acids have been used during synthesis of natural and unnatural
products. The major disadvantages associated with traditional Lewis acids such as AlCl3, BF3,
TiCl4 etc. is that more than stoichiometric amounts of the acid are required in most cases.
Furthermore, these Lewis acids are moisture sensitive and easily decompose in the presence of
even small amounts of water. But, most importantly, these Lewis acids cannot be easily
5
recovered and reused, if at all, in a subsequent reaction. Recent discoveries indicate that
trifluoromethanesulfonate, or triflate (CF3SO3-), complexes are an alternative to the traditional
metal halide Lewis acids for catalysing a variety of organic transformations. In 1991, the first
report was issued on water tolerant Lewis acids, relating to lanthanide triflates [Ln(OTf)3]. 23 The
most characteristic nature of Ln(OTf)3 complexes is that they are stable and function as Lewis
acids in water. Not only Ln(OTf)3, where Ln=La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho,Er,
Tm, Yb and Lu) but also scandium (Sc) and Ytterbium (Y) were shown to be water compatible
Lewis acids and these complexes have been regarded as new set of Lewis acids since 1991.
Many organic transformations can be catalysed by these metal triflates in aqueous medium and
only catalytic amounts are required to complete the reaction in most cases. Moreover, metal
triflates can be easily recovered when the reaction is completed and reused in the subsequent
reaction without any loss of activity.24 The triflates are still active in the presence of many Lewis
bases containing hetero-atoms such as nitrogen, oxygen, phosphorus and sulfur. Metal triflate
Lewis acids are mostly used in catalytic amounts, while the conventional Lewis acids are used
in stoichiometric quantities. Thus, the use of conventional acids requires treatment of the
residues at the end of the reaction, which may induce major environmental problems and
financial cost. Metal triflates are regarded as environmental friendly Lewis acids. The efficacy of
metal triflate-based Lewis acid as catalysts may vary from one reaction to another. Recently,
studies were carried out to measure the relative acidity of Lewis acids based on their
competitive ligand dissociation from the M(OTf)3(L4) complexes, (L= hexamethylphosphoramide,
triethylphosphine oxide or trimethyl phosphate) using tandem mass spectroscopy.25 The results
showed a good correlation between the acidity and extraordinary catalytic activity of Sc(III) and
Yb(III) in the Lewis acid catalysed reactions. The high Lewis acidity of Sc(III) and Yb(III) may be
associated with their small ionic radii, which implies high charge density, and hence high
catalytic activity.26
The metal triflate Lewis acids are prepared by heating metal oxides or chlorides in an aqueous
trifluoromethane sulfonic acid (TfOH).27 These metal triflate-based Lewis acids can also be
prepared by reacting aqueous silver triflate with metal halides.28 The metal triflate molecule
normally contains nine water molecules, and anhydrous samples can be prepared by drying at
higher temperatures under high vacuum.29
6
1.3 General applications of metal triflate as catalysts
1.3.1 Mukaiyama Reaction
Lewis acid catalysed carbon-carbon bond forming reactions have been of great interest in
organic synthesis due to the selectivity achievable and for the mild reaction conditions used.30
The Mukaiyama reaction is one of the important C-C bond forming reactions. It involves the
reaction of silyl enol ethers with aldehydes or ketones in the presence of a Lewis acid such as
TiCl4.31 In the past, TiCl4 was found to be the best Lewis acid as catalyst for the reaction;
however, this Lewis acid requires strictly anhydrous conditions.
The use of lanthanide triflate salts as catalysts for the Mukaiyama reaction was first reported by
Kobayashi et al.32 Interestingly, the reactions were performed in the presence of water (1:1
mixture of water and THF) and it was found that silylenol ethers react readily with aldehydes in
the presence of Yb(OTf)3 (Scheme 1.1). Catalytic amounts (1.0 mol%) of Yb(OTf)3 were used
for the reactions, with yields ranging from 77 to 94%, depending on the silyl enol ether used.
Other aldehydes and ketones such as benzaldehyde, salicylaldehyde, 2-
pyridinecarboxyaldehyde etc. can also be used in the Mukaiyama reaction.
1.1 1.2 1.3
1.1 1.4 1.5 1.6
1.1 1.7 1.8
OSiMe
Ph
O
Ph OH
O
H H
OSiMe O
OHYb(OTf)3
92%
O
SEt
OSiMe
Yb(OTf)3 O
SEt
OH
H
OSiMe
OH
O
OSiMe
83% overall
Yb(OTf)3
94%
O
H H
O
H H
Scheme 1.1: Yb(OTf)3 catalysed Mukaiyama reactions
7
The optimisation studies carried out in the presence of benzaldehyde showed that Yb(OTf)3,
Lu(OTf)3 and Gd(OTf)3 gave the highest yields, and a water to THF ratio of 1:4 was found to be
the most effective solvent mixture. In his study, Kobayashi mentioned that salicylaldehyde is
incompatible with Lewis acids because of the free hydroxyl group, and 2-
pyridinecarboxyaldehyde is also difficult to use with Lewis acids because the nitrogen
coordinates with the metal and resulting in catalyst deactivation.33 The application of Ln(OTf)3 as
catalysts is not only restricted to aqueous solutions. Kobayashi employed organic solvents to
perform the lanthanide triflate catalysed aldol reaction of silyl enolates with aldehydes and
acetals (Scheme 1.2).
1.9
1.9
1.10 1.11
1.12 1.13
PhCOHOSiMe3
OMe
Yb(OTf)3Ph
OH O
OMe
95%
PhCOHOSiMe3
SEt
Yb(OTf)3Ph
OH O
SEt
100%syn:anti 35:65
Scheme 1.2: Lanthanide triflate catalysed aldol reactions of silyl enolates with aldehydes and acetals
It is important to note that these reactions are heterogeneous when performed in organic
solvents without any water present, and the yields are still generally good (75 to 95%).
The lanthanide triflates also catalyse the Michael addition reaction, where the conjugate addition
of silyl enolates to unsaturated ketones occurs to give 1,5-dicarbonyl compounds (Scheme 1.3).
8
O
Ph Ph
OSiMe3
OMePh
O Ph O
OMeYb(OTf)3 H+
1.14 1.10 1.15
Scheme 1.3: Michael addition reaction catalysed by Yb(OTf)3.
Scandium triflate is reported to be the best catalyst for Michael addition reactions, giving 1,5-
dicarbonyl compounds in 80 to 88% yield with no 1,2-addition products.34 These reactions are
performed at room temperature in the presence of dichloromethane as a solvent, followed by
acid work-up. Furthermore, it is reported that the lanthanides evaluated in the study were
reusable. Also noteworthy is the fact that reactions proceeded even in the presence of 1.0 mol%
of catalyst.35
1.3.2 Diels Alder Reactions
The Diels-Alder reaction forms part of the most important transformations in organic chemistry.
This reaction also leads to the formation a carbon-carbon bond. Furthermore, this reaction
allows the formation of a six-membered cycloadducts of biological importance with fine control
over their steroselectivities. This reaction can be performed in the absence of a catalyst at
elevated temperatures.36 However, some organic compounds are thermally unstable, thus
reactions have to be carried out at mild conditions (temperature and pressure). The reaction of
methyl vinyl ketone with dienes in the presence of Sc(OTf)3 with dichloromethane as a solvent,
followed by water workup gave Diels-Alder products with high selectivity to a desired endo
products (Scheme 1.4).37
1.16 1.17 1.18
OO
Sc(OTf)3
CH2Cl2
91%
Scheme 1.4: Diels-Alder reaction of methyl vinyl ketone with isoprene in the presence of Sc(OTf)3
9
The Diels-Alder reaction between cyclopentadiene and butyl acrylate in the presence of
Sc(OTf)3 and supercritical carbon dioxide (scCO2) as reaction medium was reported by Rayner
et al.38 During their study, it was noted that the reaction performed in the presence of scCO2
was complete within 15 hours at 50 °C and 6.5 mol% catalyst concentration, while the
uncatalysed reaction was only 10% complete over a period of 24 hours under the same set of
conditions. Furthermore, the reaction afforded high selectivity to the endo product. In the
conventional solvents such as toluene, the reaction yielded 10:1 endo:exo stereoselectivity;
changing to a solvent such as chloroform slightly increased the stereoselectivity to 11:1. On the
other hand, the reaction performed in scCO2 at the same temperature with variation of pressure
allowed the optimisation of selectivity with a maximum of 24:1 endo:exo, which is a significant
improvement of stereoselectivity. The optimisation study also undertaken by Rayner and co-
workers,39 showed that, as the density of the reaction medium was increased (by increasing
pressure), the stereoselectivity also increased and reached a maximum (attained above the
critical conditions of the reaction medium) and then begins to decline. Scandium
perfluoroalkanesulfonate was also found to be an efficient catalyst for Diels-Alder reactions.40
Rayner has further showed that better results are obtained when bulky amines are used during
preparation of the catalyst. For example, a yield of 82% with 85/15 endo/exo adducts and
70%ee to the endo adduct was obtained when diisopropylethylamine was used. In comparison,
though, Et3N gave slightly better yield, but the selectivity was worse (87% yield, endo/exo =
76/24 and 33% ee). Furthermore, they have shown that even better results are obtained when
bulky amines are combined with molecular sieves 4Å (cis-1,2,6-trimethylpiperidine as the
additive, 91% yield, endo/exo=86/14, endo=90%ee), and the enantiomeric excess was further
improved when the reaction was performed at 0 °C.
The metal triflates salts are known to be more stable in the presence of water compared to
metal chloride counterparts.41 Consequently, Rideout et al.42 have reported the use of Sc(OTf)3
as catalyst for Diels-Alder reaction of naphthaquinone with cyclopentadiene in aqueous medium
to give high yields with high selectivity to the desired endo adduct (Scheme 1.5). Interestingly, it
was highlighted that, when this reaction is performed in an organic solvent (CH2Cl2), low yields
are obtained, although the endo adduct selectivity remains high.
10
O
O
CH2Cl2, 83%, endo/exo (100/0)THF/H2O (9:1): 93%, endo/exo (100/0)
O
O
H
H10 mol% Sc(OTf)3
1.19 1.20 1.21
Scheme 1.5: Sc(OTf)3 catalysed Diels-Alder reaction in aqueous medium
It has also been reported that polymer-supported Sc(OTf)3 has high activity in promoting the
Diels-Alder reaction in aqueous medium (Scheme 1.6).43
O
ON
O
H2O, rt, 12h O
O
CON
cat. (1.6 mol%)
cat.=polymer-supported Sc(OTf)3
(endo/exo = 92/8)99.9%
1.22 1.20 1.23
Scheme 1.6: Diels-Alder reaction in water catalysed by polymer supported Sc(OTf)3
The application of ionic liquids as solvents and catalysts for Diels-Alder reactions has also been
reported in the literature.44 Aggarwal et al.45 have reported the reaction of cyclopentadiene with
methyl acrylate in the presence of ionic liquids. The highest yield (93%) was obtained when
using 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6] ionic liquid with endo:exo
= 4.8. Consequently, the investigation of the combined effect of metal triflates with ionic liquids
in promoting the Diels-Alder reactions was carried out by Kumar et al.46 The ionic liquids used in
their study are shown in Scheme 1.7 below.
11
NN(CH2)n X-
n=1 [EMIM]=1-ethyl-3-methylimidazolium
n=3 [BMIM]=1-ethyl-3-methylimidazolium
n=1 [EMIM]=1-ethyl-3-methylimidazolium
X=BF4, PF6, LactateTFA, NTf2
Scheme 1.7: Ionic liquids used in the investigation
The results obtained by Kumar and co-workers have shown that usage of catalytic amounts (2.0
mol%) of metal triflates (La(OTf)3 and Sc(OTf)3) concurrently with ionic liquids to promote Diels
Alder reactions shown in Scheme 1.8 significantly accelerate the reaction rate, as compared to
the reactions performed in ionic liquids in the absence of metal triflate Lewis acids.
O
O
O
O
O
O
O
O
R
O
ON
O
O
R
ON
O
O
R
ON
O
1.20 1.191.21
1.241.25
1.261.27
1.28
1.19
1.20
Scheme 1.8: Diels-Alder reactions catalysed by ionic liquids and metal triflates
Some of the results obtained in the duration of their studies are shown in Table 1.2. Other
examples of Diels-Alder reactions (Scheme 1.8) catalysed by various ionic liquids combined
12
with metal triflate are also given in the article, which also serves to support the notion of
combined ionic liquid-metal triflate catalysis.
Table 1.2: Diels-Alder reaction of 1 or 4 with 5
Entry Diene Catalyst Ionic liquid Time Yield (%)
1 20 - [BMIM][BF4] 0.5 h 77
2 20 - [BMIM][PF6] 0.5 h 74
3 20 - [EMIM][TFA] 0.5 h 78
4 20 - [EMIM][NTF2] 0.5 h 79
5 24 - [BMIM][BF4] 6 h 42
6 24 - [BMIM][BF6] 6 h 48
7 24 - [BMIM][TFA] 6 h 49
8 24 - [BMIM][NTF2] 6 h 50
9 20 aLa(OTf)3 [BMIM][BF4] 10 min 82
10 20 aSc(OTf)3 [BMIM][BF4] 10 min 84
11 24 bLa(OTf)3 [BMIM][BF4] 2 h >99
12 24 bSc(OTf)3 [BMIM][BF4] 2 h >99
a 1.0 mol% catalyst, b 2.0 mol% catalyst
Kobayashi and co workers47 have reported the use of ytterbium triflates as catalysts for Diels-
Alder reaction at temperatures as low as 0 ˚C (Scheme 1.9). It is noteworthy that catalytic
amounts of the acid were required to promote the reaction and they were able to recover and
reuse the catalyst.
13
CHO
O
O
O
Yb(OTf)3 (20 mol%)
CH2Cl2, 0 deg.C
Yb(OTf)3 (20 mol%)
CH2Cl2, 0 deg.C
Yb(OTf)3 (10 mol%)
CH2Cl2, 0 deg.C
O
O
86% (exo/endo=10/90)
93% (exo/endo=0/100)
CHO
77% (exo/endo=93/7)
H
O
1.29 1.20
1.20
1.20
1.30
1.311.32
1.19 1.21
Scheme 1.9: Diels-Alder reactions catalysed by Yb(OTf)3 at 0˚C
The Diels-Alder reaction of various electron deficient dienophiles with 1,3-cyclohexadiene under
high pressure (13 kbar) were effectively catalysed by Yb(OTf)3, (Scheme 1.10).
1.33 1.34 1.35
R1 R2
O
13 kbar, CH2Cl2
Yb(OTf)3.H2O (10 mol%)
COR2
R1
60-94%60-95% ee
Scheme 1.10: Reaction catalysed by Yb(OTf)3-H2O under high pressure.
The intramolecular Diels-Alder reaction of oxazole-olefins (Scheme 1.11) are catalysed by Sc(OTf)3, Yb(OTf)3 and most effectively by Cu(OTf)2, yielding pyridine derivatives, as shown in Table 1.3, as reported by Ohba et al.48
14
R1
R2R2O
NO
M(OTf)3
o-dichlorobenzene150 oC
M= Sc, Cu, Yb
O
R2R2
NR1
1.36 1.37
Scheme 1.11: Intramolecular Diels-Alder reaction of oxazole-olefin
Table 1.3: Metal triflates catalysed intramolecular reaction of oxazole olefin
R1 R2 Catalyst (mol%) Time (h) Yield (%)
H Me - 24 21
Yb(OTf)3 (10) 2 37
Sc(OTf)3 (10) 3 40
Cu(OTf)2 (10) 3 48
Cu(OTf)2 (2)a 1 55
H H - 24 6
Sc(OTf)3 (10) 8 15
Cu(OTf)2 (10) 8 24
CO2Me Me Cu(OTf)2 (2)a 0.5 95
Enantioselective Lewis acid-promoted Diels-Alder reactions have been reported in the
literature.49,50,51 A chiral Yb(OTf)3–derived catalyst was reported by Kobayashi and co-workers
for the Diels-Alder reaction.52 Chiral catalysts are prepared via a reaction of (R)-(+)-binaphthol
with metal triflates, especially those of Yb and Sc and in the presence of dichloromethane and
an amine (Scheme 1.12).
15
M(OTf)3OH
OH
2.4 eq. amine
0 deg oC, 30 min.
Chiral M(OTf)3
(1.2 equiv.)
M=Sc, Yb
OH
OH
M(OTf)3
N
N1.38
1.39
Scheme 1.12: Preparation of chiral rare-earth M(OTf)3 catalysts.
In their study, Kobayashi and co-workers used the Diels-Alder reaction as a model reaction for
testing the activity of their chiral Yb(OTf)3 catalyst (Scheme 1.13). The use of additives to the
Diels-Alder reactions was of importance in stabilising the catalysts and also helped in controlling
the enantioselectivities. The usage of 3-acetyl-1,3-oxazolidin-2-one as an additive enhanced the
selectivity to the endo-adduct to 93% ee, with (2S,3R) configuration, and the usage of 3-
phenylacetylacetone as an additive gave endo-adduct in 81% ee with (2R,3S) configuration
(Table 1.4).
1.22 1.20 1.23
1.40 1.41
O
ON
O "Chiral M-triflate"(20 mol%)
MS 4A, CH2Cl2, 23 oCO
O
CON
ON
O O O O
Ph
Additive:
Scheme 1.13: Diels-Alder reaction catalysed by “chiral Yb triflate.”
16
Table 1.4: Enantioselective Diels-Alder reactions catalysed by chiral rare-earth metal triflates.
Catalyst (mol%) Additive Yield (%) endo/exo ee (%), configuration
Yb (20) none 77 89/11 95 (2S,3R)
Yb (20) 40 77 89/11 93 (2S,3R)
Yb (20) 41 83 93/7 81 (2S,3R)
Sc (20) none 94 89/11 92 (2S,3R)
Sc (10) none 84 86/14 96 (2S,3R)
Sc (3) none 83 87/13 92 (2S,3R)
Aza-Diels-Alder reactions (conversion of imines and dienes into tetrahydropyridines, where the
nitrogen atom can be part of the diene or dienophile involved during the Diels Alder reaction)
promoted by metal triflates are also reported in the literature.53 These reactions allow easy
excess to nitrogen containing compounds. Sc(OTf)3 was found by Kobayashi and co-workers to
be efficient as a catalyst for the latter reactions, Scheme 1.14. 54,55 Other metal triflate Lewis
acids such as Yb(OTf)3,56 In(OTf)357 and chiral metal triflate58 salts are also reported to promote
these types of reactions. It is therefore clear that metal triflate salts play a major role as Lewis
acid catalysts for Diels-Alder reactions.
17
1.42 1.431.20
N
R
Sc(OTf)3 (10 mol%)
CH3CN, rtN
H
H
Ph
R
H
tetrahydroquinolines
Scheme 1.14: Preparation of tetrahydropyridines in the presence of Sc(OTf)3
1.3.3 General Friedel-Crafts alkylation reactions
Friedel-Crafts alkylation is among the most fundamental reactions in the field of synthetic
organic chemistry, and leads to the synthesis of various important aromatic compounds via
formation of C-C bonds. This reaction is widely utilised in both the laboratory and at the
commercial industrial scale for the production of fine chemical and valuable synthetic
intermediates. Anhydrous AlCl3 has maintained its wide use as catalyst for the process ever
since it was introduced by Friedel and Crafts in 1877.59 Since then, a number of Lewis and
Brønsted acids were introduced for the process. This section of the literature survey will focus
on the use of metal triflate Lewis acids as catalysts for Friedel-Crafts alkylation reactions.
It has been reported in the literature that lanthanide triflates and Sc-triflate Lewis acids were
found to be efficient catalysts for Friedel-Crafts reactions.60,61 The benzylation of aromatic
compounds with various benzyl alcohols (Scheme 1.15) using scandium triflate as catalyst was
disclosed by Fukuzawa and co-workers.62 In their study, it was shown that different metal
triflates promote alkylation of benzene (56.1mmol) with benzyl alcohol (1.0 mmol) differently
(Table 1.5).
18
HO
MX3 H2OM=Yb, Sc, Nd, Sm, Y
X=Cl, OTf1.44 1.45 1.46
Scheme 1.15: Friedel-Crafts alkylation of benzene with benzyl alcohol.
Table 1.5: Lewis acid-catalysed benzylation with benzyl alcohola
MX3 Yield (%)
YbCl3 Trace
ScCl3 Trace
Nd(OTf)3 quantitative
Sm(OTf)3 quantitative
Yb(OTf)3 24
Sc(OTf)3 91
Y(OTf)3 trace
a Reaction conditions: MX3 = 0.1 mmol; 115-120 °C
Their study has shown that metal halides were less active in the alkylation reaction, which could
be due to weak Lewis acidity of the salts. On the other hand, metal triflates of Nd, Sm and Sc
efficiently catalysed the reaction, and the triflates salts of Yb and Y gave low yields. Fukuzawa
and co-workers have further showed that Sc(OTf)3 could catalyse Friedel-Crafts reactions using
various alkylating agents such as allylic alcohols, arenecarbaldehydes and arenecarbaldehyde
acetals with alkylated benzenes in the presence of 1,3-propane diol, giving high yields. It was
also shown that the catalyst is recyclable with a slight loss of activity with the yield from the
original run being 91%, and that of the two subsequent runs being 84%.
19
In an independent study by Fujiwara and co-workers,63 it was demonstrated that Sc(OTf)3 could
be recycled during benzylation of aromatic compounds using benzyl halides as alkylating
agents. Olah disclosed a patent which describes the usage triflates of boron, aluminium and
gallium as efficient catalysts for Friedel-Crafts alkylation reactions.64 The metal triflates were
prepared via a reaction of triflic acid with the corresponding metal halides.
MX3 3CF3SO3H 3HX
M = B, Al, Ga; X =Cl, Br
M(CF3SO3H)3
The evaluation of the metal triflates was carried out using the Friedel-Crafts alkylation reaction
of toluene with various alkyl halides in a weakly coordinating solvent (dichloromethane) and
strongly coordinating solvent (nitromethane), Scheme 1.16. In Olah’s study, it was observed that
B(OTf)3 was soluble in both solvents, whereas Ga(OTf)3 and Al(OTf)3 were only soluble in
nitromethane, hence were studied as heterogeneous catalysts in CH2Cl2.
R=Me, Eth, i-Pr, t-Bu
R XR
R
R
M(OTf)3
Solvent, 25 deg.C
M=B, Al, Ga; X=Cl, F
Solvent = CH2Cl2, CH2NO2
1.47 1.48 1.49 1.50
Scheme 1.16: Friedel-Crafts alkylation of toluene with alkyl halides
The latter reactions were performed at 25 °C, using toluene/alkyl halide/ catalyst mole ratio of
12:2:1. The yields of methylation of 14-41%, ethylation 21-53%, iso-propylation = 29-60% and
tert-butylation = 30-78% were obtained. In the case of B(OTf)3, dimethylated and diethylated
products (3-8%) were obtained, with 3-6% di-alkylated products obtained during propylation and
butylation. Ga(OTf)3 gave 1-2% diisopropylated and dibutylated products and Al(OTf)3 gave no
apparent dialkylated products. It is known in the literature that the reaction conditions such as
20
temperature, catalyst amount and, most importantly, solvents have a large effect on the
orientation of products formed.65
The Friedel-Crafts alkylation of aromatic compounds such as anisole, methylnaphthalene, furan,
etc. with α-chloro-α-(ethylthio) acetate in the presence of Yb(OTf)3 was reported.66 The catalyst
showed high activity and selectivity, even during alkylation of furan, affording only
monoalkylated products in high yields (Scheme 1.17), while ZnCl2 afforded mono and
dialkylated products.
O Yb(OTf)3 (5 mol%)
Cl-CH(SEt)CO2Et, CH3NO2, 6h
OCO2Et
SEt
81%
1.50 1.51
Scheme 1.17: Friedel-Crafts alkylation of furan with α-chloro-α-(ethylthio)acetate
The alkylation of aromatic compounds with olefins in the presence of Yb(OTf)3 immobilised in
ionic liquid was also reported.67 (Scheme 1.18).
1.52 1.53 1.54
Yb(OTf)3 (20 mol%)
ionic liquid20 deg.C, 12h
R R
R=H, OH, OMe
NNBuSbF6
-ionic liquid:
Scheme 1.18: Friedel-Crafts alkylation in ionic liquids
During the Friedel-Crafts alkylation of indole with aromatic and aliphatic aldehydes and ketones
to form bisindolyl-methanes (Scheme 1.19), Dy(OTf)3 was found to be most effective among the
lanthanide triflate salts in aqueous medium and the results (Table 1.6) showed high yields when
aldehydes are used as compared to ketones.68 Wang has also reported the use of Dy(OTf)3 and
Y(OTf)3as the best catalyst for the reaction of indole with imines. 69 Other lanthanide triflates (La,
21
Nd, Eu, Gd and Er) and lanthanide chlorides (Nd, Dy and Y) also catalysed the reaction, while
no reaction occurred in the absence of catalyst.
1.55 1.561.57
R2
O
R3N
R1
HEtOH/H2O12-36 h
(10 mol%)Dy(OTf)3
N
R2 R3R1
N
R1
H H
Scheme 1.19: Alkylation of indoles with aldehydes and ketones using Dy(OTf)3
Table 1.6: Dy(OTf)3 catalysed alkylation of indoles with aldehydes and ketones
R1 R2 R3 Yield %
H Ph H 95
H p-MeOC6H4 H 98
H p-ClC6H4 H 99
H n-Pent H 84
MeO n-Pent H 81
H Me Me 76
H Ph Me 77
The lanthanide triflate salts of La, Nd, Dy, Yb and Sc were used as catalysts for alkylation of
electrophillic arenes with ethylglyoxylate. The highest yields up to 90% were obtained with
Yb(OTf)3. The metal halide Lewis acids did not afford any of the desired products.70 It was also
reported that the Friedel-Crafts reaction of phenolic compounds with α-imino esters was
effectively catalysed by Sc(OTf)3 and high yields of the products were obtained.71 The use of
Hf(OTf)3 as catalyst for Friedel-Crafts alkylation of benzene with benzylchloride in the presence
of lithium perchlorate-nitromethane solvent mixture was reported by Kobayashi et al.72 The
22
monoalkylated and dialkylated products were obtained in 39% and 29% respectively, and
thereafter the reaction parameters were optimised to get high yields.
1.3.4 Friedel-Crafts alkylation of phenolic compounds
Alkylphenols are very important compounds due to their diverse applications. For instance,
butylated hydroxyl toluene (BHT) in is an important industrial antioxidant, 4-methyl-2,6-ditert-
butylphenol is used in motor and aviation fuel, insulating oils, natural and synthetic rubber
stabiliser. 6-Isopropyl-3-methylphenol (thymol) leads to the formation of menthol when
hydrogenated.73 Menthol is used as raw material for the production of antiseptic, anaesthetic,
antibacterial and antifungal preparations, flavours, fragrances and preservatives.74 Dibutyl m-
cresol is reported to be one of the best softeners for certain types of synthetic rubber,75 while
thymol is also used as an antioxidant.76,77 Alkylphenols are manufactured via addition of the alkyl
group to the corresponding phenols. The alkylating reagents include alcohols, alkylchlorides,
olefins and tertiary ethers such as methyl tertiary butyl ether (MTBE). Olefins are more
preferred due to their low cost and ease of handling. There are numerous homogenous and
heterogeneous acidic catalyst systems that have been reported in the literature to promote
Friedel-Crafts alkylation reactions of phenolic compounds. The advantages associated with
heterogeneous or solid acids for the process are well known and include ease of catalyst
recovery. This section of this literature survey will focus on catalysts that have been cited in the
literature to date for alkylation of phenolic compounds.
1.3.4.1 Friedel-Crafts alkylation of cresols
Weinrich and co-workers have reported the use of concentrated sulphuric acid for butylation of
p-cresol with isobutylene to form 2-tert-butyl-4-methylphenol (mono-butylated p-cresol) and 2,6-
di-tert-butyl-4-methylphenol (di-alkylated p-cresol) or BHT.78 In their study, the dehydration of
tert-butanol to form isobutylene in the presence of activated alumina was carried out at 625 °C
(step1 of Scheme 1.20) and thereafter the butylation reaction was performed at 60-75 °C and
using 5% concentrated H2SO4 (step 2 and 3 of Scheme 1.20). While m- and p-cresols form one
monobutylated cresols, o-cresol formed two mono-butylated products i.e., 4-tert-butyl-o-cresol
and 6-tert-butyl-o-cresols, and on their second butylation only one 4,6-di-tert-butyl-2-
methylphenol is formed.
23
OHalumina
625 deg.C
OH OH
H2SO4
OH OH
Step1
Step2
Step3
H2O
H2SO4
1.58 1.59
1.59
1.60 1.61
1.59
1.61 1.62
Scheme 1.20: Dehydration of tert-butanol and butylation of p-cresol
It has also been stated that oligomerisation of isobutylene (side reaction) to form diisobutylene
and triisobutylene was also evident. The amount of isobutylene oligomers is dependent on the
reaction time and that, when the reaction is carried out in liquid phase, more oligomers are
obtained compared to a melt phase reaction. It was evident that the butylation reaction
proceeds faster than the oligomerisation reaction. The butylation reactions are exothermic and,
when the heat generation drops, the reaction is almost complete. It is evident that H2SO4 has
been widely used for the alkylation of cresol in the past. For example, Koenig79 used an excess
of H2SO4 for the alkylation of cresol with olefins, while Niedel and Natelson80 used equimolar
amounts of the acid for alkylation below 0°C.
Some alkylated phenols, such as m- and p-cresols, 2,4-, 2,5- and 2,6-xylenols have similar
boiling points and it is therefore difficult to separate these compounds by distillation. In a study
by Sharma and co-workers,81 the alkylation of a mixture of m/p-cresol with α-methyl styrene was
carried out in the presence of a homogeneous para-toluenesulfonic acid (pTSA) and with a
heterogeneous ion exchange resin (Amberlyst 15) at 60-100 °C, and cumene was used as a
solvent. It was observed that the alkylation of cresols resulted in the formation of di-alkylated
cresol products. On prolonged stirring at reaction temperature, dealkylation occurred giving
24
back the cresol. It was also observed that at higher temperature (100 °C) Amberlyst 15 formed a
substantial amount of phenylindan, while pTSA promoted dialkylation of p-cresol. There was no
significant difference in the rate of conversion of both m- and p-cresols between heterogeneous
and homogeneous catalysts. At 33 mol% conversion of α-methyl styrene, the ratio of p-cumyl-
m-cresol to o-cumyl-p-cresol was found to be 77:33. This mixture was successfully separated
via dissociation extraction (the mixture was treated with 50% w/w cumene and 20% aqueous
NaOH) and 95% pure p-cumyl-m-cresol was obtained. Cracking of the alkylated isomers (p-
cumyl-m-cresol: o-cumyl-p-cresol; 95:5) under mildly acidic conditions and atmospheric
pressure gave back 98%of m-cresol and 2% of p-cresol at 50% cracking level, suggesting that
p-cumyl-m-cresol underwent cracking at faster rate than o-cumyl-p-cresol.
The kinetics for tert-butylation of p-cresol with isobutylene in the presence of an ion exchange
resin (Amberlyst 15) was carried out by Santacesaria and co-workers.82 The kinetics of all the
possible reactions were considered in their study, i.e. mono-alkylation and successive di-
alkylation of cresol, dimerisation and trimerisation of isobutylene. A second order rate law was
found to be suitable to describe the behaviour of all the reactions involved.
Santacesaria et al.83 have also used Amberlyst 15 as a catalyst for alkylation of p-cresol with
isobutylene, which was selected as a model reaction when performing comparative studies
between a well-stirred slurry reactor and a spray tower loop reactors. The quantitative
conversion of p-cresol was obtained. They have also found that the reaction occurs in two
steps, the first step being mono-alkylation of p-cresol to give 2-tert-butyl-p-cresol and the
subsequently di-alkylation takes place, giving 2,6-di-tert-butyl-p-cresol. The side reaction where
dimerisation and trimerisation of isobutylene also occur was evident. In their study it was found
that spray tower loop reactor has low performances at lower temperatures (60 °C). At 72 °C the
performances are comparable. According to Santacesaria, the explanation to the differing
behaviour of the two reactors is that at low temperature the spray nozzle is not efficient enough
to produce very small droplets for the high viscosity liquid.
Sulfated zirconia (S-ZrO2) is a super acid with a Hammett acidity (H0) value of -16.04.84 The
latter acid was reported by Yadav and co-workers as an efficient catalyst for the alkylation of p-
cresol with isobutylene.85 It was found that the S-ZrO2 exhibits more surface area and high
selectivity towards alkylated products as compared to Amberlyst 15. Yadav has also reported
the use of sulfated zirconia (20% w/w dodecatungstophosphoric acid supported on K10 clay and
ZnCl2/K10) as catalyst for alkylation of p-cresol with cyclohexene.86 The catalyst was highly
selective to 1-cyclohexyloxy-4-methylbenzene (O-alkylated product).The C-alkylated product (4-
25
cyclohexyl-4-methyl phenol) was also formed. The production of O-alkylated product is favoured
by lower temperatures (80 °C) and C-alkylated product by higher temperatures. The
comparative study of the activity of Nafion® resin/silica composite and Amberlyst 15 as catalysts
for alkylation of p-cresol with isobutylene was undertaken by Harmer and coworkers. They have
shown that a Nafion® resin/silica composite is more effective (Table 1.7). The latter catalyst also
has the advantages of being used at high temperatures, while the Amberlyst 15 is thermally
unstable.
Table 1.7: The products afforded by Nafion® resin/silica and Amberlyst 15.
Catalyst Conversion (%)
Selectivity
(%)
Alkylation rate
(mM/g cat H)
Ether Alkylates
13% Nafion®/SiO2 82.6 0.6 99.4 581
Nafion®-NR50 19.5 28.2 71.8 54.8
Amberlyst15 62.4 14.5 85.5 171
The use of 12-tungstophosphoric acid supported on zirconia as a catalyst for butylation of p-
cresol with tert-butanol (Scheme 1.21) was studied by Halligudi and co-workers.87 The reaction
gave three alkylation products (2-tert-butyl-p-cresol, 2,6-di-tert-butyl-p-cresol and an ether. The
ether is formed when p-cresol undergoes alkylation on the oxygen (O-alkylation), water is
formed as by-product of this side reaction.
26
Ether
OH
catalystOOHOH
H2OOH
1.62
1.58
1.61 1.62 1.63
Scheme 1.21: Alkylation of p-cresol with tert-butanol in the presence of TPA/ZrO2
Halligudi and co-workers optimised the reaction conditions by focussing on the effect
temperature, space velocity and molar ratio of reactants. Their study showed that a catalyst with
15% loading of TPA on ZrO2 calcined at 750 °C was the most effective for butylation reactions.
The study also showed that the optimum conditions were: temperature of 150°C, with tert-
butanol to p-cresol mole ratio of 3:1 and liquid hourly space velocity of 4 h-1. Under the optimised
conditions, conversion of p-cresol was found to be 61 mol%, with 81.4% selectivity to 2-tert-
butyl-p-cresol, 18.1% to 2,6-di-tert-butyl-p-cresol and 0.5% tert-butyl-p-tolyl ether (ether). The
catalyst showed loss of activity in terms of cresol conversion to be 6%, with catalyst time on
stream of 100 hours.
Halligudi et al.88 has performed a similar study, where the reaction of p-cresol with tert-butanol
was carried out in the presence of tungsten oxide (WO3) supported on zirconia (WO3/ZrO2). In
this study, different loadings of WO3 (3-30 wt%) were prepared and calcined at 800 °C. The
catalyst with 15% WO3/ZrO2 was found to be most effective. At the optimum conditions
(temperature of 130°C, tert-butanol to p-cresol mole ratio of 3:1 and flow rate of 10 ml.h-1) the p-
cresol conversion of 69.8% with 92.4% selectivity to 2-tert-butyl-p-cresol, 6.3% to 2,6-di-tert-
butyl-p-cresol and 1.3% to tert-butyl-p-tolyl ether (ether) were obtained. In the course of their
study, the reactions catalysed by sulphated zirconia, USY- and Hβ-zeolites as well as K-10
montmorillonite at optimum conditions were performed and these catalysts (USY-, K-10 ans Hβ-
gave low conversion (25%) of p-cresol.
The tert-butylation of cresols (including phenol) with tert-butanol in the presence of FeCl3-
modified montmorillonite K-10 as catalyst was performed by Samat and co-workers.89 During
27
butylation reactions, high excess of phenol was used, the products formed are shown in
Scheme 1.22.
1.64 1.65 1.66 1.67 1.68
OH OHOHOHO
tert-BuOH
K10-Fe catalyst
Scheme 1.22: tert-Butylation of phenol
The phenol butylation reactions were performed at 80 °C and 100% butylation was obtained
with all the K10 catalysts. The Fe-modified K10 catalysts exhibited high activity, while the
unmodified catalyst gave low rates of reaction (Table 1.8). The O-alkylated product 1.65 did not
form in these reactions, and the authors suggest that selectivity to O-alkylation is dependent on
the acid strength of the catalyst. In general, C-alkylation requires stronger acid sites while the O-
alkylation requires weaker acid sites
Table 1.8: Butylation of phenol with tert-butanol using K10 catalysts at 80 °C
Catalyst Time (h)c Selectivity (%)
1.66 1.67 1.68
K10-120 6 35.4 62 2.6
K10-Fe-O120a 1 34.8 62.2 3.0
K10-Fe-A120b 0.5 30.5 66.8 2.7
aCatalyst prepared in acetonitrile, bCatalyst prepared in water, cTime for 100% butylation
In their study, it was found that K10-Fe-120 was the most effective catalyst for butylation of
phenol, hence the latter catalyst was evaluated for butylation of cresols with tert-butanol
(Scheme 1.23). The quantitative conversion of cresols was observed within 30 min. in all
28
instances. Dibutylation of m- and p-cresol was evident, while only mono-alkylated products were
obtained in the case of o-cresol. Interestingly, this is the first report where 3-tert-butyl-p-cresol is
observed, and presumably arises due to the presence of the activating p-CH3 group. They have
also shown that the catalysts could be recycled three times with no significant loss of activity
and selectivity.
OH
OH
OH
OHOHOH
OHOHOH
OHOHOH
(17%) (83%) (0%)
(86.7%) (11.5%) (1.8%)
(11.6%) (86.7%) (1.7%)
1.69 1.70 1.71 1.72
1.73 1.74 1.75 1.76
1.60 1.61 1.61 1.62
Scheme 1.23: Butylation of cresols with tert-Butanol using K10-Fe-120 at 80 °C.
Yadav et al.90 have reported the butylation of p-cresol with MTBE in the presence of zirconia
based-mesoporous superacid catalyst (UDCaT-1),91 Scheme 1.24. UDCaT-1 is prepared by via
combination of hexagonal mesoporous silica and sulfated modified zeolite. This reaction occurs
in two steps. In the first step, cracking of MTBE to form isobutylene and methanol takes place.
In the second step, the addition isobutylene to p-cresol forming 2-tert-butyl-p-cresol, followed by
addition of another molecule to eventually 2,6-di-tert-butyl-p-cresol. According to Yadav,
isobutylene formed in situ is quantitatively consumed and none of the isobutylene is in the gas
phase, hence no oligomerisation side reaction occurs. Furthermore, it was noticed that no O-
alkylated products were formed above 100 °C.
29
OH OHOH
OH+
CH3OH
H+ H+
1.58 1.59
1.60 1.61 1.62
Scheme 1.24: Butylation of p-cresol with MTBE
All the catalysts evaluated in their study were selective to 2-tert-butyl-p-cresol (
Table 1.9).. However, UDCaT-1 gave the highest conversion. In order to avoid excessive
formation of isobutylene, the conversion of p-cresol was limited to 50% using 1:1 mole ratio of p-
cresol to MTBE, stirring at 700 rpm and the reaction performed at 100 °C to avoid the
oligomerisation side reaction. Hence less than 1% oligomers were obtained. At higher
temperatures, up to 10% oligomers were formed. UDCaT-1 was proven to be recyclable, with
conversions being marginally lower by 5%from the previous use.
Table 1.9: Activity of various acids for butylation of p-cresol with MTBE
Catalyst Conversion (%)
Selectivity to 2-tert-butyl-p-cresol (%)
UDCaT-1 45 97
Indion 130a 39 92
Fitrol-24b 19 96
Sulfated zirconia 15 91
K-10b 12 96
DTPA/K-10 30 96
aion exchange resin; bclay; c20% dodecatungstophosphoric acid (DTPA) on clay
30
The isopropylation of m-cresol over three different mesoporous molecular sieves was carried
out by Murugesan and colleagues.92 In their study, the reaction of m-cresol with isopropanol
was performed in the presence of Al-MCM-41 molecular sieves with Si/Al ratios of 59, 103 and
202. Three products were obtained from the reaction, i.e., 2-isopropyl-4-methylphenol 78,
isopropyl-3-methylphenyl ether 79 and isopropyl-(2-isopropyl-5-methylphenyl) ether 81, Scheme
1.25. Of the three catalysts studied, Al-MCM-41 (59) was found to be more stable than Al-MCM-
41 (103) and Al-MCM-41 (202). At the mole ratio of 1:2 of m-cresol to alcohol, good conversion
of m-cresol was obtained with 100% selectivity to 78.
OHOH
OOH
OHOH
O
1.73
1.77
1.78 1.79
1.80
1.81
Scheme 1.25: Alkylation of m-cresol with isopropanol
A number of patents have been granted on the alkylation of cresols with olefins to form alkylated
cresols. This patent overview will focus on the catalysts used for alkylation of cresols with
olefins. Wetzel et al.93 have reported the use of highly acidic aryl sulfonic acids including para-
chlorobenzenesulfonic acid, nitrobenzenesulfonic acid, 4,4-diphenyldisulfonic acid, 2,4,6-
trinitrobenzenesulfonic acid, trifluoromethane sulfonic acid and meta-benzenedisulfonic acid for
this purpose. They performed butylation of o-cresol (647 g) with isobutylene (300 g) in the
presence of m-benzenedisulfonic acid (5 g) at 150 °C for 1 hour and 15 minutes. The product
was found to contain 79% 4-tert-butyl-ortho-cresol.
The butylation of m/p-cresol mixture (67% m-cresol and 33% p-cresol) with isobutylene in the
presence of H2SO4 (0.5 wt%) as catalyst was disclosed by Hess.94 The butylation reaction was
31
performed at 70 °C, under atmospheric pressure and starting off with 100 moles of the cresol
mixture. The product was neutralised with NaOH. The analysis showed the presence of mono-
alkylated m- and p-cresol to be 47.5% and 13.5% respectively, 17.0% and 19.0% mole of di-
alkylated m- and p-cresols respectively and finally, 2.5% mole of m-cresol and 0.5% mole of p-
cresol remained un-reacted. The reaction was stopped at 68.5% extent of butylation (to reduce
oligomerisation of isobutylene).
In a similar invention disclosed by Stevens et al.,95 the alkylation of m- and p-cresol mixture
(60% m-cresol and 40% p-cresol) with isobutylene in the presence of H2SO4 or AlCl3, BCl3 and
FeCl3 was carried out. Their invention consists of first alkylation of both m- and p-cresol
quantitatively, forming di-alkylated products. Unlike in the invention by Wetzel (where di-
butylation is allowed to proceed to some extent followed by separation), the latter invention
leads to a complete di-butylation of cresols, followed by separation of the two di-butylated
products via distillation. The di-butylated-p-cresol is already a valuable antioxidant, and the less
valuable di-butylated m-cresol is further treated by mixing it with pure m-cresol in the presence
of H2SO4 and heating the mixture at 70-80 °C. Since Friedel Crafts alkylation is reversible, de-
butylation to yield one equivalent of isobutylene molecule from di-butylated meta-cresol occurs.
The isobutylene molecule then alkylates the added m-cresol. The end product is mostly
composed of mono-butylated m-cresol.
In a separate patent by Stevens and Bowman,96 the reaction of isobutylene with m-cresol was
performed with an aim of synthesising 4-tert-butyl-m-cresol in the presence of H2SO4 as
catalyst. However, it is mentioned that other acids such as H3PO4; AlCl3; BF3; FeCl3 and HCl
could be used. Apart from the desired product, a mono-butylated isomer 6-tert-butyl-m-cresol
and the di-butylated product 4,6-di-tert-butyl-m-cresol were obtained. In their invention, a 0.8:1
mole ratio of m-cresol to isobutylene was used with a catalyst concentration being between
0.001-0,1 wt% with respect to m-cresol. A reaction temperature between 0 and 40 °C is
preferred: according to the invention, temperatures higher than 40 °C favour the formation of 6-
tert-butyl-m-cresol. When the reaction is complete, caustic is added to neutralise the acids.
They have found that the desired 4-tert-butyl-m-cresol is soluble in caustic together with un-
reacted m-cresol, which then provides a means of separation. The undesired products (6-tert-
butyl-m-cresol and 4,6-di-tert-butyl-m-cresol) may be subjected to dealkylation to reproduce m-
cresol and isobutylene, which is then recycled to form 4-tert-butyl-m-cresol.
A patent by Gershanov97 disclosed the use of aluminium catalysts for the preparation of di-
alkylated p-cresol via a reaction of p-cresol with olefins. Dodd et al. filed a patent where the
32
xylenols are alkylated with isobutylene in the presence of Amberlyst 15.98 The separation of a
mixture of m/p-cresol via the reaction of cresols with isobutylene in the presence of acid
catalysts such as aluminium chloride, ferric chloride, boron trifluoride, phosphoric acid, and
sulfuric acid was disclosed by Stevens et al.99 In their invention, the separation of di-butylated
m- and p-cresols via distillation is performed. The di-butylated p-cresol is a valuable antioxidant
(BHT) and is retained, while the dibutylated-m-cresol is of lower value and may be subjected to
de-alkylated which leads to reformation of valuable m-cresol as an essentially pure isomer.
The use of hydrogen fluoride as catalyst for the alkylation of m-cresol with isobutylene in the
presence of carbon dioxide was disclosed in a patent by Hervert.100 His research showed that
the butylation reaction performed in the absence of CO2 leads to lower yields. The invention by
Kurek,101 shows that butylation of p-cresol with isobutylene in the presence of a highly cross-
linked polystyrene divinylbenzene resin with an internal surface area of about 540 m2/g and an
average pore side of 51 Å, at 100 °C and 100 psig afforded 94% 2,6-di-tert-butyl-p-cresol, 9% 2-
tert-butyl-p-cresol and 99% of the reactant was converted to a product. On the contrary,
Amberlyst 15 yielded 99% conversion of p-cresol, but only 27% 2,6-di-tert-butyl-p-cresol and
68% 2-tert-butyl-p-cresol under the same set of conditions. A process for separation of a
mixture consisting of 30% p-cresol and 70% m-cresol via alkylation with isobutylene in the
presence of H2SO4 was also resported by Luten and De Benedictis.102 The reaction was
performed at 90 °C, for 12 minutes and the resulting mixture was neutralised with caustic, the
resulting products, yielding the un-reacted cresols; mono-butylated cresols and di-butylated
cresols which were eventually subjected to fractional distillation.
1.3.4.2 Friedel-Crafts alkylation of anisole
Alkylated anisoles are important industrial compounds which are used as antioxidants, dye
developers and stabilisers for fats, oils, plastic rubbers, etc.103 The preparation of 4-tert-
butylanisole via alkylation of anisole with tert-butyl alcohol in the presence of ZrCl4 and
trifluoroacetic acid was reported by Sartori and co-workers.104 Alkylation of anisole with tert-butyl
acetate as an alkylating agent in the presence of H2SO4 and also with tert-butyl nitrate in the
presence of SnCl4105 as a catalyst, was also reported by Fernholz et al.106 Other catalysts such
as triflic acid,107 Amberlyst 15,108 silica-alumina,109 zeolites110 and activated clays111 have been
reported for the alylation of catechol.
33
The reaction of anisole with isobutylene generated from MTBE in the presence of 20%
dodecatungstophosphoric acid supported on K10 montmorillonite clay (20% DTPA/K10) was
reported by Yadav and colleagues.112 They found that the reaction of anisole with isobutylene
yield three products, two of which are mono-butylated anisoles (2-tert-butylanisole and 4-tert-
butylanisole), and one di-butylated product (2,4-di-tert-butylanisole) was also present,
(Scheme 1.26:).
1.821.59
1.83
1.84
1.85
O O O O
H+
Scheme 1.26: Butylation of anisole with isobutylene
The catalyst (20% dodecatungstophosphoric acid supported on K10 montmorillonite) was found
to be the best among other catalysts evaluated. The best reaction conditions for the reaction of
anisole were found to be, 170 °C and anisole to MTBE mole ratio of 1:3 and catalyst loading of
1.5 g. The results reported on the alkylation of anisole with n-propanol, using Amberlyst 15 as
catalysts in the presence of supercritical CO2 showed high selectivity (96.4%) to mono-alkylated
products in a monophasic system.113 The alkylation of anisole with primary and secondary
olefins in the presence of niobium phosphate was reported by Lachter and co-wrokers.114
Niobium phosphate gave high selectivity to monoalkylated anisole products and no dialkylated
anisoles were formed under the conditions. Lachter has also reported the use of niobium
phosphate and niobic acid as catalysts for alkylation of anisole with 1-octene-3-ol.115 Their study
showed that niobium phosphate gave higher activity than niobic acid. A quantitative conversion
of the alcohols was obtained with high selectivity (>80%) to mono-alkylated products. The two
mono-alkylation products were observed including linear and branched alkylated anisoles.
The alkylation of anisole with benzyl alcohol in the presence of niobia supported on alumina was
also reported by Lachter et al.116 In this study, the unsupported Nb2O5, AlO3 and alumina-
supported niobia were evaluated. The study showed that alumina exhibited low activity and poor
selectivity to alkylated products. On the other hand, niobia and alumina supported niobia gave
high activity and selectivity to alkylated products. The reaction of anisole with various olefins
34
was reported by Kretchmer et al.117 in the presence of AlCl3. The reaction resulted in the
formation of mostly ortho-alkylated products. They have found that the extent of ortho-alkylation
is dependent of the solvent and functionality of the alkylating agent.
The Friedel-Crafts alkylation of anisole with n-propanol in the presence of supercritical carbon
dioxide (scCO2) was investigated by Poliakoff and colleagues.118 In their study, the activity of
five different heterogeneous acids, including ion exchange resins (Amberlyst 15 and purolite
CT-175), inorganic supported catalysts (Nafion SAC-13 and Deloxan ASP I/7) a zeolite (Zeolyst
CBV 600) were investigated. The results showed that Amberlyst 15 and Purolite CT-175
provided the best performance between 100-150 °C. At temperatures above 150 °C,
desulfonation of the catalysts was evident, resulting in a decrease of the yield. The inorganic
supported catalysts (Zeolyst CBV 600, Nafion SAC-13 and Deloxan ASP I/7) showed a higher
optimum temperature range, but the reaction became less selective to mono-alkylated products.
The alkylation of anisole with various dienes such as 2-methyl-1,3-butadiene (isoprene), 2,3-
dimethyl-1,3-butadiene and 1,3-cyclohexadiene using K10 montmorillonitres exchanged with
different cations as catalyst was reported.119 Their study showed that para-mono-alkylation is
the preferred reaction and the regio selectivity in the diene is controlled by the attack on the
least hindered position of the most stable carbocation. It is also mentioned that the catalysts
were partially deactivated under the conditions used, and that the yield may be increased by
adding the dienes in small portions.
The alkylation of anisole with tert-butanol in the presence of mesoporous aluminosilicate (Al-
MCM-41) molecular sieves with Si/Al ratios of 25, 50, 75 and 100 was reported by Pandurangan
et al.120 The alkylation reactions were performed at temperatures between 150 and 250 °C
under atmospheric pressure and the results showed that Al- MCM-41 (25) was the most active
catalyst. The major products were found to be 4-tert-butyl anisole, 2-tert-butylanisole and 2,4-di-
tert-butylanisole. The maximum conversion of anisole was observed at 175 °C and thereafter it
decreased with an increase of reaction temperature.
In the alkylation of anisole with isoamylenes in the presence of zinc chloride on alumina at 200
°C and with Kationit KU-1 at 100 °C,121 two products were obtained from the reaction, i.e., p-
pentylanisole and 2,4-di-pentylanisole. Among the catalysts evaluated, zinc chloride showed
better catalytic activity.
The use of tungsten oxide supported on zirconia (WOx/ZrO2) as catalyst for alkylation of anisole
with 1-dodecene between 95-100 °C was reported.122 The reactions were performed using an
35
olefin to anisole mole ratio of 2.25:1 and 3.2% WOx/ZrO2 with respect to anisole. After the
removal of a used catalysts and purification of the crude product by distillation, 94% yield
colourless oil was obtained consisting of mono-, di-, and tri-alkylated anisole.
The alkylation of anisole with tert-butanol using molybdenum pentachloride (MoCl6) as catalyst
was reported by Qiaoxia et al.123 The mole ratio of anisole to tert-butanol to MoCl6 used in the
study was 1:1.2:1. MoCl6 exhibited high yield of 4-tert-butylanisole and only 6% of 2,4-di-tert-
butylanisole, 2-tert-butylanisole was not present.
1.3.4.3 Friedel-Crafts alkylation of diphenylether (DPE)
The alkylation of diphenyl ethers forms part of the present study where the Lewis acids and
Lewis assisted Brønsted acids were evaluated for butylation of substituted phenols. Hence, a
literature review of the catalysts used to date for the reaction was undertaken. The alkylation of
diphenyl ether with olefins, alcohols and alkyl halides yields commercially important products.
There are numerous applications of alkylated DPE such as heat transfer fluids.124 Alkylated DPE
can be used as a dielectric agent in transformers as claimed in a patent of Westinghouse
Electric Corporation.125 This patent discloses the use of up to 99 wt% of mono ethylated, mono
propylated, mono-butylated DPE and up to 20 wt% dialkylated DPE as dielectric fluid in a
transformer.
Coleman et al.126 disclosed the use of AlCl3 as catalyst for alkylation of DPE with olefins
(propylene and diisobutylene), alkyl halides (ethyl chloride, sec-butyl chloride, tert-butyl chloride
and tert-butyl-amyl-chloride) and lauryl alcohol. The reactions of tert-butyl chloride with DPE
were performed using 1:1 mole ratio of tert-butyl chloride to DPE in the presence of 0.2 mol of
catalyst at 100 °C. When the reaction mixture was distilled, the first fraction consisting of mono-
tert-butyl-DPE (clear and clourless liquid) with a boiling point of 150.5-152.5 °C at 6 mm
pressure was obtained, followed by an isomeric crystalline mono-tert-butyl-DPE boiling at 153.5-
155.5 °C under 6 mm pressure. This pure isomer recrystallised from ethanol and had a melting
point of 54-54.5 °C. The liquid di-tert-butyl-DPE was also isolated via distillation at 191.3 °C
under 6 mm pressure. The quantities of mono-alkylated products were 26% for the liquid isomer
and 41% for the crystalline isomer. The former isomers are believed to be ortho- and para-
isomers, respectively. The remaining 31% is for the di-tert-butyl-DPE. Klingel and Ellison also
used AlCl3 as catalyst for alkylation of DPE with diisobutylene to form di-tert-octyl DPE.127
36
A process for the alkylation of DPE with 1-hexadecene in the presence of zeolite catalyst (MCM-
22 and the Engelhard catalyst (USY)) was disclosed by Wu and Lapierre.128 The reaction was
performed using 1:1 mole ratio of DPE to 1-hexadecene at 175 °C and the mixture containing
DPE (42.9%) and 1-hexadecene (57.1%) was fed into the reactor at 4g/hour. Wu and Lapierre
observed that the catalyst activity remained constant for 180 hours, and that when the reaction
was terminated the catalyst was still active. In their study they obtained overall conversion of
83% and the conversion of 1-hexadecene was 96%, while that of DPE was 66%. The selectivity
to alkylated products was >95%. Furthermore, their study showed that zeolite MCM-22 exhibit
higher activity than USY catalyst. USY catalyst gave a total conversion was <10%.
Rudnick et al.129 has disclosed a patent where the alkylation of DPE with C14, C16 and C18 olefins
was carried out using zeolites as catalyst. The examples given demonstrated that the zeolite
gives 98-100% monoalkylated compounds as compared to non-zeolite catalysts such as BF3,
which give 56% monoalkylated products and 44% polyalkylated products. Three zeolites have
been found to be active for the alkylation of DPE with 1-hexadecene, namely:130
(1). BB10, a USY-zeolite with 20% exchange sites occupied by sodium cations and the
remaining occupied by protons.
(2). 500PN, a USY-zeolile with 100% ammonium ions in the exchange sites
(3). DD-12, a USY-zeolite with fully protonated exchange sites.
The reactions were carried out using 1:2 mole ratio of 1-hexadecene to DPE, with 1wt% of
catalyst. The results showed that the zeolites are highly selective to mono-alkylation.
Furthermore the controlled additions (metering valve) of the olefin to the reaction mixture gave
complete reaction of olefins at low level of zeolite. On the other hand, bulk addition of the olefin
resulted in quick deactivation of the catalyst prior to completion of the reaction. The alkylation of
DPE with C1-C7 alcohols using zeolites as catalysts was reported131
The alkylation reaction of DPE with isobutylene in the presence of concentrated aqueous H2SO4
and AlCl3 was reported by Cobb and Mitchell.132 In one instance they performed a reaction of
isobutylene with DPE using 9 g of AlCl3 as catalyst and the olefin to ether mole ratio of 4.18:1 of
at 60 °C. The results showed the presence of 2% mono-alkylated DPE, 41% di-alkylated DPE
and 20% tri-alkylated DPE. The product was pale-yellow oil with low viscosity. When they
performed a similar reaction with an olefin to ether mole ratio of 6.4:1, only 2% mono-alkylated,
31% di-alkylated and 27% tri-alkylated products were obtained. The product obtained from the
latter reaction also had low viscosity (918 CPS at 25 °C). Cobb and Mitchell have also evaluated
37
other Lewis acid type catalysts such as BF3•H3PO4, Amberlyst 15 and H3PO4•P2O5, which also
gave products of low viscosity (50-300 CPS at 25 °C).
The use of H2SO4 (10 ml) as catalyst for the reaction of DPE with isobutylene at 27 °C gave 1%
mono-alkylate, 19% di-alkylate and 63% tri-alkylated products, the viscosity of the products was
5600 CPS at 25 °C. When the olefin to ether mole ratio was increased to 7.15:1, 1% mono-
alkylate, 25% di-alkylate and 57% tri-alkylated products were obtained with viscosity of 2447
CPS at 25 °C. Hence Cobb and Mitchell have showed that the viscosity of alkylated DPE can be
varied by changing the olefin to ether mole ratio. The use of AlCl3 as catalyst for of DPE with
hexadecane at 90 °C for 6 hours was reported by Yunqin et al.133 The mole ratio of DPE, AlCl3
and hexadecane is 16:1.14-2.28:9.4-11.4. The hexadecyl DPE was subsequently sulfonated
with Na2SO4 to yield sodium hexadecyl-DPE-disulfonate which is used as a surfactant of the oil
displacing agent for the tertiary oil recovery. The alkylation of DPE with fatty alcohols (alkylating
agent) in the presence of H2SO4 at 40-100 °C for 1-10 hours was reported.134
The use of chloroaluminate ionic liquids with an anion constituent being aluminium trichloride
dimer (Al2Cl7) and the cation constituent being quaternary ammonium salt (pyridine, chloro-
alkylpyridien or alkylimidazole) with a mole ratio of anion to cation being 1.5-3.1:1 as catalysts
for alkylation of DPE with alkenes was reported.135 In that study, a DPE to olefin mole ratio of
30:1 was used and the reaction was performed at 120-220 °C. The mono-alkylation of DPE
with 1-dodecene in the presence of an ionic liquid was also reported elsewhere.136, 137 The ionic
liquid used in the study was 1-butyl-3-imidazolium aluminium chloride {[BMIM]Cl-AlCl3} and the
results showed that a selectivity of 34% of 5- and 6- dodecyl-DPE could be obtained at 80 °C,
when the mole ratio of ionic liquid to the olefin was 0.5 and mole ration of AlCl3 in ionic liquid
was 0.67.
The use of sulfated zirconia as catalyst for alkylation of DPE with enzylchloride was reported by
Yadav and co-workers.138,139 In their study, it was found that optimum yield is obtained when
using the mole ration of DPE to benylchloride of 7:1 at 110 °C with a catalyst loading of 50
kg/m3 and stirring the reaction at 20-25 rps. It was also found that the particle size of 74-88
microns gave the best activity and that the catalyst is reusable.
The application of heteropolyacids such as tungstosilicic acid on SiO2 as catalyst for alkylation
of DPE with propylene was reported by Hasebe et al.140 Undecane was used as solvent in the
reactions at 160 °C for 2 hours to give 24% isopropyl-DPE and 67.4% di-isoporpyl DPE. Rennie
and colleagues have reported the use of SiO2-Al2O3 as catalyst for alkylation of DPE with
isobutene or propene at 140 °C and 5 bar (propene) to give 71% propylated DPE containing
38
35% o- propylated DPE.141 The alkylation of DPE with isobutylene using an ion exchange resin
(KU-2) in the H form as catalyst was reported.142
1.4 Etherification of alcohols and olefins Oxygenated compounds such as MTBE, tert-amyl methyl ether (TAME) and tert-amyl ethyl
ether (TAEE) are known to improve the burning efficiency of gasoline and reduce the carbon
dioxide emissions because of their low volatility.143 These oxygenates also help to reduce the
formation of atmospheric ozone resulting from gasoline emissions. In the past MTBE was the
most common oxygenate used as an additive to gasoline for improving the octane number.
However, the water pollution problems created by extensive use of MTBE diverted the focus of
researchers to alternative fuel additives such as tert-amyl methyl ether (TAME) and tert-amyl
ethyl ether (TAEE) as octane enhancing gasoline blending components.144 The ethers such as
TAME and TAEE derived from the reaction of C6 olefins with methanol have other properties
(e.g. higher energy density, low water solubility, hence, higher molecular weight) that are
desirable for reformulated gasoline.145 These tertiary ethers are produced via the reaction of
isoamylene olefins {2-methyl-2-butene (2M2B) or 2-methyl-1-butene (2M1B)} with methanol and
ethanol, respectively, in the presence of homogenous or heterogeneous acid catalyst systems,
Scheme 1.27.
1.88
1.86
1.87
CH3OH O
(2M1B)
(2M2B)
H+
Scheme 1.27: Etherification reaction of methanol and isoamylene
39
This section of literature review will focus mainly on the catalysts reported for the production of
TAME via etherification of alcohols and isoamylenes. Amberlyst 15 as a catalyst for the
etherification of olefins and alcohols has been widely reported in literature146,147 as a catalyst for
the production of TAME. Wang and James have also reported the use of Amberlyst 15 and
sulphated zirconia for the same purpose.148,149 They have carried out the reactions in a 25 ml
stainless steel batch reactor under helium atmosphere (1.8 MPa) at 80 °C for 2 hours. An
alcohol to olefin mole ratio of 1:1 was used with a catalyst loading of 0.5 g and the solvent being
heptane (4 g). It was found that the olefin undergoes isomerisation to a low extent, i.e. 2M1B
can isomerise to 2M2B, but both olefins react with methanol to form the same ether (TAME). A
small amount of 2,3-dimethyl-2-butanol was detected which is potentially formed via the reaction
of olefins and trace amounts of water in catalysts and reactant solution. Amberlyst 15 afforded
91% conversion of 2M1B and an ether yield of 18.8% with selectivity of 78.7% to 2M2B and only
20.6% to the ether product, while sulphates zirconia supported on SiO2 gave 2M1B conversion
of 51.8%, the ether yield of 29.8% and selectivities of 57.6% and 41.7% to the ether and 2M2B
respectively. Hence the results showed that while Amberlyst 15 gave high conversion of 2M1B,
lower ether, selectivity was afforded by the catalyst. Sulphated zirconia gave low conversion
and higher selectivity to the ether, making sulphated zirconia a catalyst of choice for the
process.
The production of C7 ethers via the reaction of methanol with 2,3-dimethyl-1-butene (DM1B)
and 2,3-dimethyl-2-butene (DM2B) in the presence of a microporous cation exchange resin
(Amberlyst 15) was investigated by Guin et al.150 The reactions were performed in a batch
reactor at 50-70 °C, under helium atmosphere (1.7 MPa). A high methanol to olefin mole ratio
(46:1) and 0.1g of catalyst (0.4-0.7 mm) were used. It was found in their study that 2,3-dimethyl-
1-butene was more reactive than DM2B and that isomerisation was a prominent reaction when
using DM1B as starting material. Under the set of conditions employed for this reaction, the
ether product obtained at equilibrium was about 75% at 50 °C and 61% at 70 °C, suggesting
that the reaction is exothermic.
The synthesis of TAEE and (TAA from a mixture containing isoamylene, ethanol and water via
etherification and hydration reaction of 2M2B in a batch reactive distillation column was reported
by Varisli and Dogu.151 The reactions were performed using Amberlyst 15 as catalyst, it was
showed that increasing the reaction temperature from 90-124 °C resulted in a significant
conversion of 2M2B, reaching 99%. The formation of TAA via reaction of 2M2B and water
occurred. In some cases, selectivity to TAA was higher than to the desired TAEE. Varisli and
40
Dogu suggest that the high selectivity to TAA is due to the higher adsorption equilibrium
constant of water than ethanol on Amberlyst 15. However, a significant increase in conversion
of 2M2B to TAEE was observed in the absence of water. The comparison of the activities of
various commercial cation exchange resin beads supplied by Rhom & Haas (Amberlyst 16,
Amberlyst 35 and XCE586) and fibre catalyst from Smoptech (SMOPEX-101, a sulfonated
polyethylene fibre with styrene) during production of TAME was reported.152 The etherification
reaction of methanol with isoamylenes (2M2B (93%) and 2M1B (7%)) with methanol were
performed at 60-80 °C. Mole ratios of methanol to isoamlyene of 0.5, 1.0 and 2.0 were used in a
batch reactor set-up and isopentane was used as solvent. The activity of the catalysts was
found to follow the trend Amberlyst 35>Amberlyst 15>SMOPEX-101> XE586. Amberlyst 35 was
found to be most active especially at elevated temperature (≥75 °C). This could be due to the
fact that
The evaluation of a number of solid acid catalysts for etherification of DM1B and DM2B with
methanol was reported by Wang and Guin.153 The catalysts included sulphated zirconia,
tungstated zirconia, two silica-supported sulfated zirconia catalysts (SZ/SiO2-N and SZ/SiO2-S)
together with two commercial ion exchange resins (Nafion NR50 and silica supported Nafion
SAC-13). Additionally, H-ZSM-5 zeolite was also tested. All the catalysts were benchmarked
against the commonly used Amberlyst 15. The reactions were performed in a stainless steel
batch reactor at 80 °C, for 2 hours under helium pressure of 1.8 MPa. A catalyst loading of 0.5 g
was used in all instances and an alcohol to olefin mole ratio of 1:1 was used and the reactions
were carried out in hexane (4 g) as a solvent. The results obtained from their study are shown in
Table 1.10.
41
Table 1.10: Comparison of various solid acid catalysts during etherification of DM1B with methanol.
Catalyst DM1B Conv. (%)
DM2B Select. (%)
Ether Select. (%)
Ether Yield (%)
Amberlyst 15 91.0 78.7 20.6 18.8
Nafion NR50 29.0 44.0 53.9 15.6
Nafion SAC-13 3.2 21.7 58.9 1.9
HZSM-5 23.2 93.5 1.1 0.3
ZrO2-WO3 0.9 19.4 64.2 0.6
SZ 4.7 23.2 66.2 3.1
SZ/SiO2-S 51.8 41.7 57.6 29.4
SZ/SiO2-N 38.2 34.4 63.8 24.4
SZ/SiO2-NP 21.2 28.7 67.4 14.3
According to Wang and Guin, the isomerisation product 2,3-dimethyl-2-butene and the ether
were major products of the reaction. A small amount of 2,3-dimethyl-2-butanol was detected,
due to the reaction of olefin with trace amount of water from the catalyst and the reactant
mixture. The commercial catalyst (Amberlyst 15) showed high conversion of 2,3-dimethyl-1-
butene, but low selectivity to the desired ether, while silica-supported sulphated zirconia showed
comparable and even higher ether yields than Amberlyst 15.
A comparative study of MTBE production via the etherification reaction of methanol with
isobutylene in the presence of various zeolite catalysts (Scheme 1.28) was under taken by
Hunger et al.154 They performed all the reactions in a fixed bed reactor, using 0.2 g of catalyst,
and the reactions were performed at 60-80 °C, using a methanol to isobutylene ratio of 1:1 and
2:1. The reaction mixture was analysed by GC coupled to an NMR spectrometer.
42
1.59 1.89
CH3OHzeolites
O
MTBE
Scheme 1.28: Zeolites catalysed etherification of methanol with isobutylene
The results of their study showed that for the reactions performed using a methanol to
isobutylene mole ratio of 2:1, at 60 °C, fluorinated HBeta- and HBeta zeolites gave comparable
activity to those afforded by a commercial ion exchange resin (Amberlyst 15). The equilibrium
yield obtained by the fluorinated HBeta zeolite and Amberlyst 15 was 47-50 mol%. HY and
HZSM zeolites showed relatively less activity, giving low yield of 8-10 mol% under the same set
of conditions. At higher temperature (80°C), the activity of fluorinated HBeta, HBeta and
Amberlyst 15 was significantly low, with an MTBE yield of 20 mol%, while the activity of HY and
HZSM-5 zeolites increased to yield 20 mol% of product. In another study carried out by Chu
and Kühl,155 the synthesis of MTBE over HZSM-5 and HZSM-11 zeolites was performed and the
activity thereof of was compared to that of Amberlyst 15. The reactions were performed in the
liquid phase below 100 °C at 200 psig, with 10 g of the catalyst being used. The by-products
observed in their study were diisobutylene formed from dimerisation of isobutylene and tert-
butanol from the reaction of water with isobutylene. The results showed that both zeolites gave
the higher activity and selectivity than Amberlyst 15. The advantage of zeolites over the
commercial Amberlyst 15 is that zeolites have high thermal stability. Furthermore, zeolites gave
high selectivity to the ether and less oligomerization product.
The synthesis of MTBE over titanium silicate (Ti-silicate) catalysts was also reported156 and the
activity thereof was compared to that of HZSM-5 zeolite. The vapour phase production of MTBE
was performed in a fixed bed reactor, at atmospheric pressure. The reaction was performed at
90 °C, using a 6.5:1 isobutylene to methanol mole ratio. Both catalysts gave steady total
conversion of the substrates to product and good MTBE selectivity without deactivation for 20
hours. ZSM-5 gave a small amount of dimethyl ether, which was formed via methanol
dehydration, whereas Ti-silicate gave high selectivity to MTBE (100%) and no by-products such
as dimethylether or tert-butylether. These reactions demonstrated that Ti-silicate was a more
active and selective catalyst for this chemistry than HZSM-5. Their study also showed that the
reaction of isobutylene with methanol is highly exothermic, hence increasing the reaction
43
temperature resulted in a considerable decrease in the production of MTBE, but it was also
shown that at low temperature the reaction is sluggish.
Tejero and co-workers have reported the synthesis of isopropyl-tert-butyl ether via the reaction
of isopropanol and isobutylene in the presence of various solid acids such as Amberlyst 15,
Amberlyst 35, Purolite CT275 and HZSM-5 zeolites (Scheme 1.29).157 According to Tejero, the
inherent characteristics of isopropyl-tert-butyl ether such as high octane blending values, lower
oxygen content and low vapour pressure make the compound attractive as a fuel blending
ether.
OH H+
O
0.7-2 ROH/alcohol70-90 oC1.6 MPa
1.77 1.59 1.90
Scheme 1.29: Etherification of isopropanol with isobutylnene
They conducted the reactions using alcohol to olefin mole ratios between 0.7 and 2, at 70-90
°C, and a pressure of 1.6 MPa for the resin-catalysed experiments, 0.4-1 g catalyst loading
(equivalent to 1% with respect to liquid mixture). On the other hand, 10-30 g of zeolites were
used representing 5-15% catalyst loading. Their results showed that various by-products such
as diisobutylene, tert-butyl alcohol and diisopropyl ether are produced in the course of the
reactions catalysed by ion exchange resins. It is also mentioned that at fixed temperature, the
equilibrium conversion increases with an increase of the alcohol to olefin mole ratio. On the
other hand, the equilibrium conversion decreases with an increase of temperature, since the
reaction is exothermic (ΔH0 = -22.9kJmol-1). For the reactions catalysed by zeolites, it was
evident that the rate of reaction was low, with the main by-product being tert-butyl alcohol, which
was formed by water released during the formation of diisopropyl ether. Diisobutylene was also
obtained. Their study has also shown that HZSM-5 was less active and selective to than resins.
The gas phase synthesis of MTBE from methanol and isobutylene in the presence of
dealuminated zeolites clays and Amberlyst 15 was reported by Poncelet and colleagues. 158The
reactions were performed in a fixed bed glass reactor at atmospheric pressure, using a
44
methanol to isobutylene mole ratio of 1.02 and the space velocity of 3.25 h-1. The reactions were
studied at temperatures between 30 and 120 °C. The results obtained showed that beta zeolites
are the most active and the activity is comparable to that of Amberlyst 15.
The synthesis of octadienyl ethers and butenyl ethers via etherification of 1,3-butadiene with
methanol, followed by hydrogenation of the unsaturated linear ether to the corresponding
saturated ether, in the presence of homogeneous palladium complexes {Pd(di-benzylidene-
acetone)2 and [Pd(allyl)Cl]2} was reported by Patrini et al.159 The reactions were performed in a
300 mL autoclave reactor at 60 °C and in the presence of phosphine ligands. In another study,
the polymer supported palladium (II) complex was used to catalyse etherification of 1,3-
butadiene and methanol.160
A comparative study for the reactivity of branched C6 olefin (2,3-dimethyl-1-butene and 2,3-
dimethyl-2-butene), C8 olefins (2,4,4-trimethyl-1-pentene and 2,4,4- trimethyl-2-pentene) and
linear olefins {1-hexene, 1-pentene and 1-octene } with methanol in the presence of Amberlyst
15 showed that branched olefins have greater reactivity than linear olefins. It was also found
that the reactivity of C6 olefins with methanol was higher than that of C8 olefins. Furthermore, it
was shown that increasing the methanol to olefin mole ratio resulted in increased ether
production. The reaction temperature range of 70-100 °C is suitable for the reaction.161
For the Fisher-Tropsch products 1-hexene and 1-pentene, purification is normally hampered by
the presence of close-boiling branched olefins such as 2-methyl-1-butene; 2-ethyl-1-butene and
2-methyl-1-pentene. A report by de Klerk162 showed that it is possible to selectively etherify the
branched olefins with methanol forming gasoline ethers with high octane number in the
presence of α-olefins, with insignificant loss of α-olefins. In his study, two ion exchange resins
(Amberlyst 15 and 35) were used and it was found that isomerisation of olefins and
etherification took place. Furthermore, it was also found that the temperature range of 65-80 °C,
high space velocity and methanol to tert-olefin ratio of 2 would be beneficial to suppress the 1-
hexene isomerisation.
The use of silica-supported heteropoly acids as catalysts for the gas phase synthesis of MTBE
via the reaction of methanol and isobutylene was reported by Shikata et al.163 In their study, the
Dawson-type tungsophosphoric acid (H6P2W18O62/SiO2), Kiggen-type heteropoly acid
(H3PW12O40/SiO2), unsupported heteropoly acids (H3PW12O40 and H6P2W18O62) and Amberlyst
15 were evaluated. The results showed that silica-supported catalysts exhibited comparable
activity to a commercial Amberlyst 15 and are more active than unsupported heteroply acids.
45
Other heteropoly acids such as carbon-supported Ag3PW12O40;164 20 wt% H4SiMoO14/SiO2
165 are
also reportedly used during synthesis of ethers.
1.5 Condensation of phenols with dienes
Assisted acid systems have been evaluated as catalysts for the condensation of dienes with
phenolic compounds. The condensation reaction involves both alkylation and etherification
reactions sequentially. 2,2-Dimethylbenzopyran is frequently encountered in natural products
such as vitamin E, its derivatives166 and in flavonoids,167 some of which exhibit important
biological activities.168,169 This system is also present in the recently discovered class of HIV-
inhibitory benzotripyrans.170 Several approaches for the synthesis of such compounds are
reported in the literature. The reactions can be promoted by Brønsted171 or Lewis acids172 and
require high temperature, with moderate yields reported. Ahluwalia et al.173 have reported usage
of H3PO4 as catalysts for isopentylation of phenols with isoprene to form 2,2-dimethylchromans
(3), Scheme 1.30.
1.17 1.91 1.92
H3PO4
OH OH O
X
H2PO4-
H+
1.93
1.94 1.95 1.96
Scheme 1.30: Mechanism for synthesis of 2,2-dimethylchromane
According to Ahluwalia, the reaction is initiated by protonation of isoprene with H3PO4 to form
the mesomer 1.91 and 1.92. The mesomers can alkylate phenol to give 1.94 and 1.95. The allyl
phenol 1.95 is more likely to form, because it is thermodynamically stable, hence 1.95
undergoes cyclisation in the presence of an acid catalyst to give the desired chroman. The
reaction was performed at 30-35 °C, with slow addition of isoprene to a mixture of phenol and
H3PO4 in an inert solvent. The reaction of resorcinol with isoprene resulted in the formation of
46
three products 1.97, 1.98 and 1.99. In a ratio of 1:2:5, with an overall yield of 80% (Scheme 1.31).
O O
O OH1.97 1.98
1.99
HO O
Scheme 1.31: Products from the reaction of phenol and isoprene.
The use of Amberlyst 15 as catalyst for a one step prenylation of phenols was reported by
Banerji and co-workers,174 where it was found that the catalyst efficiently catalysed the
condensation of substituted phenols 1.100 with isoprene giving improved yields and high
positional selectivity for the synthesis of 2,2-dimethylcromans 1.101. They extended the method
to the synthesis of 2,2-dimethylcromenes 1.103 via a reaction of 9 with 3-hydroxy-3-methylbut-
1-ene 1.102.
OH
R
O
R
O
RHO
+Amberlyst 15
Amberlyst 15
1.102
1.101
1.103
1.100
1.17
Scheme 1.32: Production of chromans and chromenes catalysed by Amberlyt 15
The use of [(acac)2Mo(SbF6)2] complex as a catalyst for synthesis of 2,2-dimethyl-6-methyl-
chroman 1.107via the reaction of p-cresol with prenyl alcohol 1.104 or 1.106 was carried out by
47
Kočovský and colleagues.175 Under the set of conditions used they have used, 1.107 was
isolated in 28% yield, (Scheme 1.33).
OHOH
OH
or [(acac)2Mo(SbF6)2]OH
O
CH2Cl2, rt
1.1051.60
1.106
1.104
1.107
Scheme 1.33: [(acac)2Mo(SbF6)2]-catalysed preparation of chroman
The reaction of phenol with conjugated dienes in the presence of aluminium phenoxide was
investigated by Dewhirst and Rust.176 Four products could be isolated during the reaction of
phenol with isoprene (Scheme 1.34). The product distribution of 1.96:1.108:1.109:1.110 was
found to be 0.38:0.25:0.24:0.13 at 80 °C, with phenol to isoprene mole ratio of 1.2:2 and in the
absence of a solvent. Dewhirst and Rust also performed a reaction of phenol with 1,3-
butadiene, and the reaction gave 1-methylchroman, ortho- and para-alkylated phenols, with
yields of 5%, 57% and 8%, respectively. The very same reaction was also studied by Bader and
Bean using H3PO4 as catalyst.177
O OHOH
O
1.96 1.108 1.109 1.110
Scheme 1.34: Products for the reaction of isoprene with phenol in the presence of Al(OPh)3.
48
The sequential addition/cyclisation of phenols with dienes catalysed by Ag(OTf) was recently
reported by Youn and Eom.178 They have investigated the activity of various metal salts
including Ag(OTf), AgSbF6, AgBF4, AgClO4, AgNO3, Ag(OTf), Cu(OTf)2,Sc(OTf)3, etc., as Lewis
acid catalysts for the addition of isoprene onto 4-methoxy phenol 1.111 as a model reaction.
They have found that Ag(OTf) was optimal for the reaction, giving 61% yield of benzopyran
1.112 (Scheme 1.35). Other silver salts were found to be ineffective for the reaction, while Sc,
Ru(III) and Au(I) triflates were moderately active. Cu(OTf)3 gave the lowest activity and triflic
acid gave only 18% yield. Thereafter they evaluated a few dienes and Ag(OTf) was found to be
efficient in promoting the reactions.
1.17 1.112
OH
O
O
OClCH2CH2Cl, rt, 24 h
5 mol% AgOTf
1.111
Scheme 1.35: Ag(OTf) catalysed reaction of isoprene with 4-methoxy phenol
Adrio and Hii179 have recently shown that Cu(OTf)2 is also an active catalyst for the reaction
shown in Scheme 1.35 when the reaction is performed at elevated temperature (50 °C).
However, a significant increase in the product yield was observed after the addition of PPh3
ligand to the Cu(OTf)2 catalysed reaction, especially when the metal to ligand ratio was
increased to 2:1. The highest yield (69%) was obtained when using Cu(OTf)2-bipy catalyst, with
ligand loading of 2.5 mol% in dicholroethane as a solvent. Thereafter various phenolic
substrates and dienes were evaluated where Cu(OTf)2 was used in conjunction with PPh3 and
with bipy ligand.
The synthesis of chromans via cyclocoupling of phenols with allylic alcohols in the presence of
the molybdenum complex [CpMo(CO)3]2 under microwave heating was investigated by
Yamamoto and Itonaga.180 As a model reaction, p-cresol (24) was reacted with prenyl alcohol
(14) to yield a chroman (25). Initially the reaction was carried out at 60 °C in the presence of 5
mol% [CpMo(CO)3]2 and 10 mol% o-chloranil for 3 hours and 69% of the desired chroman was
isolated. A similar yield was obtained at higher temperature (80 °C), and subsequently the
reaction was performed under microwave heating at 150 °C for 1 hour, 84% yield of chroman
was obtained. They found that the use of isoprene, instead of prenyl alcohol resulted in a
decrease in the yield.
49
1.6 The concept of combined acid systems
The relatively recent (2002) studies by Corey and co-workers have shown that chiral Brønsted
assisted-Lewis acids are exceptionally effective and versatile chiral Lewis acids for catalysing
enantionselective Diels-Alder reactions.181 There are four categories into which the combined
acids may be classified:
(1) Brønsted acid-assisted Lewis acid (BLA), this is the enhancement of Lewis acidity by the
combination with Brønsted acid.
(2) Lewis acid-assisted Lewis acid (LLA), which is the enhancement of Lewis acidity by
combination with Lewis acid.
(3) Lewis acid-assisted Brønsted acid (LBA), the enhancement of Brønsted acidity by
combination with Lewis acidity and finally.
(4) Brønsted acid assisted Brønsted acid (BBA), enhancement of Brønsted acidity by
combination with Brønsted acid.
When strong Lewis acids are combined with a proton donor species such as H2O and other
protic acids such as HCl, the acidity of the medium usually increases. For example, 100% HF
has a Hammett number of -15,182 whereas a medium containing equi-molar concentrations of
HF and SbF6 has an H0 value in excess of -30.183 Thus, a combination of a Brønsted acid with a
Lewis acid sometimes results in the formation of a superacid. The mixtures of HCl/AlCl3 as well
as HBr/AlBr3, (widely used in alkylation reactions) are super acidic ionic liquid systems. The
strength of HCl/AlCl3 Brønsted super acid has a Hammett number (H0)~ -15 which is similar to
that of dry HF, and this combination is very active as a catalyst for alkylation.184 The systems of
HCl/AlCl3 have been used in the industry since the 1940s for alkylation purposes.185
The main objective of this literature chapter is to review the types of acids that have been
explored as catalysts for various chemical reactions. This chapter reveals that among the
combined acid systems used thus far, combinations of metal triflate Lewis acids with Brønsted
acids have not been comprehensively studied, and this presented an opportunity to explore
such combinations as catalysts for a number of reactions reported in the forthcoming chapters
of this thesis.
50
1.7 Summary
The literature review has shown that a large number of Brønsted and Lewis acids can be used
to catalyse industrially important reactions such as Friedel-Crafts alkylation and etherification of
alcohols and olefins. The literature review has also revealed that solid acids are mostly used at
the commercial scale, for example, Amberlyst 15 is widely reported as catalyst for etherification
reaction of olefins and alcohols.
It has been revealed that metal triflate salts are preferred over metal halide Lewis acids, mostly
due to moisture stability, recyclability and ease of handling. The metal triflate Lewis acids have
been reported to promote numerous reactions such as Diels-Alder reactions, Friedel-Crafts
alkylation reactions of aromatic compounds with alkyl halides and Mukaiyama aldol reactions.
However, it is important to note that the literature has not mentioned the application of metal
triflates as catalysts for the alkylation of cresol, anisole and diphenyl ether with olefins.
Therefore this presented an opportunity to explore the catalytic activity of these Lewis acids for
industrially important reactions, one aspect of study for the present project.
The concept of assisted acid systems has recently been an area of focus in the field of acid
catalysis. However, the main emphasis has been on the use of assisted acids for asymmetric
synthesis. For example, a combination of metal halide or metal triflate Lewis acids with weak
acidic compounds such as bis-naphthol, etc. has been explored. The acid combination of metal
chlorides with Brønsted acids to yield super acids was explored intensively. But the combination
of metal triflate Lewis acids with Brønsted acids has not been widely studied. Hence this
provided another opportunity to investigate these combinations as catalysts for Friedel-Crafts
alkylation of cresols, anisole and diphenylether with isobutylene, a second focus area of the
current work.
The objective of this literature review was to identify the types of acids that have been used thus
far to catalyse alkylation, etherification and condensation reactions, with an aim to use metal
triflates and Bronsted acids as catalysts for such reactions. Furthermore, another important
objective of the study is to investigate whether combined acid systems (Brønsted acid/metal
triflate salt) would effect enhancement of the reaction rate.
The subsequent chapters will discuss the results obtained during evaluation of the activity of
various Lewis acids (mostly metal triflate salts) and Brønsted acids (mineral and organic acids).
The comparison of the activity for Lewis acids, Brønsted acids and assisted acid or combined
acid systems is also discussed.
51
Three model reactions were chosen to evaluate the activity of the acids. The first reaction
discussed in Chapter 2 involved etherification of alcohols and tert-olefins to form branched
ethers. The second model reaction (Chapter 3) was the Friedel-Crafts alkylation reaction of
phenolic compounds with isobutylene to form various alkylated phenolic compounds. The third
reaction (Chapter 4) was the condensation of phenolic compounds with dienes to form
chromanes.
52
CHAPTER 2
Hydroalkoxylation of olefins
This chapter focuses on the results obtained with the use of assisted acids made up of mineral
Brønsted acids and metal triflate Lewis acids as catalysts for etherification of various olefins with
alcohols.
2.1 Introduction Ether formation is an important transformation in fine chemicals synthesis as well as in
commodity chemicals. Ether formation may be effected by making use of the traditional
Williamson ether transformation186 or by the hydroalkoxylation of alkenes.187 Typically, the latter
requires rather harsh conditions such as strong Brønsted acids, for example triflic acid or
sulfuric acid, to ensure a successful outcome.188 The synthesis of tertiary ethers is preferably
performed with an alkene and the corresponding alcohol. Branched ethers such as tertiary-amyl
methyl ether (TAME) and tertiary-amyl ethyl ether (TAEE) are useful octane-boosting additives
for petrol and are considered to be viable alternatives to the more harmful additives currently
used. 189 Methyl tertiary-butyl ether (MTBE) is prepared via the reaction of isobutylene and
methanol in the presence of an acid catalyst.190 MTBE is used as a fuel octane rating improver.
However, its solubility in water causes environment pollution problems due to migration of this
material through soils and natural water bodies.191 Consequently, alternative oxygenates are
being researched as gasoline additives. The tertiary-amyl ethers are attractive alternatives for
MTBE to use for gasoline blending.192 They enhance gasoline burning properties which,
amongst others, reduces carbon monoxide emissions. 193,194 Furthermore, tertiary ethers have
high octane numbers, low viscosities and low densities, all of which are properties that are
essential for gasoline blending.195
The etherification of alkenes with alcohols is mostly carried out in the presence of sulfonic acid-
based cation exchange resins such as Amberlyst 15.196,197,198,199 Other catalysts such as
supported sulfated zirconia,200 Si-MCM-41201 and zeolites202 are also used.
53
Metal triflates are known to promote numerous organic reactions.203 These catalysts have been
shown to be extremely useful in epoxide ring-opening reactions with various nucleophiles,204,205
to be capable of effecting highly efficient acetal formations,206,207 and to readily produce highly
active Pd catalysts for the co-catalysed methoxycarbonylation reaction.208 Importantly, metal
triflates may be readily recycled,209,210 and are capable of catalysing organic reactions in a
hydrous environment as opposed to their corresponding metal halides that are unstable in the
presence of even minute amounts of water.211
This chapter will focus on the results obtained during the evaluation of various Lewis, Brønsted,
and assisted acid systems as catalysts for the etherification of olefins with various alcohols
Scheme 2.1, where 2M2B is 2-methyl-2-butene). The Lewis acids evaluated include metal
triflate salts (such as the triflates of aluminium, zirconium, and scandium) and selected metal
triflate salts of the lanthanide series of elements. The activity of metal chloride Lewis acids of
zirconium, aluminium and lanthanum were also evaluated for comparison purposes. A variety of
Brønsted acids including mineral acids (such as H2SO4, H3PO4 and HNO3) and organic acids
(such as methanesulfonic acid, benzoic acid and para-toluenesulfonic acid) were also evaluated
for the etherification reactions.
The main objective of evaluating these acids is to subsequently prepare various combinations of
Lewis and Brønsted acids, and evaluate their activity for etherification reactions in order to
confirm if there is any improvement on the reaction rate.
ROHmetal triflate RO
R = C1-4 aliphatic group2.1 2.2
Scheme 2.1: Etherification of alcohols with 2M2B
The proposed mechanism, through which metal triflates catalyse the etherification reaction, is
shown in Scheme 2.2. The alcohol is first coordinated to the metal via a lone pair of electrons
from the oxygen atom, followed by a nucleophillic attack of the olefin onto the proton of the
coordinated methanol, which leads to the formation of a tert-carbocation and methoxide anions.
The ionic species eventually bond together forming the desired ether.
54
CH3OHM(OTf)n
[CH3O-]O
H3C OH
M(OTf)n
M = Al, Zr, Sc or lanthaniden = 3 or 4
Scheme 2.2: Lewis acid catalysed etherification
It is also possible that the metal triflate directly activates the alkene as is the case in some
recently reported Friedel-Crafts reactions of alkynes with aromatic systems, Scheme 2.3. 212
CH3OH
O
M(OTf)n
M(OTf)nO
HH3CM(OTf)n
Scheme 2.3: Another possible mechanism for a Lewis acid catalysed etherification
55
2.2 Screening of Lewis acids
The time-limited reactions of methanol and 2-methyl-2-butene (2M2B), designed to highlight
rate differences between the various metal triflate catalysts, were performed in a 300 mL
autoclave batch reactor equipped with gas entrainment stirrer and a dip tube for sampling. All
experiments were performed at 100 ˚C, 6 bar N2 pressure over a period of 150 minutes using
methanol (65.72g; 1.960 mol) and 2-methyl-2-butene (11.39 g; 0.163 mol), in a mole ratio of
13:1 and catalyst concentration of 0.1 mol% with respect to the olefin. The results obtained
during the screening of Lewis acids and their correlation to the metal ion radius is shown in
Table 2.1.
Table 2.1: Reaction of methanol with 2M2B and correlation to ionic radiia
Entry M(OTf)n Yield
(Mol%)
Metal Ionic Radius213
(Å)
1 Al(OTf)3 55 0.675
2 Zr(OTf)4 55 0.860
3 Sc(OTf)3 16 0.885
4 Yb(OTf)3 7 1.008
6 Sm(OTf)3 3 1.078
5 La(OTf)3 2 1.098
7 Gd(OTf)3 2 1.172
8 ZrCl4 0 0.860
9 AlCl3 0 0.675
The triflate salts of Zr and Al were found to efficiently catalyse ether formation from the reaction
of 2-methyl-2-butene with methanol. Sc(OTf)3 showed significantly lower activity (Table 1, entry
3) while lanthanide (Yb, La, Sm, Gd) triflates, AlCl3 and ZrCl4 were found to be inactive.
Amongst the triflates, there is a loose correlation between activity and the ionic radius of the
56
metal triflate concerned, which ties the catalytic activity of the triflates in this instance more
strongly to charge density (z/r).214 The harder metals showed improved catalytic activity for
these reactions over the softer lanthanide triflates.
The observation relating to the ineffectiveness of metal chlorides also mirrors the relative
hardness of given metal systems with different counter ions (in this case triflate vs chloride) and
the influence thereof on the activity of the Lewis acid as a catalyst. Thus, for a given metal with
an apparently given charge density, the counterion plays a role in determining the hardness and
hence also the activity of the catalyst.215 It should also be noted, though, that the metal chlorides
involved here are hydrolytically sensitive and may have undergone methanolysis to some extent
leading to inactive M(OMe)x(Cl)n materials. The reaction is highly selective towards the
formation of the desired ether, although minor levels (<1%) of isomerisation of 2-methyl-2-
butene to 2-methyl-1-butene were observed in the process (GC-FID analysis). These two
isomers provide the same ether product and this side reaction is of no consequence here. Small
amounts of 2-methyl-2-butanol (2%) were formed from trace amounts of water present in the
methanol, Scheme 2.4. However, this reaction does not significantly affect the selectivity since
the amount of water in methanol was found to be small (600 ppm or less by Karl Fischer
titration) and if the alcohol was dried prior to the experiment this alcohol product did not form.
H2OHO
2.1 2.3
Scheme 2.4: Hydration reaction of 2M2B
2.3 Screening of Brønsted acids
The Brønsted acid catalysed reactions follow the Markovnikov mechanistic pathway, the
proposed mechanism for the reaction is shown in Scheme 2.5.
57
HX HOCH3 O HXO
HX-
Scheme 2.5: Brønsted acid catalysed etherification reaction of methanol and 2M2B
The Brønsted acids screening reactions were performed at 100 ºC, using 0.1 mol% of catalyst
and an alcohol to olefin mole ratio of 13:1. The results thereof are presented in
Table 2.2. All the reactions were terminated at 150 minutes of reaction time. At this stage, the
reactions had not attained equilibrium conversion, and hence are crudely indicative of the rate of
reaction afforded by each acid catalyst.
Table 2.2: Catalytic activity of Brønsted acids during etherification reaction
Acid pKa 216
Yield
(Mol%)
HOTf -14.9 22.0
HCl -8.0 1.5
H2SO4 -3.0 18.0
p-TsOH -2.8 18.1
CH3SO3H -2.0 19.4
HNO3 -1.5 8.0
H3PO4 2.0 1.0
PhCOOH 4.2 <1
58
It is well known that in many cases catalytic activity of Brønsted acids is dependent on their
dissociation constants (Ka), which is commonly reported in terms of its negative logarithm,
pKa.217
pKa = - logKa
This equation implies that a high value of pKa indicates a very small value of Ka, because Ka =
10-pKa and hence a weak acid. The reaction outcomes showed a correlation between pKa values
of different acids with their activities, with triflic acid giving the highest activity as expected. HCl
was almost inactive as catalyst for the reaction and it is well known that HCl may undergo
addition reaction to olfins, which would lead to the formation of an unreactive chloroalkane
(Scheme 2.6). The lack of activity shown by H3PO4 and PhCOOH may be directly linked to their
pKa values. It is thus evident that several of the metal triflate salts (Table 2.1) showed superior
activity compared to Brønsted acids.
HClCl
2.1 2.4
Scheme 2.6: Addition of HCl to 2M2B
2.4 Optimisation of reaction conditions
The optimisation of the reaction conditions was performed using Al(OTf)3. This catalyst
(Al(OTf)3) together with Zr(OTf)4 exhibited good activity among the Lewis and Brønsted acids
evaluated for hydroalkoxylation of olefins and alcohols. The initial set of conditions under which
catalyst screening was performed was chosen arbitrarily, and therefore it became imperative to
optimise the reaction parameters. Three reaction parameters were optimised i.e. temperature,
catalysts concentration and the alcohol to olefin mole ratio.
2.4.1 The influence of varying the alcohol to olefin mole ratio.
The etherification of olefins with alcohols is an equilibrium controlled reaction.218 This was also
reflected in the results of this investigation, where the reaction failed to proceed to completion.
Therefore it is crucial to identify the optimum alcohol to olefin mole ratio required to achieve
maximum conversion or yield. The experiments were conducted at constant temperature (100
ºC), and a fixed amount of catalyst (1.5 mol%), while varying the methanol to olefin mole ratio
59
(Figure 2.1). The initial rates (0 to 30 minutes) were comparable in all reactions. However, for a
4:1 reaction, a slight decrease of reaction rate after 30 minutes was evident. A similar
equilibrium yield (55 mol%) for 13:1 and 10:1 reactions was achieved, whereas a slight
decrease of equilibrium yield (50 mol%) was evident for the 4:1 experiment. The latter results
were expected, because when the concentration of one of the reactants is decreased in an
equilibrium controlled reaction, the reverse reaction becomes favourable as explained by Le
Chatelier’s Principle. It was therefore decided to perform the optimisation of other parameters
using the 13:1 mole ratio of methanol to the olefin. The curves representing yield over time
resemble those of a first order reaction rate.
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120 140 160
TAM
E Yi
eld
(Mo
l%)
Time (Min.)
13:1
10:1
4:1
Figure 2.1: Influence of varying the methanol to olefin mole ratio using 1.5 mol% Al(OTf)3.
2.4.2 The influence of changing catalyst concentration
The reactions to investigate the effect of varying catalyst concentration were performed at 100
C, with a fixed alcohol/alkene molar ratio (13:1), Figure 2.2. While a slow reaction rate was
observed in the absence of catalyst, the reaction was sensitive to changing Al(OTf)3
concentration at a fixed alcohol/alkene molar ratio of 13:1 at 100 C. Steadily increasing rates
60
were noted with increasing catalyst concentrations. This trend held true up to approximately 0.7
mol%, after which gains in the rate were minimal and the equilibrium concentrations of the
product remain essentially unaffected.
Figure 2.2: The influence of changing the catalyst concentration
2.4.3 The influence of changing the reaction temperature
The reaction performed at 100 C proceeds rapidly when using 1.5 mol% catalyst concentration.
Hence, it was decided to perform these reactions using a lower catalyst concentration of 0.1
mol% and methanol to olefin mole ratio of 13:1 (Figure 2.3) in order to be able to identify the
changes to the rates of the reaction. The reaction was somewhat sensitive to temperature with a
110 C reaction temperature providing higher reaction rates than those performed at lower
temperatures. Nonetheless, the reactions are sufficiently fast at the latter temperature to allow
the reaction to proceed to completion.
61
Figure 2.3: Influence of changing the reaction temperature
2.5 Recycling of Al(OTf)3 and Zr(OTf)4
The literature reveals many instances in which metal triflates are recyclable without loss of
activity.205,208 Hence, several experiments were performed to recycle Zr(OTf)4 and Al(OTf)3 for
etherification reactions in order to determine whether deactivation of the catalyst would occur.
The reactions for both catalysts were performed in a 300 mL stainless steel auto-clave reactor
at 100 ˚C, and starting off with a catalyst concentration of 1.5 mol% relative to the olefin. At the
end of each experiment, the catalyst was recovered by distilling off the reaction contents. In the
subsequent experiments, fresh reagents (alcohol and olefin) were charged into the reactor
(containing the catalyst residue), and the mixture was then heated to the operating temperature.
The recycled catalyst (pre-dissolved in methanol) was then added into the reactor via a pre-
pressurised sample bomb (6 bar N2). The results of the reactions are shown in Figure 2.4 and
Figure 2.5.
62
Figure 2.4: Recycling of Al(OTf)3 during etherification reactions.
In the reactions catalysed by Al(OTf)3, a slight decrease in reaction rate from the original to the
second run is evident. Thereafter the rate is similar in all the catalyst recycling experiments. The
equilibrium conversion is similar in all instances. It could be deduced that catalyst deactivation
did not prevail in these reactions.
For the reactions catalysed by Zr(OTf)4, the rate of reaction is comparable from the original
experiment up to recycle 5. The equilibrium conversion is also similar in all runs. It can therefore
be concluded that both catalysts could be recycled at least five times (excluding the original run)
without any loss of activity. In addition to that, the equilibrium conversion was not affected in all
instances.
63
Figure 2.5: Recycling of Zr(OTf)4 during etherification reactions.
2.6 The evaluation of Lewis assisted Brønsted acids Up to this point, our study has shown that lanthanide triflate salts and some mineral Brønsted
acids such as H3PO4 are inactive as catalysts for the present etherification reactions of olefins
with alcohols under the set of conditions specified above. It was then decided to use the two
types of acids in combination, in an attempt to capitalise on the now well-known principle of
assisted acidity.219 Accordingly, reactions were set up to include the two reagents (2M2B and
methanol) along with equimolar amounts of the two inactive catalysts (La(OTf)3 and H3PO4).
The results of this study (Figure 2.6) show that the activity of the combined Lewis/Brønsted
catalyst was enhanced significantly when the acids are used as combinations.
64
Figure 2.6: Etherification reactions catalysed by La(OTf)3/H3PO4 assisted acid
The mechanistic pathway through which the Brønsted acid binds to the Lewis acids is not well
understood at this stage. However, Barrett et al.220 used Yb(OTf)3 as a catalyst during the
nitration of aromatic compounds instead of a commonly used Brønsted acid (H2SO4) catalyst.221
The product distribution (isomers) was in accordance with electrophilic attack by NO2+ of carrier
type 2.5. On the other hand, bidentate binding of the counterion in lanthanide nitrates 2.6 is
known on the basis of well characterised structures as revealed in the literature.222 Therefore
nitration may proceed via direct attack of the protonated species or the arene may attack the
metal bound nitrate species directly.
2.5
O N
O
O
Ln
H
O
OLn N O
2.6
Barrett and co-workers223 have also reported the acylation of alcohols with acetic acid in the
presence of scandium(III) and lanthanide(III) triflates as catalysts. It was found that Yb(OTf)3
and Sc(OTf)3 were good catalysts for the reaction and they obtained remarkable rate
acceleration in their reactions. They therefore suggested that, in a reaction where Brønsted
acids are used as reagents (e.g. HNO3 in the nitration reaction) and metal triflates as catalysts,
65
the Brønsted acid binds to the Lewis acids forming a complex (Scheme 2.7) that represents a
stronger Brønsted acid than the parent Brønsted acids (nitric or acetic acids). 224
They proposed two possible ways in which the metal triflates may interact with Brønsted acids
to initiate the reactions. The first proposal was that metal triflate salts may bind to the Brønsted
acid forming the complexes 2.7 and 2.8 shown in Scheme 2.7 and that the complexes are
stronger Brønsted acids than nitric and acetic acids and may be responsible for initiating the
reactions. The second proposition was that the Brønsted acids may protonate the triflate ligands
and liberate a strong acid (triflic acid), which then instigates the reaction.
HNO3 Yb(OTf)3
3+
3OTf -O
N(H2O)YbO
OH
Yb(OTf)3
3+
3OTf -CH3COOHO
C(H2O)YbO
H
2.7
2.8
Scheme 2.7: Proposed reaction of Brønsted and Lewis acid
It was an objective of the present study to evaluate assisted acids (combination of metal triflates
and Brønsted acids) as catalysts for the etherification of olefins and alcohols. As part of the
process, 31P NMR studies were performed in order to verify that a reaction between H3PO4 and
La(OTf)3 occurs. Initially, a 31P NMR spectrum of neat H3PO4 dissolved in deuterated methanol
was obtained and gave a chemical shift of 2.13 ppm. In the subsequent experiment, 0.25 mol
equivalents of La(OTf)3 were added into the NMR tube, and the phosphorus peak was noted to
shift to -5.40 ppm. Increasing the amount of La(OTf)3 to 0.5 mol equivalents resulted in a
chemical shift of the phosphorus peak to -4.55 ppm. A further increase of La(OTf)3 to 1
66
equivalent shifted the signal to δ= -3.18 ppm while the addition of La(OTf)3 in excess (2 mole
equivalents) gave a signal at δ= -0.34 ppm for the phosphorus peak.
Given the ability of lanthanides to expand their coordination spheres, it is likely that a variety of
complexes were formed during this study, including a 2:1 acid/La, 1:1 acid/La and a complex in
which the acid binds two La ions. Therefore, the NMR spectroscopy result suggests that the first
proposal by Barrett is plausible, namely that the acid binds to the metal to generate a strong
Lewis-assisted Brønsted acid. The excellent reaction rate enhancement afforded by the
La(OTf)3/H3PO4 system, while giving high selectivities, prompted an evaluation of other metal
triflates in combination with a variety of Brønsted acids (Figure 2.7 onwards).
Figure 2.7: Activity of metal triflates/H3PO4 acid combinations
It is evident that all lanthanide triflate-based assisted acids gave high yields of the desired
product, with high selectivity (99.9%) and within the same reaction time as for the very active
triflate salts (of Al and Zr), indicative of highly active combination catalysts. On the other hand,
Zr(OTf)4 and Al(OTf)3 had already exhibited excellent activity as individual catalysts. An attempt
67
to use a combination of these Lewis acids with H3PO4 did not yield to any rate improvements,
with the activities obtained being similar to those afforded by the individual Lewis acids.
The evaluation of lanthanide triflate salts in combination with H2SO4 and HNO3 also yielded
some enhancements of the etherification rate (Figure 2.8). Each of these Brønsted acids and
Yb(OTf)3 showed insignificant activity for etherification as individual acids (remembering that
these are time-limited incomplete reactions in which relative reactivities may be gleaned from
yield data). The results showed that the individual acids (H2SO4 and HNO3) are moderately
active for the etherification reaction, while La(OTf)3 is inactive. The yields obtained when the
triflate salts of Yb and La were used in conjunction with H2SO4 and HNO3 showed appreciable
enhancements.
0
5
10
15
20
25
30
35
40
Yiel
d (M
ol%
)
Figure 2.8: Comparison of metal triflate/mineral acids activity.
68
Each of the Brønsted acids used for the Lewis/Brønsted combinations afforded some activity.
Importantly, the sum of the yields afforded by the two individual types of acid is lower than the
yield obtained by the combination, indicative of a synergistic effect. It has already been shown
that organic Brønsted acids such as triflic acid (HOTf), para-toluenesulfonic acid (p-TsOH) and
methanesulfonic acid (MsOH) gave good activity when used on their own. It was decided to also
test their activity as combinations with lanthanide triflates (Figure 2.9).
Figure 2.9: Comparison of metal triflates/ organic acids for etherification
The yield afforded by the Yb(OTf)3/p-TsOH acid combination (blue bars) is comparable to the
quantity obtained when summing the yields afforded by the Lewis acid and the Brønsted acid in
separate reactions (brown bars), indicating parallel reactions rather than an assisted acidity
reaction. In the case of MsOH, the sum of the yields from the separate reactions is slightly
greater than that of assisted acid counterpart. Therefore it can be concluded that combining the
lanthanide triflates and organic Brønsted acids does not result in rate enhancement, with the
possibility of a measure of suppression of the activity. An attempt to evaluate AlCl3/H3PO4 as
assisted acids was unsuccessful since the reaction did not yield any product.
69
2.7 The influence of varying La(OTf)3/H3PO4 concentration
Having observed the tremendous rate enhancement for the reactions catalysed by lanthanide
triflates in combination with mineral Brønsted acids, it was decided to investigate the effect of
decreasing the catalyst concentration on the etherification reaction catalysed by La(OTf)3/H3PO4
(Figure 2.10).
Figure 2.10: Effect of increasing La(OTf)3/H3PO4 concentration
The results show a considerable increase in the reaction rate as the catalyst concentration was
increased from 0.1 mol% to 0.8 mol%. The reaction performed with 0.1 mol% did not attain a
state of equilibrium within the reaction time.
2.8 The influence of varying temperature on La(OTf)3/H3PO4 catalysed reactions
An evaluation the influence of temperature on the reactions catalysed by La(OTf)3/H3PO4 was
performed using 0.8 mol% catalyst concentration and varying temperature from 80 °C to 100 °C
(Figure 2.11). The results show an increase of the reaction rate with an increase in the reaction
70
temperature. At higher temperatures (90 °C and 100 °C), the equilibrium conversion was
attained faster, whereas the reaction took longer than 80 minutes to reach equilibrium at 80 °C.
Figure 2.11: Effect of changing the reaction temperature
The TOF of the reactions where the effect of temperature reduction was evaluated has
demonstrated that the catalyst is more active at high temperature (Table 2.3). This is due to
larger amounts of product that are formed at 100 °C in comparison to that obtained at low
temperatures (80 °C and 90 °C). At 80 °C, the catalyst productivity (TOF) is low.
Table 2.3: Turn over frequencies over a period of 15 minutes.
Temp (°C) TOF (mol prod./mol cat. h)
100 182
90 123
80 59
71
2.9 Effect of varying the catalyst composition
The influence of changing the relative amounts of H3PO4 and La(OTf)3 used to generate the
active catalyst for the etherification reaction was investigated to determine the influence of this
ratio on the reaction rate. This part of the study stemmed from the 31P NMR work which
indicated that the specific ratio of these two entities generated different types of complexes. It
was thought that this study may shed light as to whether a changing ratio would lead to more or
less active assisted catalysts. The reactions were performed at 100 °C, using an alcohol to
olefin mole ratio of 13:1 (Figure 2.11). The ratios of the acids used also reflect their mol% values
as catalysts in the reactions (but where 1:1, for example, represents 0.1 mol% and 0.1 mol% of
the Brønsted and Lewis acids, respectively).
The results revealed some dependency by the reaction rate on the relative amounts of catalyst
present in the reaction mixture. There appears to be a subtle influence on the catalyst’s activity
by the H3PO4, in that higher ratios of the phosphoric acid (8:1 in Figure 2.12) apparently led to
inhibitory effects, while stoichiometric or sub-stoichiometric ratios give the substantial rate
enhancement previously noted. This observation is in accordance with the studies carried out by
Flowers225 on SmI2, where it was shown that HMPA can bind to SmI2 and displace the iodide to
the outer sphere, producing Sm(HMPA)6I2 in the process. In the present instance, if one accepts
that the metal is activating the acid, and that the lanthanide may bind to more than one
equivalent of acid as shown by the NMR study (and indirectly according to the Flowers study),
then excess phosphoric acid may well bind to the metal, donating electron density to the metal
ion and reducing the activating effect of the metal ion on the Brønsted acid in the process.
72
0
10
20
30
40
50
60
0 20 40 60 80 100 120 140 160
Yiel
d (M
ol%
)
Time (Min.)
1 H3PO4/2 La(OTf)3
0.5 H3PO4/1 La(OTf)3
1 H3PO4/1 La(OTf)3
8 H3PO4/1 La(OTf)3
2 H3PO4/1 La(OTf)3
Figure 2.12: The effect of varying the catalyst composition
The results also demonstrate that increasing the amount of La(OTf)3 from 1 to 2 mole
equivalents, while maintaining the relative ratio of H3PO4 (1:2 run, Figure 2.12, line 1 on the
legend) does not notably influence the reaction rate. Very interestingly, the 1:2 and 0.5:1 runs in
Figure 2.12 afforded extremely high rates of reaction and, notably, that the 0.5:1 rate is higher
than that of the 1:1 reaction. It is thus recommended that a 2:1 mole ratio of La(OTf)3 to H3PO4
is used in a reaction catalysed by the acids combinations to attain the maximum rates of
reaction
2.10 Recycling of La(OTf)3/H3PO4 assisted acids
A set of experiments aimed at investigating whether La(OTf)3/H3PO4 could be recycled after the
etherification reactions was performed. The initial experiment was performed using 0.2 mol%
catalyst concentration (Figure 2.13). The catalyst recovery was done by distilling the reaction
mixture of a given experiment from the reactor. The remaining contents were dissolved in
methanol and returned to the reactor, which was then charged with all the required reagents
and performing the subsequent reaction.
73
Figure 2.13: Recycling of La(OTf)3/H3PO4
The reaction rates of the subsequent reactions are comparable to the original run up to
recycle 4. This is a strong indication that the catalyst may be recycled without any loss of
activity. In all experiments the reaction reached equilibrium conversion after approximately the
same lapsed period of time and all rate profiles are essentially identical.
2.11 Solid phosphoric acid (SPA) catalysis
Solid phosphoric acid catalysis is traditionally used for the oligomerisation of propene and
butene in crude oil refineries.226 The catalyst is produced by mixing 85% H3PO4 and silica or
kieselguhr, then extruding and calcining the material so obtained at high temperature.227 It has
been shown in the present project that a combination of various metal triflate salts with mineral
Brønsted acids, especially H3PO4, gives excellent activity as homogeneous catalyst for the
etherification of methanol and 2M2B. It was then decided to broaden the study, whereby a
combination of SPA (as source of H3PO4) and La(OTf)3 was prepared and used as catalyst for
the etherification experiments. Initially, SPA was evaluated on its own as a catalyst for the
74
reaction and was proven to be inactive. This reaction was far from a trivial step in the study
since the support onto which a catalyst is loaded is known to sometimes dramatically influence
the activity of the catalyst. Subsequently, La(OTf)3/SPA assisted acid (1.03 g, which is
equivalent to 0.9 mol% as free La(OTf)3/H3PO4) was evaluated as a heterogeneous catalyst for
the etherification transformation and the results thereof were compared to those of Amberlyst 15
(a well-known commercial catalyst for etherification processes).228 The results obtained from the
study are shown in Figure 2.14.
Figure 2.14: The activity of La(OTf)3/SPA during etherification
SPA was shown to be completely inactive as a catalyst for the etherification of 2M2B with
methanol and La(OTf)3 has already proven to be inactive (see Figure 2.7). On the other hand,
the La(OTf)3/SPA combination showed significant enhancements in the reaction rate. But when
the solid was filtered and reused in a subsequent experiment, the solid was completely inactive.
It was then decided to distil the products from the filtrate and the residue so obtained was used
as a catalyst, which was shown to be highly active. The residues could be recycled at least
three times without loss of activity. It is outlined in the literature that H3PO4 leaches out of the
support into aqueous media, leading to catalyst deactivation.229 Hence, it is highly possible that
75
La(OTf)3/H3PO4 leached out of the support into the polar methanolic medium, leaving behind the
inactive solid (SiO2).
2.12 Comparison of activity of Amberlyst 15 and La(OTf)3/H3PO4
A comparison of the catalytic activity of La(OTf)3/H3PO4 to one of the most highly investigated
catalysts cited in literature, namely Amberlyst 15, was made on the basis of experimentally
determined data. The reactions were performed at 100 °C, using the methanol to 2M2B mole
ratio of 13:1. Two stirring speed rates were evaluated for the Amberlyst 15 promoted reaction, to
ensure that mass transfer limitations are taken into consideration if occurring. The equi-molar
concentration of the Amberlyst 15 was used (calculated based on the active species of the
catalyst, i.e. 4.8 mol equivalents of acid per kilogram of catalyst), Figure 2.15.
Figure 2.15: Comparison of La(OTF)3/H3PO4 and Amberlyst 15 for etherification reactions
The reactions catalysed by 1.5 mol% Amberlyst 15 proceeded at slow rate compared to that
catalysed by La(OTf)3/H3PO4 at 0.8 and 0.4 mol% catalyst loading. In order to achieve
comparable activity of the catalyst, the concentration of La(OTf)3/H3PO4 had to be reduced to
0.2 mol%. The reactions catalysed by Amberlyst 15 exhibited similar activity at different stirring
speed (1000 and 500 rpm), hence the mass transfer limitations did not affect the rate of the
76
reaction. This has thus shown that the combined acid system has high efficacy than the ion
exchange resin (Amberlyst 15). However, the main advantage associated with solid acids is on
the ease of catalyst recovery (via filtration) and thus can be reused.
2.13 The reactivity of other olefins with methanol
The scope of the reaction was broadened using various other alcohol and alkene substrates.
Among the olefins evaluated were 2-methyl-1,3-butadiene (isoprene), methylenecyclopentane
and styrene, Scheme 2.8.
Isoprene Styrene Methylenecyclopentane
Scheme 2.8: Other olefins used for etherification with methanol.
2.13.1 The reactivity of isoprene with methanol
The reaction of isoprene with methanol in the presence acid leads to the formation of three
ether products, (Scheme 2.9).
77
CH3OHMeO
2-methoxy-2-methyl-3-butene(2M2M3B)
OMe1-methoxy-3-methyl-2-butene
(1M3M2B)
OMe
MeO
2,4-dimethoxy butane(2,4DMB)
Acid
2.9
(2.10)
(2.11)
(2.12)
Scheme 2.9: Products distribution during etherification of isoprene
The very first reaction of isoprene with methanol was performed in the absence of a catalyst
(blank run), and the reaction was proven be essentially non-existent. The second experiment
was catalysed by Zr(OTf)4 (1.0 mol%) at 100 °C, using methanol to olefin mole ratio of 13:1. The
results thereof are shown in Figure 2.16. The products obtained from these experiments were
purified via distillation techniques and characterised using GC-MS and nuclear magnetic
spectroscopy (1H NMR and 13C NMR). The quantification of products was performed using gas
chromatography with flame ionisation detection (FID).
78
0
5
10
15
20
25
30
35
40
45
50
0 20 40 60 80 100 120 140 160
Mo
l%
Time (Min.)
Conversion
2,4DMB
2M2M3B
1M3M2B
Figure 2.16: Etherification of isoprene with methanol in the presence of Zr(OTf)4.
The equilibrium conversion of approximately 46 mol% was achieved in these experiments. Two
intermediate products (2-methoxy-2-methyl-3-butene and 1-methoxy-3-methyl-2-butene) were
formed during the initial stages of the reaction, and were subsequently converted to 2,4-
dimethoxybutane. The selectivities of the products were 59% to 2-methyl-2-methoxy-3-butene,
24% to 1-methoxy-3-methyl-2-butene and 18% to 2,4-dimethoxybutane at 60 minutes. The next
set of reactions was performed using La(OTf)3 and H3PO4 independently under the same set of
conditions as for Zr(OTf)4. La(OTf)3 gave no products, while H3PO4 gave a small amount of
products (<1%) over a period of 150 minutes, each catalyst being present at a loading of 1.0
mol%. A combination of the two acids was prepared (La(OTf)3/H3PO4), 1.0 mol% of the
combined acid system was prepared from 1 mol% of each of the components) and evaluated for
the etherification of isoprene with methanol under the same set of conditions (100 °C, 6 bar
(N2), 1.0 mol%), (Figure 2.17).
79
Figure 2.17: Reaction of isoprene with methanol catalysed by La(OTf)4/H3PO4
The results afforded by the combined acid system (La(OTf)3/H3PO4) gave a substantial increase
of the reaction rate, which is comparable to that shown by Zr(OTf)4. The equilibrium conversion
(47 mol%) was achieved within 75 minutes, and the two intermediates products were also
obtained, each of which was eventually converted into 2,4-dimethoxybutane. In both instances,
the formation of 2-methoxy-2-methyl-3-butene was fast. The selectivities to intermediate
products were 67% to 2M2M3B and 19% to 1M3M2B while the selectivity to 2,4DMB was 14%
(based on GC analysis). These results have once again showed that two inactive acids can
jointly catalyse the reaction, giving high activity.
2.13.2 Etherification of styrene with methanol
The etherification of styrene with methanol yielded to only one product, namely 1-
methoxyethylbenzene (Scheme 2.10), not unexpectedly given the stability of benzylic carbon in
comparison with the primary analogue. Styrene is a conjugated molecule, and as a result it is
relatively stable compared to other secondary olefins. Therefore the compound can form a
secondary carbocation that reacts with methanol to form the ether product.
80
CH3OH
O
Acid
2.13 2.14
Scheme 2.10: Reaction of styrene with methanol
The initial set of reactions was performed at 100 °C, 6 bar (N2) and methanol to olefin ratio of
13:1, using 0.1 mol% of Al(OTf)3. This reaction afforded < 1 mol% of the product. Hence, the
subsequent reactions catalysed by Al(OTf)3 and Zr(OTf)4 were performed using the catalyst
loading of 1.0 mol% (under the same set of conditions as the initial experiment), but only 5
mol% of the product was obtained after a reaction period of 150 minutes. There was no product
obtained from the reactions catalysed by 1.0 mol% of La(OTf)3 and 1.0 mol% H3PO4
independently. Due to the sluggish nature of these reactions, a reaction catalysed by 6.5 mol%
of Al(OTf)3 was performed to establish the equilibrium conversion (Figure 2.18), which was
found to be 57 mol% over a period of 60 hours.
Figure 2.18: Results for etherification of styrene with methanol
81
The assisted acid [La(OTf)3/H3PO4] was prepared and evaluated in this reaction, 1 mol%
catalyst loading was utilised and the acid combination also gave similar activity to the triflate
salts of Zr and Al, while the individual acids showed no activity. This set of experiments also
served to demonstrate that the mixed acid system is applicable to styrene, which may
potentially polymerise under these conditions as a side reaction. A possible explanation to the
low yields obtained from the styrene reactions could be attributed to the fact that styrene is a
secondary olefin, and that its reactivity would be lower than those of tertiary olefins. However,
styrene is a conjugated compound, which would lead to resonance stabilisation of any
carbocation that forms at the benzylic position. This substrate should, therefore, be more
reactive and should undergo the etherification reaction to a greater extent compared to non-
conjugated secondary olefins where resonance stabilisation of cationic species is not possible.
The 60 hour reaction using Al(OTf)3 as catalyst demonstrated that this substrate is indeed
susceptible to this type of chemistry.
2.13.3 Etherifcation of methylenecyclopentane (MCP) with methanol
Methylenecyclopentane is a tertiary olefin that may form relatively stable tertiary carbocations in
the presence of acid. If this is the case, then such carbocation species may undergo addition of
methanol to form the desired tertiary ether. The reaction of methylenecyclopentane with
methanol yields methyl 1-methylcyclopentyl ether. During this process, the olefin also
undergoes a small measure of an isomerisation reaction, forming 1-methylcyclopentene
(Scheme 2.11).
CH3OH
Oacid
Etherification reaction
Isomerisation reaction
2.15 2.16
2.15 2.17
Scheme 2.11: Etherification and isomerisation of methylenecyclopentane
82
The blank reaction (no catalyst added) was performed at 100 °C, and using methanol to olefin
mole ratio of 13:1. The reaction was performed under N2 atmosphere (6 bar) to retain the
reagents in the liquid phase. The results show that the reaction occurred to a minor and
insignificant extent. Subsequently, Lewis acidic metal triflates were evaluated as catalysts, at a
catalyst concentration of 0.1 mol% in all experiments. Figure 2.19 shows the results obtained
when using Al(OTf)3 as catalyst. This Lewis acid effected high conversion of methylene
cyclopentane, with equilibrium yield of approximately 60 mol% reached within 30 minutes. The
isomerisation reaction leads to the formation of approximately 27% of 1-methylclopentene by
the time equilibrium had been achieved. The olefin isomer should form the same ether product
via an identical tertiary carbocation, in line with Markovnikov’s rule. The isomerisation proceeds
presumably because the internal alkene formed is more stable than a terminal alkene, which is
in accordance with Zaitsef’s rule which states that “if more than one alkene can be formed
during elimination reaction, the more stable alkene is the major product”. This rule is relevant
because the reaction is believed to proceed via a carbocation intermediate. Apart from being
able to react with methanol to form the desired ether, this intermediate may also undergo an
elimination reaction to form an alkene product again. It is during this elimination step that
Zaitsef’s rule comes into play. Since the internal alkene is thermodynamically more stable than
the exocyclic methylene alkene, the former should form by preference.
83
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70
Mo
l%
Time (Min.)
Methylenecylopentane 1-methylcyclopentene 1-methoxymethylether
Figure 2.19: Etherification of MCP with methanol in presence of Al(OTf)3.
The reaction catalysed by Zr(OTf)4 also showed a high rate of conversion of the substrate,
leading to equilibrium within 15 minutes. All of the results obtained when using various Brønsted
and Lewis acids are shown in Figure 2.20. The isomerisation reaction was noted in all instances
where the etherification reaction was found to be promoted by the various catalysts, as the
Figure shows. This should necessarily be the case since the reaction is believed to proceed via
a carbocation intermediate which may also eliminate under the reaction conditions to again
provide an alkene, as already stated.
84
0
10
20
30
40
50
60
Zr(OTf)4 Al(OTf)3 H2SO4 La(OTf)3
Mo
l%
Methyl-1-methylcyclopentyl ether 1-methylcyclopentene
Figure 2.20: Products distribution afforded by various acids
The Brønsted acid H2SO4 also showed good activity but which was lower than that obtained
with the Zr and Al triflates. On the other hand, H3PO4 failed to catalyse the reaction, giving the
same minimal yield of the ether as that of the blank reaction, thereby suggesting that H3PO4
was essentially inactive as a catalyst for this reaction under these conditions. La(OTf)3 gave
some activity, indicating that the acid was slightly active for this type of chemistry, as had been
previously established in this project.
The reactions catalysed by combinations of La(OTf)3/H3PO4 showed a significant enhancement
of the reaction rate (Figure 2.21) over the individual catalyst components, as was now expected
to be the case. The reaction was performed at 100 °C, using a 13:1 mole ratio of methanol to
MCP, and a mixed catalyst concentration of 0.1 mol% relative to the alkene. The equilibrium
yield was reached within 60 minutes and the selectivity remained >99.9%. The isomerisation
reaction was noted to take place, with 1-methylcyclopentene accounting for an increasing
amount of the alkene component as a function of time, as would normally be expected where a
given reaction (in this case the isomerisation of the alkene) is allowed to run to its
thermodynamic conclusion.
85
0
10
20
30
40
50
60
70
80
90
0 20 40 60 80 100 120
Mol
%
Time (Min.)
Methylenecylopentane 1-methylcyclopentene Methyl-1-methylcyclopentyl ether
Figure 2.21: Etherification of MCP with methanol catalysed by La(OTf)3/H3PO4.
The results of the experiment catalysed by La(OTf)3/H3PO4 also showed high conversion of
methylenecyclopentane, forming the ether and the alkene isomerisation product (Figure 2.22).
The amount of product formed in a given time frame is higher than the instances where
individual acids were used. It is also noticeable that the rate of the latter experiment is
comparable to that of a reaction catalysed by La(OTf)3/H3PO4.
86
0
10
20
30
40
50
60
70
80
0 10 20 30 40 50 60 70
Mol
%
Time (Min.)
MCP Conversion 1-methylcyclopentene Methyl-1-methylcyclopentyl ether
Figure 2.22: Etherification MCP with methanol catalysed by La(OTf)3/H2SO4
The results in Table 2.4 show a comparison of TOF afforded by each catalyst over the period of
10 minutes during etherification of methylenecyclopentane with methanol. These results show
that metal triflates of Zr and Al (entry1 and 2) exhibit high activity, whereas the combined acids
(entry 3 and 4) show lower activity than the latter, with La(OTf)3/H3PO4 giving higher activity that
H2SO4 analogue. It is also evident that individual acids exhibited the least activity (entry 5 and
6). The activity of H3PO4 is comparable to the blank run, hence H3PO4 is virtually inactive.
87
Table 2.4: Comparison of activity of various catalysts for etherification of MCP and methanol.
Entry Catalyst system TOF (mol prod./mol cat. h)
1 Zr(OTf)3 2170
2 Al(OTf)3 1308
3 La(OTf)3/H3PO4 754
4 La(OTf)3/H2SO4 516
5 H2SO4 286
6 La(OTf)3 262
7 blank run 56
2.14 Etherification of tertiary olefins in the presence of other olefins It was anticipated that the etherification of tertiary olefins may be performed selectively in the
presence of other olefins such as 1-hexene. It was thus decided to investigate this proposal by
performing the etherification reaction using a mixture of olefins. The reaction was performed
using an olefin mixture consisting of 1-hexene and 2-methyl-2-butene with methanol. The mole
ratio composition of 1-hexene to 2-methyl-2-butene to methanol was 1:1:15. The reactions were
performed in the presence of 0.1 mol% Zr(OTf)4. The results showed that only TAME was
formed, while 1-hexene remained un-reactive. The GC trace in Figure 2.23 shows a comparison
of the reaction mixture peaks at the beginning of the experiment (before the addition of the
catalyst) and at the end of the experiment (after 150 minutes). Clearly there is only one product
peak being that for TAME, which indicates the etherification of 2M2B only. No secondary
products were noted, from which can be concluded that etherification of 1-hexene does not
proceed under the reaction conditions used during the investigation.
88
Figure 2.23: GC trace for selective etherification of 2M2B
A similar observation was also evident when using both (primary and secondary olefins, i.e. only
tertiary olefin (2M2B) was reactive with methanol, Figure 2.24. This study has thus shown that
tertiary olefins can undergo selective etherification with methanol in the presence of primary and
secondary olefins, an observation that is important in instances where selectivity may be
required.
89
Figure 2.24: Reactivity of methanol with 2M2B in the presence of 1-hexene and cyclohexene
2.15 Etherification of other alcohols with 2-methyl-2-butene
The etherification reaction of ethanol with 2-methyl-2-butene in the presence of an acid is shown
in Scheme 2.12. TAEE (tert-amyl ethyl ether) also finds it use as fuel additive, due to its high
octane number.230
OHAcid
O
TAEE2.1 2.18
2.19
Scheme 2.12: Etherification of ethanol with 2M2B
The reaction of ethanol with 2M2B is highly selective to one product. However, in the presence
of water, hydration of the olefin occurs, resulting in the formation of tert-amyl alcohol, which may
lead to a decrease of selectivity. This side reaction was only noted when the water content of
90
the ethanol was relatively high, at about 0.5% content. By-product formation could be altogether
eliminated if 100% ethanol was used instead. Furthermore, the isomerisation of the olefin
forming 2-methyl-1-butene (2M1B) also occurred to a small extent, but the latter reaction does
not affect selectivity, since the etherification reaction of this material leads to the desired tertiary
ether. The first reaction in this set of experiments was performed in the presence of Zr(OTf)4
(0.1 mol%) at 100 °C and using an ethanol to olefin mole ratio of 13:1 (in line with the reactions
making use of methanol). It was quickly established that these reactions proceed only slowly,
and the catalyst concentration was therefore increased to 0.5 mol% in the subsequent
reactions, thereby allowing product formation in good yields in acceptable time frames. The
comparison of TAEE yields afforded by various acids is shown in Figure 2.25.
Figure 2.25: The activity of various acids during etherification of ethanol and 2M2B.
The blank reaction showed virtually no product formation in the absence of a catalyst.
Furthermore, the usage of H3PO4 did not improve the conversion, while lanthanides led only to
91
minor improvements, as would now be expected on the basis of prior results from this study. On
the contrary, Zr(OTf)4 gave the best yield and highest rates of reaction, followed by H2SO4 and
Al(OTf)3. The acid combinations (assisted acids) were also evaluated in this study (Figure 2.26).
Figure 2.26: Reaction catalysed by assisted acids.
2.16 Conclusions
The study has shown that the etherification of olefins with alcohols in the presence of
homogeneous acid catalysts (either Brønsted or Lewis acids) is possible. Hence the following
concluding remarks are made based on the results obtained from the study:
The study has shown that the metal triflate Lewis acids of aluminium and zirconium give the
highest activity for etherification reactions. Scandium triflate also showed some activity, while
the triflate salts of the lanthanide series were virtually inactive. The metal halide Lewis acids of
Al, Zr and La were also inactive as catalysts for the etherification reactions.
Among the Brønsted acids evaluated, it was shown that the organic acids such as
methanesulfonic acids para-toluenesulfonic acid and triflic acid showed some activity for the
92
reaction. Only sulfuric acid and nitric acid were active among the mineral Brønsted acids
evaluated, with H3PO4 and HCl being completely inactive under the reaction conditions. The
solid phosphoric acid (55% H3PO4 supported in silica) was also proven to be inactive for the
reaction.
This study has shown that the use of Lewis acids such as La(OTf)3 in combination with mineral
Brønsted acids such as H3PO4 as catalysts for etherification reactions leads to a significant
enhancement of the reaction rate, which is indicative of the fact that highly active systems are
formed that effectively catalyse the reaction. However, the combinations of the already active
Lewis acids [Zr(OTf)4 and Al(OTf)3] with mineral Brønsted acids did not yield to any rate
enhancement. Furthermore, the combinations based on organic Brønsted acids also did not
afford any rate enhancement. The NMR-spectroscopy experiments showed that a new complex
is formed when a lanthanide triflate salt is mixed with H3PO4.
It has been shown in this study that metal triflate salts of Al and Zr can be recycled at least five
times without significant loss of activity. Furthermore, the combined acid systems (assisted
acids) can also be recycled four times with no substantial loss of activity. However, in the case
of La(OTf)3/solid phosphoric acid assisted acid, the active species, which is La(OTf)3/H3PO4
leaches out of the support (silica), but the leached material remains active in the reaction.
The reactivity of alcohols varies significantly, with methanol being more reactive than ethanol,
while a bulkier alcohol (n-butanol) did not react with 2M2B; di-n-butyl ether was formed instead.
This study has also shown that primary and secondary olefins are not reactive during
etherification reactions, hence the tertiary olefins can be etherified selectively, even if the
primary and secondary alkenes are present
The literature review has shown that solid acids such as Amberlyst 15 (commercial catalyst),
and zeolites are widely used for the etherification of tertiary olefins with alcohols. But, there has
not been any mention of the metal triflates, assisted acids or combined acids systems as
catalysts for etherification reactions. Furthermore, the current study has showed that the
combined acid system is more effective than Amberlyst 15.
93
CHAPTER 3
Friedel-Crafts Alkylation This chapter discusses the experimental results on the use of assisted acids composed of metal
triflates and mineral Brønsted acids as catalysts for Friedel-Crafts alkylation of phenolic
compounds with isobutylene.
3.1 Introduction
The Friedel-Crafts alkylation reaction is among the most fundamental reactions in the field of
synthetic organic chemistry, and leads to the synthesis of various important aromatic
compounds via formation of C-C bonds. This reaction is widely utilised in both the laboratory
and commercial industrial scale for the production of fine chemical and valuable synthetic
intermediates. The anhydrous AlCl3 has maintained its wide use as catalyst for the process ever
since it was introduced by Friedel and Crafts in 1877.231 Since then, a number of Lewis and
Brønsted acid catalysts have been introduced for the process. The Brønsted homogeneous
acids identified for the reactions include concentrated H2SO4, HF, p-toluenesulfonic acid232,233
and trifluoromethanesulfonic acid (triflic acid).234 Furthermore, metal halides such as BF3,235
SnCl4,236
SbF5 and ZnCl2 and lately, metal salts of trifluoromethanesulfonate237 also known as
metal triflates, were identified as alternative Lewis acid catalysts for the process. Olah et al.238
reported the use of metal triflate salts of boron-, aluminium- and gallium as catalysts for the
alkylation of toluene, the alkylating agents being alkyl halides. It was found in the study that all
three Lewis acids were effective, convenient and safer during the alkylation reactions.
Furthermore, it was observed that aluminium and gallium triflate complexes have low solubility
in the reaction mixture, and thus these Lewis acids were used as heterogeneous catalyst
systems. However, the addition of nitromethane facilitated the solubility of the Lewis acids and
hence the reaction became homogeneous.239
The heterogeneous catalysts for the Friedel-Crafts alkylation reaction that have been reported in
literature include sulfated metal oxides,240 mesoporous molecular sieves,241 clays and
zeolites.242 The common advantages associated with using heterogeneous catalysts is in the
94
ease of catalyst recovery and recycling, less potential of contamination of the product with the
catalyst, and also the possibility of carrying out the reactions in a continuous reactor set-up,
rather than in batch mode. Poliakoff and co-workers243 have reported the use of solid acids such
as Amberlyst 15 and Purolite CT-175, inorganic supported solid acids (Nafion SAC-13 and
deloxan ASPP1/7), and also a Zeolite (Zeolyst CBV 600) as catalysts for alkylation of anisole
with n-propanol in supercritical CO2. Amberlyst 15 showed maximum conversion of anisole at
150 ˚C, and thereafter the activity dropped due to de-sulfonation of the catalyst. Similar results
to Amberlyst 15 were also achieved with Purolite CT 175, except that this catalyst was inactive
at lower temperatures, possibly due to a high moisture content in the catalyst. Nafion SAC-13
showed high optimum temperature, since 91% conversion was achieved at 200 ˚C (the catalyst
was de-sulfonated above 250 ˚C). A conversion of 73% was achieved with Zeolyst CBV 600 at
200 ˚C, with low selectivity to mono-alkylated products.
In a study undertaken by Yadav et al.244, numerous heterogeneous acids were evaluated for
alkylation of 4-methoxy phenol with MTBE. The solid acids include Filtrol-24, K-10
Montmorillonite clay, dodecatungstophosphoric acid supported on clay (DTP/K-10), sulfated
zirconia and cation exchange resin (Deloxane ASP). The order of activity was found to be
Filtrol-24>DTP/ K-10>Deloxane ASP resin>K-10 Montmorillonite>sulphated zirconia (S-ZrO2). In
this study, only two products were obtained (2-tert-butyl-4-methoxyphenol and 2,6-di-tert-butyl-
4-methoxyphenol) with high selectivity to the monoalkylated product.
Kawi and co-workers245 have reported the alkylation of 4-methoxyphenol with tert-butanol over
Zn-Al-MCM-41 mesoporous solid acid to form 2-t-butyl hydroxyanisole. The highest conversion
of 92.2% with selectivity of 99.7% to 2-tert-butylhydroxy anisole was obtained at 150 ˚C, using
2:1 mole ration t-BuOH to 4-methoxyphenol and at an autogenous pressure of 1030 kPa. This
reaction is normally performed in the presence of a homogeneous Lewis acid such as AlCl3,
BF3, SbF5, ZnCl2 and also with Brønsted acids such as H2SO4, HF, H3PO4 and HCl246 during the
alkylation of 4-methoxyphenol with tert-butanol247 or isobutylene.248
The disadvantages associated with conventional metal halide catalysts for Friedel-Crafts
alkylation reactions is that they are moisture sensitive, corrosive and generally pose a safety
hazard. Brønsted acids such as HF and H2SO4 are also corrosive, and as a result the reaction
set-up has to be constructed using special materials, such as hastelloy. The heterogeneous
acids are safer, but they normally exhibit low activity and require energy intensive recycling of
substrates. Hence, a significant research effort has been focussed on the exploration of
environmentally friendly and efficient catalysts for the Friedel-Crafts alkylation. Thus, it is the
95
main objective of this part of the study to develop the chemistry around acids that are moisture
stable and safer to use for Friedel-Crafts alkylation reactions. The concept of assisted acidity
forms the basis of the study where various combinations of Brønsted and Lewis acids will be
prepared and evaluated as catalysts for Friedel-Crafts alkylation. In this study, three phenolics
substrates, i.e. cresols, anisole and diphenyl oxide will be alkylated with isobutene to test the
activity of the acids.
3.2 Alkylation of cresol
The alkylated cresols are commercially important compounds due to their broad applications.
For example, 2,6-di-tert-butyl-p-cresol or butylated hydroxytoluene (BHT) is an industrially
important antioxidant used to inhibit gum formation in motor and aviation gasoline,249 as
insulating oil and as an antioxidant for natural and synthetic rubbers. 250,251 3-Methyl-6-tert-
butylphenol is used as an intermediate in the manufacture of musk ambrette, while 6-isopropyl-
3-methylphenol (thymol) is used in perfumes252 and also as a disinfectant.253
Alkyl phenols are generally manufactured by addition of an alkyl group to the corresponding
phenol. The source of the alkyl group can be an alkyl halide, alcohol or an olefin. Olefins are
commercially preferred due to their ease of handling and atom efficiency during alkylation. The
alkylation of cresols is often carried out in the presence of Brønsted or Lewis acid catalysts. In
the presence of an acid catalyst, alkylation occurs on the ortho- or para-position and the product
distribution is largely dependent on the positions already occupied by substituent groups. In the
case of tert-alkylphenols, rearrangement and dealkylation may occur at higher temperatures.
Alkylation reactions are reversible, and this aspect of alkylation is desirable during separation of
close boiling isomers. For example, Sharma et al.254 have reported a process for the separation
of m/p-cresols; 2,5- and 2,4-xylenols, and p-cresol/2,6-xylenol by first alkylating the phenolic
mixture with α-methylstyrene and diisobutylene in the presence of p-toluenesulfonic acid and
Amberlyst 15, followed by separation and subsequent decomposition or dealkylation. According
to Sharma, di-alkylation of m- and p-cresols occurred. However, if the reaction is left for a
prolonged time at reaction temperature, decomposition of the p-alkylated product occurs giving
back meta-cresol. A patent by Koppers Company Inc., 255 disclosed a process for selective de-
alkylation of 4,6-di-tert-butyl-m-cresol to yield mainly 6-tert-butyl-m-cresol (an intermediate for
the synthesis of thymol, used as an antiseptic and as an antioxidant). This process is performed
by heating 4,6-di-tert-butyl-m-cresol in the presence of catalytic amounts of aryloxides of
zirconium, hafnium, niobium and tantalum until de-alkylation occurs. The alkylation of m-cresol
96
with isobutylene in the presence of sulfuric acid under mild conditions yields 6-tert-butyl-m-
cresol. Unfortunately, the process only provides low yields to the desired product.256 Another
patent by Leston257also provide some examples on the process of de-alkylation of 4,6-di-tert-
alkyl-meta-cresol in the presence of aluminium aryloxide catalysts.
UOP Inc. filed a patent which discloses a process for the preparation of BHT via a reaction of p-
cresol with isobutylene (mole ratio of isobutylene to p-cresol being 10:1 at 100 ˚C) in presence
of macroreticular cation exchange resins bearing sulfonic acid groups (highly cross linked
polystyrene-divinylbenzene with a surface area of about 540 m2/g and average pore size of
about 51 Å) and Amberlyst 15.258 The emphasis of this patent is that high surface area (525-575
m2/g) and low pore size or pore diameter (40-60 Å) of the catalyst leads to high BHT yields
(>90%); the rest being mono-alkylated p-cresol, which implies a quantitative conversion of p-
cresol and good selectivity to the desired product. Wetzel et al.259 disclosed a process for
alkylation of phenol and ortho-cresol with isobutylene in the presence of highly acidic
homogeneous aryl sulfonic acids (Scheme 3.1).
OH OHOH OH
(84%) (16%)
trifluoromethanesulfonic acid
1 h, 120 oC
OHOH
OH OH
(79%) (21%)
m-benzenedisulfonic acid
5 h, 150 oC
3.1 3.2 3.3 3.4 3.5
3.6 3.73.8
3.93.2
Scheme 3.1: Alkylation of phenol and o-cresol in the presence of sulfonic acids
The aryl sulfonic acids referred to in the literature as catalysts by Wetzel for such types of
reactions include para-chlorobenzene sulfonic acid, 4,4-diphenyldisulfonic acid, meta-benzene
disulfonic acid, nitrobenzenesulfonic acid, 2,4,6-trinitrobenzenesulfonic acid and
trifluoromethanesulfonic acid (Scheme 3.2).
97
3.10 3.11 3.12
3.13 3.14
3.15
CH3
SO OOH
SHO
O
O
S OH
O
O SO O
OH
NO2
SO O
OH
NO2O2N
NO2
SO O
OH
S
O
OOH
S OHF3C
O
O
para-toluenesulfonic acid 4,4'-diphenyldisulfonic acid 4-nitrobenzenesulfonic acid
2,4,6-trinitrobenzenesulfonic acid meta-benzenedisulfonic acid trifluoromethanesulfonic acid
Scheme 3.2: Aryl sulfonic acid catalysts
Wetzel et al. claim that the effectiveness of these aromatic and alkyl sulfonic acids as selective
para-alkylating agents is directly related to their acid strength. These acids can be neutralised
with any base after completion of the reaction, followed by fractional distillation of the reaction
mixture. The catalysts or their salts would remain in the reboiler, due to their high boiling point
characteristics. The patent also claims that these catalysts are effective for rearrangement of
ortho-/meta-substituted phenols to the desired para-substituted compounds (Scheme 3.3).
OHOH
m-benzenedisulfonic acid (1%)
1.5 h, 150 oC
(84%)
3.163.3
Scheme 3.3: Rearrangement of 2-tert-butylphenol to 4-tert-butylphenol
98
The acids may also function as de-alkylation catalysts (Scheme 3.4).
OHOH
m-benzenedisulfonic acid (1%)
1.5 h, 150 oC
(81%)3.5
3.3
Scheme 3.4: De-alkylation 2,4-di-tert-butylphenol
In Chapter 2 of this thesis, it was demonstrated that Lewis assisted Brønsted acids (metal
triflate salts and mineral acids combined) could be used as efficient catalysts for etherification of
tertiary olefins with alcohols, yielding various ethers. Furthermore, the literature has shown that
metal chlorides can be used in conjunction with Brønsted acids, resulting in super acidic
systems such as SbF5-HSO3F also known as “magic acid”,260 which can be used for alkylation
reactions. However, there is no mention of the catalytic activity of hydrolytically stable metal
triflate Lewis acids combined with common mineral Brønsted acids, and this has then presented
an opportunity to explore the catalytic activity of metal triflates combined with mineral Brønsted
acids as assisted acid systems for alkylation reactions.
The activity of the acid combinations was evaluated in the Friedel-Crafts alkylation of a meta-
and para-cresol mixture with isobutylene as an alkylating agent. The proposed mechanism for
the reaction of isobutylene and cresol is shown in Scheme 3.5. The hydroxyl group activates the
cresol for substitution in both ortho- and para-positions, accounting for the regioselective
outcome of the alkylation reaction. This alkylation reaction is initiated by protonation of
isobutylene, yielding a tertiary carbocation via the Markovnikov mechanistic pathway, followed
by substitution on the ortho-position (in the case of p-cresol). The 2-tert-butyl cresol
subsequently undergoes further substitution on position 6, yielding 2,6-di-tert-butyl-p-cresol
(DBPC).
99
3.2H+
OH
OHH
Base
OH
MBPC
H+
OH
DBPC or BHT
3.17
3.18
3.19
3.203.21
Scheme 3.5: The acid catalysed Friedel-Crafts alkylation of p-cresol
In the case of meta-cresol, isobutylene is first added onto the para-position, forming 4-tert-butyl-
m-cresol, followed by addition of another isobutylene molecule at the ortho- position
(Scheme 3.6) to form 2,4-di-tert-butyl-m-cresol (DBMC). According to the literature,261 the
alkylation of cresol is reversible. Thus DBMC and BHT can be de-alkylated to their mono-
alkyated products and even further to their cresylic forms. The isobutylene oligomerisation side
reaction occurs in the presence of acid catalyst. This reaction can form isobutylene dimers,
trimers and sometimes even tetrameric hydrocarbon compounds. This side reaction is
undesirable as it consumes the valuable isobutylene reactant.
100
MBMC DBMC
OH OH OH
3.22 3.23 3.24
Scheme 3.6: Alkylation of m-cresol with isobutylene
3.3 Evaluation of metal triflate Lewis acids as catalysts for the butylation of cresol
The initial set of experiments involved screening of different metal triflate Lewis acids such as
Zr(OTf)4, Al(OTf)3, Sc(OTf)3 and lanthanide triflates salts [La(OTf)3, Gd(OTf)3, Sm(OTf)3,
Yb(OTf)3] as catalysts for butylation of meta- and para-cresol mixtures, with isobutylene as an
alkylating agent. The activities of two mineral Brønsted acids (H3PO4 and H2SO4) were also
evaluated. It is well-known that the catalytic activity of a Brønsted acid is largely dependent on
its dissociation constant (pKa). For instance, H2SO4 with pKa = -3 is expected to exhibit higher
activity than H3PO4 having pKa = 2. The cresol substrate used in these reactions is a mixture of
m- and p-cresols. The m- and p-cresol balance in the mixture is 57.1% and 41.4% respectively,
the other (1.5%) is made up of unidentified substances. All of the cresol butylation reactions
were performed at 70°C under constant isobutylene pressure (1.1 bar) and the mixtures were
stirred at 1200 rpm in a Parr reactor. The catalysts were weighed directly into the reactor at
ambient conditions. Special exclusion of air or moisture was not required given the literature
assertion that metal triflate Lewis acids can tolerate moisture compared to metal halide
counterparts which are deactivated in the presence of moisture. 262
The results on the imminent tables showed that Al(OTf)3 and Zr(OTf)4 gave good activity and
selectivity to the desired products. Sc(OTf)3 exhibited lower activity compared to the triflate salts
of Zr and Al. During the alkylation reactions, it was observed that an exotherm of about 10 ˚C
prevailed soon after the introduction of isobutylene into the reactor with cresols and catalyst.
Therefore, the internal setup of the reactor was modified with a cooling coil for circulation of
water to control the exotherm and maintain the reaction mixture at the required temperature.
The lanthanide metal triflate salts were essentially inactive for the butylation of cresols, and
these Lewis acids did not lead to the production of any product.
101
The reaction products were characterised by GC analysis using authentic samples purchased
from Sigma Aldrich as standards. The analysis of the reaction mixture showed that selectivity to
mono-alkylated cresols is higher during the initial stages of the reaction. However, the mono-
alkylated products undergo addition of a second isobutylene, leading to a decrease in the
selectivity towards mono-alkylated cresols while the selectivity to di-alkylated cresols increases.
The GC analysis also showed that the oligomerisation side reaction of isobutylene occurred,
leading to the formation of C8, C12 and even small amounts of C16 hydrocarbon compounds. It
is known that olefins can easily form oligomers in the presence of an acid by a cationic
mechanism,263 Scheme 3.7.
3.2 3.17
3.17 3.2
H+
3.25
Scheme 3.7: Dimerisation of isobutylene under acidic conditions
The product distribution for the reaction catalysed by Zr(OTf)4 is shown in Table 3.1, as
determined by GC analysis. Since the two cresol isomers that make up the substrate possess
different boiling points, the individual reaction profile may be readily tracked. The data are
presented in a single table (Table 3.1) which may be used to compare the reactivity of each
cresol substrate as rates of reaction, selectivities etc. A typical graph representing the products
distribution is also shown in Figure 3.1.
The reaction was performed using 0.05 wt% of Zr(OTf)4 as catalyst at 70 ˚C. An excess of
isobutylene was used at a pressure of 1.1 bar. This experiment gave quantitative conversion of
both m-cresol (57.1 mol%) and p-cresol (41.4 mol%) in a reaction that was allowed to proceed
for 120 minutes. During the initial stages of the reaction, mono-butylated products MBMC (29.7
mol%) and MBPC (20.2 mol%) were formed within 10 minutes, as determined by GC analysis of
samples removed from the reactor. At this stage the results indicate that the reactivity of m-
102
cresol to form MBMC is higher compared to that of p-cresol to form MBPC (comparing the data
presented in Table 3.1). This could be due to the fact that m-cresol is less sterically hindered
than p-cresol, hence m-cresol can undergo substitution much easier. A more likely explanation
is that the functional groups are cooperative in their positions of activation on the ring in m-
cresol, which is not the case in p-cresol. MBMC and MBPC were subsequently converted into
the corresponding DBMC (7.2 mol%) and BHT (2.1 mol%), respectively, over a period of 10
minutes.
The addition of the first isobutylene molecule to the aromatic ring to form mono-butylated
products is facile, while the addition of a second isobutylene molecule is slow. The latter could
be explained by the fact that mono-butylated cresol is already a bulky molecule, and the steric
hindrance retards the rate at which the second isobutylene molecule is added to the compound
to form di-butylated cresols. At the end of the reaction (120 minutes), small amounts of the
mono-butylated products [MBMC (3.4 mol%) and MBPC (6.6 mol%)] were present, while a
significant quantity of di-butylated products [DBMC (47.4 mol%) and BHT (34.7 mol%)] was
formed. Comparable selectivity (~84%) to both DBMC and BHT was obtained after 120 minutes.
The selectivity of each di-alkylated product was calculated based on the yield afforded by each
cresol separately. For example:
The oligomerisation of isobutylene (side reaction) occurred, yielding a total of 3.4 wt% of
isobutylene oligomers at 120 minutes. It is, however, important to keep the oligomerisation side
reaction minimal because the oligomerisation side reaction consumes the valuable starting
material (isobutylene).
103
Table 3.1: Results for butylation of p-cresol in the presence of Zr(OTf)4
Time (minutes)
Conversion (mol%)
Butylated cresols yield
(mol%)
Selectivity
(%)
Oligomers (wt%)
MC PC DBMC BHT MBMC MBPC DBMC BHT
0 0 0 0 0 0 0 - - 0
5 18.2 12.9 3.5 0.5 14.7 12 19.2 4.0 0.1
10 36.9 24.8 7.2 2.1 29.7 20.2 19.5 9.4 0.1
15 37.1 30.3 18.1 5.9 19 23.9 48.8 19.8 1.0
20 47.3 34.3 28.0 10.5 19.2 24.2 59.3 30.3 1.5
30 52.0 37.9 35.1 17.9 16.8 20.2 67.6 47.0 1.9
40 54.0 39.4 39.2 23.6 14.7 15.9 72.7 59.7 2.0
50 55.0 40.3 41.6 25.8 13.2 14.5 75.9 64.0 3.3
60 55.1 40.5 43.3 28.3 12 12.3 78.3 69.7 3.1
120 57.1 41.4 47.5 34.7 9.1 6.6 83.9 84.0 3.4
104
Figure 3.1: Butylation of m/p-cresol in the presence of Zr(OTf)4 (0.05wt%) at 70 °C.
The reactions catalysed by Al(OTf)3 gave conversions of meta- and para-cresols of 56.6 mol%
and 41.0 mol% respectively within 120 minutes, Table 3.2. The comparable amounts of MBMC
(11.2 mol%) and MBPC (10.2 mol%) were present at the end of the reaction. Considerable
amounts of di-butylated products [DBMC (44.3 mol%) and BHT (30.8 mol%)] were obtained
after 120 minutes. In this specific experiment, the catalyst showed slightly higher selectivity to
DBMC (79.8%) than BHT (75.1%) at the end of the run. The amount of oligomers (3.3 wt%)
obtained with Al(OTf)3 are comparable to those obtained with Zr(OTf)4 (3.4 wt%). However, the
experiment catalysed by Zr(OTf)4 exhibited higher reaction rates, and hence higher selectivity to
di-alkylated products as compared to that catalysed by Al(OTf)3.
105
Table 3.2: Butylation of m/p-cresol in the presence of Al(OTf)3 (0.05 wt%), at 70 ˚C.
Time (minutes)
Conversion (mol%)
Butylated cresols yield
(mol%)
Selectivity
(%)
Oligomers (wt%)
MC PC DBMC BHT MBMC MBPC DBMC BHT
0 0 0 0 0 0 0 - - 0.0
5 12.1 8.7 2.3 0.2 10.4 7.9 18.3 2.3 0.1
10 25.9 18.7 5.8 0.9 23.5 14.4 19.9 5.7 0.2
15 30.3 21.9 13.6 2.3 16.7 19.5 44.9 10.4 0.9
20 36.1 26.2 18.6 4.1 19.2 21.9 49.2 15.7 1.5
30 43.1 31.2 25.9 8.0 16.9 23.3 60.5 25.4 2.4
40 47.5 34.4 31 12.0 16.1 22.5 65.8 34.9 2.9
50 50.5 36.6 34.7 16.6 15.6 19.9 69 45.5 2.2
60 52.4 37.9 36.7 19.0 15.2 19.0 70.7 50.0 3.0
120 56.6 41.0 44.3 30.8 11.2 10.2 79.8 75.1 3.3
While Zr(OTf)4 completely dissolved in the reaction mixture, the majority of the Al(OTf)3
remained insoluble, noted by the catalyst deposits that were observed when the reactor was
opened upon completion of a run. The latter observation is in agreement with the literature264
(the metal triflate salts of boron, aluminium and gallium were insoluble catalysts during
alkylation of toluene with alkyl halides, according to this paper). The latter observation suggests
that metal triflates may function as heterogeneous catalysts during the butylation of cresols. The
heterogeneous catalysts are attractive due to ease of recovery and recycling purposes. It is also
stated in the literature, that improvements in the solubility of metal triflates can be facilitated by
addition of nitromethane (CH3NO2).265
106
The reaction catalysed by Sc(OTf)3 also showed high conversion of m/p-cresol, i.e. 53.9 mol%
and 39.1 mol% conversions of MC and PC, respectively, within 120 minutes (Table 3.3). When
the reaction was terminated, higher amounts of mono-butylated products (21.2 mol% and 11.8
mol% of MBPC and MBMC) were present, and only 17.9 mol% and 41.1 mol% of BHT and
DBMC were obtained respectively. Thus, it is evident that the rate of the reaction catalysed by
Sc(OTf)3 was relatively slow compared to that of Zr(OTf)4 and Al(OTf)3. It was noticeable that
the catalyst gave higher selectivity towards DBMC (77.7%) than BHT (45.8%). This catalyst also
gave greater amounts of oligomers (5.6 wt%) compared to those obtained from the reactions
catalysed by Al(OTf)3 and Zr(OTf)4.
Table 3.3: Butylation of m/p-cresol in the presence of 0.05 wt% Sc(OTf)3, at 70 ˚C.
Time (minutes)
Conversion (mol%)
Butylated cresol yields
(mol%)
Selectivity
(%)
Oligomers (%)
MC PC DBMC BHT MBMC MBPC DBMC BHT
0 0 0 0 0 0 0 - - 0
5 13.8 8.7 2.8 0.2 11 8.5 20.3 2.3 0.8
10 30.1 15.4 5.9 0.9 24.2 14.5 19.6 5.8 1.5
15 30.2 21.4 12.9 1.9 17.3 19.5 42.7 8.9 2.0
20 36.4 25.5 17.2 3.1 19.2 22.4 47.3 12.2 2.4
30 41.6 30.1 23.7 5.5 17.9 24.6 57.0 18.3 3.1
40 44.9 32.9 28.1 7.6 16.8 25.3 62.6 23.1 3.4
50 47.6 34.8 31.5 9.7 16.1 25.1 66.2 27.9 4.7
60 49.3 36.1 34.1 11.5 15.2 24.6 69.2 31.9 5.1
120 52.9 39.1 41.1 17.9 11.8 21.2 77.7 45.8 5.6
107
All of the lanthanide triflate salts [La(OTf)3, Sm(OTf)3 and Gd(OTf)3] evaluated in the study did
not yield any product, hence the lanthanide triflates were not active for the reaction under the
conditions used. The results have in essence shown that there is a significant difference in the
activity of the Lewis acids evaluated in this study [(Zr(OTf)4, Al(OTf)3, Sc(OTf)3] and lanthanide
triflates. Zr(OTf)4 and Al(OTf)3 gave the highest activity with conversion >99% for both m- and p-
cresols. Sc(OTf)3 also gave high conversion (~90%) of both-cresols. The comparison of activity
of different catalysts over time is shown in Table 3.4.
Table 3.4: Comparison of activity of the triflate salts of Zr, Al and Sc.
Catalyst Time (minutes)
Conversion (mol%)
Butylated cresol yields
(mol%)
Selectivity
(%)
Oligomers (wt%)
PC MC MBPC MBMC BHT DBMC BHT DBMC
Zr(OTf)4
10 22.3 36.9 20.2 29.7 2.1 7.2 9.4 19.5 0.1
30 38.1 51.9 20.2 16.8 17.9 35.1 47.0 67.6 1.9
120 41.3 56.5 6.6 9.1 34.7 47.4 84.0 83.9 3.4
Al(OTf)3
10 15.3 29.3 14.4 23.5 0.9 5.8 5.9 19.8 0.2
30 31.3 46.4 23.3 16.9 8.0 29.5 25.6 63.6 2.4
120 41.0 55.5 10.2 11.2 30.8 44.3 75.1 79.8 3.3
Sc(OTf)3
10 15.4 30.1 14.5 24.2 0.9 5.9 5.8 19.6 1.8
30 30.1 41.5 24.6 17.9 5.5 23.6 18.3 56.9 3.0
120 39.1 52.9 21.2 11.8 17.9 41.1 45.8 77.7 5.6
Zr(OTf)4 gave similar selectivity of BHT (84%) and DBMC after 120 minutes. The remaining
products are MBPC and MBMC, respectively. Al(OTf)3 gave only 75% selectivity to BHT and
79% to DBMC, which is comparable to the results obtained with Zr(OTf)4. The outcomes of the
108
reactions using Sc(OTf)3 reflected its lower activity. Furthermore, the results have shown that
butylation of the m-cresol proceeds much faster than that of p-cresol and that the second
butylation of mono-butylated products is a rate-limiting step. It was evident that tripositive metal
triflate salts are less or completely insoluble in the cresol and isobutylene reaction mixture,
because the deposits of these salts were observed at the bottom of the reactor at the end of
each experiment. On the contrary, Zr(OTf)4 was mostly soluble in the reaction mixture under the
conditions, forming a homogeneous mixture with the reaction matrix.
3.3.1 Catalyst recycling studies
The high activity and selectivity and low solubility characteristic of Al(OTf)3 in the reaction
mixture (affording the possibility of recycling) prompted exploration of the influence of various
reaction parameters on the outcome of the reaction. Thus, it was decided to first explore
whether the catalyst could be recycled without any loss of activity and selectivity. All of the
experiments were performed at 70 ˚C under 1.1 bar isobutylene pressure and the stirring speed
was kept constant at 1200 rpm. The catalyst concentration used for the initial experiment was
0.09 wt% (0.053 g, relative to the cresol substrate). The catalyst was recovered by means of
decanting the reaction mixture from the previous experiment, leaving the solid catalyst in the
reactor, followed by charging the reactor with fresh m/p-cresol substrate and carrying out the
subsequent experiment, Table 3.5.
109
Table 3.5: Recycling of Al(OTf)3 (0.09 wt%) during butylation of m/p-cresol at 70 °C, stirring at 1200 rpm and using 1.1 bar of isobutylene.
Exp. # Time
(minutes)
Cresols conversion
(mol%)
Selectivity
(mol%)
Oligomers* (wt%)
PC MC BHT DBMC
Original
15 24.9 40.6 20.6 47.4
60 41.3 57.1 87.9 82.8
120 41.7 57.7 95.5 87.5 4.7
Recycle 1 15 28.5 39.4 19.6 43.7
60 41.4 56.8 83.5 74.9
120 41.7 56.7 87.2 77.9 5.0
Recycle 2 15 28.8 39.8 24.5 50.5
60 41.4 57.2 86.2 76.7
120 41.7 57.7 95.5 84.0 4.5
Recycle 3 15 26.8 37.0 19.2 51.1
120 41.8 57.8 94.4 77.0 5.2
Recycle 4 60 41.3 56.9 87.9 79.1
120 41.8 57.8 95.4 85.2 4.3
*The oligomers reported were obtained after 120 minutes.
The results reported in Table 3.5 demonstrate that a quantitative conversion of both cresol
substrates was obtained in all the reactions after 120 minutes. The general trend showed that
the catalyst give higher selectivity to DBMC during initial stages of the reaction (15 minutes). At
60 and 120 minutes, the reaction showed higher selectivity to BHT than DBMC. This
observation implies that the first addition of isobutylene molecule to m-cresol is faster than to p-
110
cresol as has already been noted. However, the second isobutylene addition to MBPC is faster
than to MBMC under the conditions used.
When 0.05 wt% Al(OTf)3 was used, the selectivity to BHT and DBMC was similar (75% and
80%, respectively, Table 3.2, indicative of the fact that higher Al(OTf)3 concentration favours the
formation of BHT rather than DBMC, but this effect is incremental only. The results in Table 3.5
show that Al(OTf)3 could be recycled at least four times without any significant loss of catalytic
activity and it retained its overall selectivity profile.
3.3.2 The influence of catalyst concentration
The influence of catalyst concentration was the second parameter to be studied using Al(OTf)3.
In this part of the study, other reaction parameters such as temperature, stirring speed (1200
rpm) and isobutylene pressure was kept constant. Hence all reactions were performed at 70 °C
under 1.1 bar pressure of isobutylene and the stirring speed was maintained at 1200 rpm. A
constant amount of the m/p-cresol mixture (60.0 g; 0.55 mol) was used in all of the reactions.
The results obtained from this study are shown in Table 3.6.
111
Table 3.6: The influence of catalyst concentration during butylation of m/p-cresol in the presence of Al(OTf)3 at 70 °C, 1.1 bar isobutylene pressure and stirring at 1200 rpm.
Catalyst
(wt%)
Time
(minutes)
Conversion
(mol%)
Selectivity
(mol%)
Oligomers (wt%)
PC MC BHT DBMC
0.8
15 29.1 40.1 21.2 51.3
60 40.8 56.4 85.8 82.3
120 41.7 57.5 94.7 86.6 3.9
0.35
15 29.8 41.2 19.9 49.2
60 40.7 56.3 79.1 68.0
120 41.7 57.5 93.3 80.8 2.9
0.18
15 27.1 37.5 17.1 48.3
60 39.7 54.8 69.2 71.6
120 41.1 56.7 85.9 75.7 2.9
0.05
15 21.9 30.3 10.1 44.9
60 37.9 52.4 50.1 70.1
120 41.0 56.6 75.1 78.3 3.3
The results obtained after 15 minutes showed that the rate of m/p-cresol conversion decreased
as the catalyst concentration was decreased. The same also holds for the results obtained at 60
and 120 minutes. It is, however, important to note that improvements to the rates of conversions
at catalyst loadings above 0.05 wt% are all marginal, indicative of mass transfer limitations
occurring at 0.05 wt% reaction. This is due to the fact that isobutylene is in the gas phase and is
at relatively low pressure (1.1 bar). Nevertheless, it was imperative to maintain low pressure in
112
order to form the mono-alkylated cresol products, which would virtually be impossible to form at
high pressures.
These reactions all show high conversion (>95%) of m- and p-cresol after 120 minutes. At
higher catalyst loadings, the rate of the reaction was faster, such that almost all the MBPC was
converted to BHT, accounting for the high selectivity to BHT. The selectivities to BHT for
reactions containing 0.8 wt% and 0.35 mol% catalyst were 94.7 and 93.3 mol%, respectively,
compared to 86.6 and 80.8% selectivity to DBMC after 120 minutes. Apart from a reduction of
the rate of the reaction, a reduction in the catalyst concentration favoured the formation of
DBMC. For instance, at 0.05 wt%, the selectivity to DBMC was 78.3 wt% compared to 75.1 wt%
to BHT. This shift in the selectivity presumable arises due to subtle reactivity differences that are
exaggerated at lower catalyst loading and concomitantly lower reaction rate.
3.3.3 The influence of varying stirring speed
When studying the influence of changing the stirring speed, one gathers data on whether the
reaction rate is influenced by mass transfer limitations related to stirring speed. This is important
in the present context because the catalyst is heterogeneous in nature. It is well known that the
rate of heterogeneous reactions is dependent on the rate at which the substrate comes into
contact with the catalyst, an aspect which is facilitated by stirring. These experiments were
performed at 70 ˚C using 60.0 g (0.55 mol) of m/p-cresol mixture. A high excess of isobutylene
(1.1 bar with constant feeding) was used and Al(OTf)3 was present at a loading of 0.09 wt% with
respect to cresol. The speed of the stirrer was varied from 512 to 1512 rpm (Table 3.7).
113
Table 3.7: Influence of stirring speed on butylation of m/p-cresol in the presence of 0.09 wt% Al(OTf)3 at 70 °C.
Stirring speed (rpm)
Time (minutes)
Conversion
(mol%)
Selectivity
(mol%)
Oligomers (wt%)
PC MC BHT DBMC
1512 15 27.5 38.0 18.7 56.5
60 40.5 55.9 71.4 77.8
120 41.7 57.6 90.7 85.7 2.7
1052 15 25.1 34.6 15.8 47.1
60 39.1 54.0 60.2 72.8
120 41.0 56.6 81.9 81.7 2.8
512 15 22.9 31.7 9.9 27.6
60 40.3 55.6 72.3 75.6
120 41.7 57.5 91.5 84.8 3.1
A steady increase of the reaction rate with an increase of stirring speed from 512 to 1512 rpm
was evident. The results for the experiment performed at 512 rpm showed high rate of
conversion of m-cresol compared to that of p-cresol. Consequently, the selectivity to DBMC was
higher than that of BHT during the initial stages of the reaction. At 120 minutes, the selectivity to
BHT and DBMC are similar with cresol substrates being converted quantitatively. Thus, it can
be concluded that stirring speed affects the rate of these reactions (mass transfare limitations).
The amount of oligomers formed in all instances was comparable, which indicates that the rate
of a side reaction is not affected by the stirring speed.
114
3.4 Screening of Brønsted acids
The Brønsted acids evaluated for the alkylation of the m/p-cresol mixture with isobutylene
involved two mineral Brønsted acids, i.e. H2SO4 (98%) and ortho-H3PO4 (99%). The dissociation
constants (pKa) of these two acids vary significantly, with H2SO4 being a stronger acid (pKa = -3)
than H3PO4 (pKa = 2). These Brønsted acids were evaluated under the same set of conditions
as before [70 ˚C, using 60.0 g (0.55 mol) m/p-cresol], with a catalyst loading of 0.19 wt% with
respect to the cresol substrate and high excess of isobutylene (1.1 bar pressure). The stirring
speed was 1200 rpm. The results afforded by H2SO4 are shown in Table 3.8. There was no
conversion of the substrates when using H3PO4 under these conditions and so no data for these
reactions are presented in the Table.
Table 3.8: Butylation of the m/p-cresol in the presence of H2SO4
Time (minutes)
Conversion (mol%)
Alkylated cresols Yield
(mol%)
Selectivity
(%)
Oligomers (wt%)
MC PC MBMC MBPC DBMC BHT DBMC BHT
0 0 0
0 0 0 0 - - 0
5 10.0 5.9
9.8 5.7 0.2 0.2 2.0 3.3 0.2
10 19.6 13.2
18.0 11.6 1.6 1.2 8.2 9.1 0.3
20 34.7 25.8
28.5 20.2 6.2 5.6 17.9 21.7 0.6
30 42.5 30.2
28.1 19.0 14.4 11.2 33.9 37.1 0.7
40 40.2 36.9
26.1 17.9 19.0 14.1 47.3 38.2 1.4
50 48.0 38.4
25.9 16.3 22.1 17.6 46.0 45.8 1.6
60 42.2 33.7
23.6 15.1 24.2 18.6 57.3 55.2 1.8
115
Sulfuric acid showed some activity; however, retarded reaction rates were obtained with this
acid. Low conversion of both m/p-cresol, i.e. 42.2 and 33.7 mol%, respectively were obtained
within 60 minutes. This acid also led to faster formation of MBMC, as compared to that of
MBPC, as was also found to be the case with the Lewis acid catalysts. While the formation of
BHT and DBMC proceeded slowly, the formation of DBMC was faster than that of BHT. On the
other hand, the selectivity to DBMC (50.7 mol%) was slightly lower than that of BHT (55.2
mol%) after 60 minutes. There was no product obtained when using H3PO4 as catalyst under
the conditions. The significantly divergent activities of the two Brønsted acids can be attributed
to their different pKa values. The results demonstrate that the metal triflates of Zr and Al exhibit
higher activity than Brønsted acids (H3PO4 and H2SO4) under the same set of conditions used.
3.5 Evaluation of assisted acids
An objective of this study was to evaluate a variety of assisted acids (derived from the Lewis
and Brønsted acids that have already been discussed) as catalysts for Friedel-Crafts alkylation
reactions of m/p-cresol with isobutylene. During that part of the study involving the etherification
of olefins with alcohols, it was shown that the activity of Lewis and Brønsted acids, such as
La(OTf)3 and H3PO4, which were completely in-active as individual acids was enhanced by
using those acids in combination (assisted acids). The major discovery was that this
combination showed superior activity for the etherification reactions, delivering catalysts with
activities higher than HOTf, Al(OTf)3 and Zr(OTf)4. Consequently, the assisted acids were
evaluated here for the alkylation of the m/p-cresol mixture with isobutylene. The assisted acids
were prepared by combining the Lewis acids with Brønsted acids either in situ or by mixing the
acids prior to their addition to the reactor. It is proposed that the metal triflate and phosphoric
acid form a complex of the type shown in Scheme 3.8. This will be analogous with what is
claimed in the literature266 where an improved nitration reaction is held to also proceed via a
complex of the type shown in Scheme 3.8, but where the acid is nitric acid. In the present
instance, the protons of the coordinated H3PO4 should be more highly acidic than the parent
H3PO4 by virtue of the electron withdrawing effect of the binding thereof to the metal centre and
these protons should thus be available to catalyse certain types of reactions.
116
H3PO4 La(OTf)3 (OTf)3LaO
OP
OH
OH
H
3.26
Scheme 3.8: Formation of a complex via combination of H3PO4 and La(OTf)3
The following set of reactions was performed using a variety of Lewis acid and Brønsted acid
combinations. The La(OTf)3/H3PO4 acid combination was the first assisted acid to be evaluated
in the alkylation reaction at 70 ˚C. An equal molar amount of each acid (4 mmol) of La(OTf)3 and
H3PO4 (99%), were used, hence the total mass of catalyst loaded was 0.015 wt% which is much
less than the instance where individual acids were screened. The stirring speed was kept at
1200 rpm and high excess of isobutylene (1.1 bar) was utilised. The results obtained from this
experiment are showed in Table 3.9.
117
Table 3.9: Butylation of m/p-cresol in the presence of [La(OTf)3/H3PO4]
Time (minutes)
Conversion (mol%)
Butylated cresols Yield
(mol%)
Selectivity
(%)
Oligomers (wt%)
MC PC MBPC MBMC BHT DBMC BHT MBPC
0 0 0 0 0 0 0 0 0 0
5 15.2 9.6 9.3 11.9 0.3 3.3 3.1 21.7 0.7
10 32.0 12.6 11.3 25.1 1.3 6.9 10.3 21.6 1.5
15 35.7 22.8 19.9 20.9 2.9 14.8 12.7 41.5 3.7
20 38.7 25.9 21.3 19.2 4.6 19.5 17.8 50.4 4.7
30 41.8 29.8 21.9 17.6 7.9 24.2 26.5 57.9 4.4
40 44.5 32.3 21.8 16.7 10.5 27.8 32.5 62.5 4.2
50 47.8 34.2 20.4 16.3 13.8 31.5 40.4 65.9 3.4
60 47.9 38.6 20.0 16.1 18.6 31.8 48.2 66.4 5.5
120 50.2 37.4 15.9 14.6 21.5 35.6 57.5 70.9 6.7
It was evident during the screening of various acids that individual lanthanide triflates and
H3PO4 exhibited no activity for the butylation of cresols. However, when the acids were used as
a combination, a significant enhancement of activity was achieved. This is an indication of a
synergistic effect which prevails upon combining the two acids. However, the assisted acid gave
lower activity towards alkylation reactions than Zr(OTf)4 and Al(OTf)3. Although the assisted
catalyst loading was low in this particular experiment, the reaction rate was high compared to
the instance where the individual Brønsted acids were used. The conversions of m- and p-
cresols were 50.7 and 36.7 mol% respectively after 120 minutes. The assisted acid showed
faster alkylation of both m-cresol and MBMC, resulting in a high selectivity to DBMC (70.9%),
118
while the selectivity to BHT was only 57.7% after 120 minutes. The assisted acid gave 6.7 wt%
of oligomers over a period of 120 minutes, and this amount of oligomers is much higher than
those obtained when using Zr(OTf)4 and Al(OTf)3. It was remarkable that the assisted acid was
able to promote the reaction effectively as compared to individual acids.
The results achieved with the La(OTf)3/H3PO4 assisted acid prompted further evaluation of other
triflate salts combined with H3PO4. The second assisted acid evaluated was Gd(OTf)3/H3PO4.
The experiment was also performed using the same set of conditions as for La(OTf)3/H3PO4.
Again, this acid system exhibited significant enhancement of activity for alkylation reactions,
compared to the inactive individual acids. A similar amount of m/p-cresol conversion was
accomplished in both reactions, Table 3.10.
Table 3.10: Butylation of m/p-cresol in the presence of [Gd(OTf)3/H3PO4]
Time (minutes)
Conversion (mol%)
Butylated cresols yield
(mol%)
Selectivity
(%)
Oligmers (wt%)
MC PC MBMC MBPC DBMC BHT BHT DBMC
0 0.0 0.0 0.0 0.0 0.0 0.0 - - 0.0
5 16.6 11.9 13.5 11.5 3.1 0.4 3.3 18.7 0.1
10 34.2 20.6 25.8 18.8 8.4 1.8 8.6 24.6 0.6
15 34.2 26.3 18.2 22.7 16.0 3.6 13.7 46.8 1.8
20 38.7 30.1 17.2 23.4 21.5 6.7 22.2 55.6 2.7
30 43.6 32.4 16.5 23.0 27.1 9.4 29.1 62.2 3.0
40 46.2 34.0 16.1 21.6 30.1 12.4 36.5 65.2 3.3
50 47.5 35.1 15.2 20.8 32.3 14.3 40.8 68.0
60 48.7 35.9 14.9 19.7 33.8 16.2 45.1 69.4 3.3
120 51.9 38.1 13.0 14.8 38.9 23.3 61.2 75.0 3.6
119
Gd(OTf)3/H3PO4 also showed higher activity for alkylation of m/p-cresol compared to individual
acids. This reaction has exhibited high selectivity to DBMC (70.9%) and 63.1% to BHT.
Therefore, the intermediate products (MBMC and MBPC) did not convert quantitatively to
DBMC and BHT. The amount of oligomers (3.6 wt%) formed were comparable to that obtained
when using Zr(OTf)4 and Al(OTf)3 and less than that of the assisted acid formed from
La(OTf)3/H3PO4. It has already been shown that Al(OTf)3 accomplished excellent activity for
alkylation of the cresol mixture. Furthermore, the results showed that a catalyst loading of >0.05
wt% afforded high selectivity towards the formation of BHT. It was then decided to investigate
whether a combination of Al(OTf)3 with H3PO4 will result in further enhancement of reaction rate.
The results of a reaction catalysed by Al(OTf)3/H3PO4 are shown in Table 3.11.
Table 3.11: Butylation of m/p-cresol catalysed by Al(OTf)3/H3PO4
Time (minutes)
Conversion
(mol%)
Butylated cresols Yield
(mol%)
Selectivity
(%)
Oligomers (wt%)
MC PC DBMC BHT MBMC MBPC BHT DBMC
0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
5 15.3 10.4 2.9 0.3 12.4 10.1 2.9 19.0 0.2
10 31.9 18.4 6.5 1.2 25.4 17.2 6.5 20.4 0.6
15 33.7 24.9 15.6 3.3 18.1 21.6 13.3 46.3 2.1
20 39.4 28.5 20.2 5.5 19.2 23 19.3 51.3 2.6
30 43.6 32.1 25.8 9.5 17.8 22.6 29.6 59.2 3
40 46.3 34 29.5 12.5 16.8 21.5 36.8 63.7 3.2
50 48.7 35.6 32.6 15.9 16.1 19.7 44.7 66.9 3
60 49.7 36.3 33.9 18 15.8 18.3 49.6 68.2 3.5
120 52.9 38.8 39.5 25.8 13.4 13 66.5 74.7 3.8
120
The results obtained when using Al(OTf)3/H3PO4 as a catalyst are comparable to those obtained
when using Al(OTf)3 alone. The assisted acid also gave high selectivity to DBMC (74.7%) and
only 66.5% to BHT. The selectivity trend is similar to that of a reaction catalysed by Al(OTf)3
alone, where selectivities of 79.8% and 75.1%, respectively, were noted. The quantity of the
products afforded by this assisted acid are comparable to those afforded by the assisted acids
of La(OTf)3 and Gd(OTf)3.
3.6 Evaluation of La(OTf)3/SPA assisted acid
The excellent activity afforded by the La(OTf)3/H3PO4 assisted acid also led to the evaluation of
La(OTf)3/SPA assisted acid. SPA was first evaluated on its own for the butylation reaction, and
was proven to be inactive. Thereafter, La(OTf)3/SPA was prepared and its activity evaluated
during m/p-cresol butylation reactions. The reaction was performed in a 300 mL batch autoclave
at 70 ˚C and at 1.1 bar isobutylene. The total amount of the catalyst (including silica support)
used was 0.57g (0.95 wt). This reaction was performed under the same set of conditions as the
one where SPA was used, but stirred at 700 rpm. The low stirring speed was employed to avoid
catalyst attrition, which resulted in the blockage of the sampling line. The results obtained are
shown in Table 3.12.
121
Table 3.12: Butylation of m/p-cresol in the presence of La(OTf)3/SPA.
Time (minutes)
Conversion (mol%)
Butylated cresol yields
(mol%)
Selectivity (%)
Oligomers (wt%)
MC PC MBMC MBPC DBMC BHT BHT DBMC
0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
5 24.5 18.5 18.4 14.9 6.1 3.6 19.5 24.9 1.0
10 40.2 25.4 29.9 21.4 10.3 4.0 15.7 25.6 1.3
15 41.0 31.0 21.2 24.4 19.8 6.6 21.3 48.3 1.4
20 46.4 34.9 19.2 24.1 27.2 10.8 30.9 58.6 1.8
30 51.1 37.8 16.6 19.9 34.5 17.9 47.4 67.5 2.4
40 53.1 39.1 15.0 16.5 38.1 22.6 57.8 71.8 2.7
50 54.1 39.7 13.9 12.7 40.2 27.0 68.0 74.3 3.1
60 55.0 40.3 12.8 10.8 42.2 29.5 73.2 76.7 3.2
120 56.7 41.2 9.0 4.4 47.7 36.8 89.3 84.1 4.4
The La(OTf)3/SPA catalysed reaction gave a quantitative conversion of m- and p-cresol, i.e.
56.7 mol% and 41.2 mol%, to product. This reaction showed extremely high reaction rates. The
selectivity to BHT (89.3%) is comparable to that of DBMC (84.1%) after 120 minutes. In the
reaction catalysed by La(OTf)3/SPA, the mono-butylated products (MBPC and MBMC) were
almost all converted to their corresponding di-alkylated products (BHT and DBMC). It is also
crucial to note that each individual acid was completely inactive when employed as catalyst in
this type of reaction, but when combined, the activity was significantly enhanced, as is apparent
from the results. The oligomerisation reaction afforded 4.6 wt% hydrocarbon products, resulting
122
from isobutylene oligomerisation reactions. A comparison of the products afforded by
La(OTf)3/SPA and La(OTf)3/H3PO4 combination catalysts is shown in Table 3.13.
Table 3.13: Comparison of cresols conversions and product selectivities afforded by La(OTf)3/H3PO4 and La(OTf)3/SPA after 120 minutes.
Catalyst Conversion
(mol%)
Alkylated cresol yield
(mol%)
Oligomers
(wt%)
Selectivity
(%)
MC PC MBMC MBPC DBMC BHT Oligomers BHT DBMC
La(OTf)3/SPA 57.0 41.3 9.0 4.4 47.7 36.8 4.4 89.3 84.2
La(OTf)3/H3PO4 50.2 37.4 15.9 14.6 21.6 35.6 6.7 57.5 70.9
High conversions were achieved in reactions catalysed by La(OTf)3/SPA as compared to those
catalysed by La(OTf)3/H3PO4. High selectivites to the di-butylated cresols were also achieved
with La(OTf)3/SPA. La(OTf)3/SPA also gave low amount of oligomers. The high activity and the
heterogeneous nature of La(OTf)3/SPA prompted evaluation of a possibility to recycle the
catalyst. The initial run of the catalyst recycling studies was performed at 70 ˚C, with 1.1 bar
isobutylene and m/p-cresol (61.9 g; 0.57mol), starting off with 0.50 g (0.09 wt%) of catalyst. The
catalyst recycling was performed in a 300 mL stainless steel autoclave reactor. At the end of
each experiment, the catalyst was recovered by decanting all the previous reaction contents
and the solid catalyst remained in the reactor. For the subsequent experiments, fresh m/p-cresol
was charged into the reactor containing the catalyst residue and the reactor was assembled and
heated to the operating temperature. Upon reaching the temperature, isobutylene was allowed
into the reactor, with samples taken over time. The results of the reactions are shown in Table
3.14.
123
Table 3.14: The results obtained during recycling of La(OTf)3/SPA.
Experiment # Time (minutes)
Conversion
(mol%)
Selectivity
(mol%)
Oligomers (wt%)
PC MC BHT DBMC
Original 15 29.2 40.3 11.9 12.4
60 41.8 57.7 85.9 73.6
120 41.6 57.5 80.2 65.1 4.8
Recycle 1 15 30.3 41.8 21.2 48.3
60 40.1 55.4 73.2 76.8
120 41.3 57.2 89.3 84.2 4.3
Recycle 2 15 22.2 30.7 14.2 44.8
60 34.6 47.8 42.7 68.1
120 38.0 52.5 64.6 76.3 4.8
Recycle 3 15 17.4 24.1 14.6 37.5
60 30.3 41.8 28.0 61.4
120 36.2 51.1 51.1 72.2 4.0
The results showed consistent catalyst activity for the original run and the first recycle run, but a
considerable decrease of activity to the following runs. It is known in the literature that H3PO4
leaches out of the support (SiO2), which leads to catalyst deactivation.267 The current study has
thus showed that La(OTf)3/SPA could be recycled at least four times (including the original run)
without being completely deactivated. The deactivation noted presumably arises due to leaching
124
away of the H3PO4 from the SiO2 support into the reaction medium, in line with literature
observations. A summary of the overall reaction rates afforded by various assisted catalyst
systems is depicted in Figure 3.2. It is thus evident that La(OTf)3/SPA gave the highest reaction
rate for the conversion of cresols (MC+PC) to mono-butylated products (MBMC+MBPC), which
were effectively converted to di-butylated products (DBMC+BHT). The other catalyst systems
showed comparable reaction rates.
0
10
20
30
40
50
60
70
80
90
100
110
0 20 40 60 80 100 120 140
Mo
l%
Time (Min.)
MC+PC Conv.: La(OTf)3/SPA
MC+PC Conv.: La(OTf)3/H3PO4
MC+PC Conv.:Gd(OTf)3/H3PO4
MC+PC Conv.: Al(OTf)3/H3PO4
MBMC+MBPC: La(OTf)3/SPA
MBMC+MBPC: La(OTf)3/H3PO4
MBMC+MBPC: Gd(OTf)3/H3PO4
MBMC+MBPC: Al(OTf)3/H3PO4
DBMC+BHT: La(OTf)3/SPA
DBMC+BHT: La(OTf)3/H3PO4
DBMC+BHT: Gd(OTf)3/H3PO
DBMC+BHT: Al(OTf)3/H3PO4
Figure 3.2: Summary of reaction rates for various assisted catalysts
3.7 Friedel-Crafts alkylation of anisole
Alkylated anisole is an important industrial compound which is used as an antioxidant, in dye
developers and in stabilisers for fats, oils and plastic rubbers.268 The preparation of 4-tert-
butylanisole via alkylation of anisole with tert-butyl alcohol in the presence of ZrCl4 and
trifluoroacetic acid was reported by Sartori and co-workers.269 Alkylation of anisole with tert-
butylacetate as an alkylating agent in the presence of H2SO4, and also with tert-butyl nitrate in
the presence of SnCl4270 as a catalyst, was also reported by Fernholz et al.271
125
It was therefore decided to evaluate the activity of assisted acids for alkylation of anisole with
isobutylene. The starting point in these reactions involves screening of individual acids. The
results obtained from individual acids will eventually be compared to those afforded by the
assisted acid systems. There are three major products that were obtained from the reaction of
anisole and isobutylene, i.e. two mono-alkylated anisoles (2-tert-butylanisole and 4-tert-
butylanisole), while a third product is obtained when the mono-alkylated products undergo
further alkylation to form 2,4-di-tert-butylanisole, Scheme 3.9.
O
2,4-di-t-butyl anisole4-t-butyl anisole2-t-butyl anisoleAnisole
H+
O OO
3.27 3.28 3.29 3.303.2
Scheme 3.9: Alkylation of anisole with isobutylene
MTBE (methyl tert-butyl ether) or tert-butanol can be used to generate isobutylene in situ
(Scheme 3.10), with MTBE being the most widely used and recommended reagent. The
drawback associated with tert-butyl alcohol as an alkylating agent is that the overall reaction
forms water, which may affect the activity of the catalyst and may even lead to complete catalyst
deactivation.
O
H+CH3OH
MTBE
OHH2O
H+
t-BuOH3.31
3.32
3.2
3.2
Scheme 3.10: Generation of isobutylene from tert-BuOH and MTBE
126
Cracking of MTBE is a viable source of isobutylene, resulting in the formation methanol as by-
product. Furthermore, Yadav and co-workers have shown that the rate of alkylation with MTBE
is much faster than with t-BuOH.272
3.7.1 Evaluation of individual Lewis and Brønsted acids
The reaction of anisole with isobutylene is expected to occur with ease because the methoxy
functional group on the benzene ring donates electron density to the ring, thereby making it
more highly nucleophilic. Because of the activating group, anisole undergoes alkylation at its
ortho- and para-positions. The initial set of reactions involved evaluation of metal triflate Lewis
acids and Brønsted acids as catalysts for the alkylation of anisole with isobutylene. The Lewis
acids evaluated include Al(OTf)3, Zr(OTf)4 and two lanthanide triflate salts [La(OTf)3, and
Gd(OTf)3]. The Brønsted acids included H3PO4 and triflic acid (HOTf). The first reaction was
performed at 70 ˚C, using anisole (560 mmol) and high excess of isobutylene (1.1 bar constant
feed) in the presence of Zr(OTf)4. This catalyst showed good activity for the reaction, as may be
seen in Figure 3.3.
Figure 3.3: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by 1.46 mmol Zr(OTf)4 at 70 ˚C, and stirred at 1000 rpm.
The overall conversion of anisole under this set of conditions was 55 mol%. Three major
alkylated products were identified, i.e. 4-tert-butylanisole, 2-tert-butylanisole and 2,4-di-tert-butyl
127
anisole. In the course of the reaction, 3 wt% of oligomers of isobutylene were obtained. The
results showed that 4-tert-butyl anisole and 2-tert-butylanisole were formed faster during the
initial stages of the reaction, with 4-tert-butyl isomers being formed at the highest rate. The
mono-alkylated anisole products subsequently undergo further butylation to form a di-butylated
product (2,4-di-tert-butylanisole). Al(OTf)3 together with lanthanide triflate Lewis acids [La(OTf)3
and Gd(OTf)3] were also evaluated under the same set of conditions and, interestingly, all were
shown to be inactive. Although, it was probable that lanthanide triflate salts may be inactive,
Al(OTf)3 was expected to show some activity as was the case during butylation of cresol. The
Lewis acid was unreactive for the present reaction, despite numerous attempts. The reasons for
this reactivity remain unknown.
The alkylation reactions described here are reversible under some conditions, and a large
excess of isobutylene should be used to avoid de-butylation. The reaction performed at 70 °C
was relatively slow, and hence the reaction temperature was increased to 100 °C in an attempt
to speed up the reaction, Figure 3.4.
Figure 3.4: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by Zr(OTf)4 (1.46 mmol ) at 100 ˚C, and stirred at 1000 rpm.
128
Increasing the reaction temperature resulted in an increase of the reaction rate, leading to a
high conversion of anisole (85 mol%) in the allocated period of two hours. The results of this
experiment also showed that mono-butylated products are formed at a higher rate and that
these products are subsequently converted into a di-alkylated product. The oligomerisation of
isobutene (5 wt%) was also accelerated relative to the reaction performed at lower
temperatures. However, the major products were those of the alkylated anisole.
Brønsted acids were also evaluated under the same set of conditions as the Lewis acids. These
included H3PO4 and triflic acid (HOTf). The strength or the pKa values of these acids vary
significantly, Table 3.15, as has already been indicated.
Table 3.15: Comparison of the acid strengths of H3PO4 and HOTf
Acid Acid strength (pKa) 273 Hammett (H0)
HOTf -14.1 -15.0
H3PO4 (85%) 2.0 -4.3274
It is well known that the activity of a Brønsted acid is dependent on its dissociation constant Ka,
which is normally expressed as a negative logarithm (pKa) i.e.:
pKa = -log Ka
Thus, a high value of pKa represents a very small value of Ka, and hence a very weak acid.275
Furthermore, if the Hammett number of a particular acid is large and negative, it implies that the
acid is stronger. Therefore, HOTf is expected to exhibit higher activity between the two Brønsted
acids evaluated, and undeniably, the better results were obtained from the reaction catalysed by
triflic acid (Figure 3.5).
129
Figure 3.5: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by HOTf (0.2 mol%) at 100 ˚C, and stirred at 1000 rpm.
Triflic acid afforded quantitative conversion of anisole (>99%) to the desired products. The
reaction proceeded at an extremely high rate, and almost all of the anisole was converted into
2- and 4-tert-butyl anisole within 30 minutes. The mono-butylated products were essentially
completely converted into 2,4-di-tert-butylanisole. The rate of conversion of mono-butylated
products was high, such that the reaction was complete within 60 minutes. However, the
reaction was allowed to proceed until 120 minutes (with a post run of 60 minutes).
The second Brønsted acid evaluated was H3PO4. Initially, the reaction was performed using 0.2
mol% catalyst at 100 °C, and the rate was extremely low. Thereafter the catalyst concentration
was increased to 2.0 mol%. Interestingly, this acid showed some activity, although the rate was
low relative to that obtained with triflic acid, Figure 3.6. Despite H3PO4 exhibiting a slow
reaction, high conversion of anisole (90 mol%) was achieved by prolonging the reaction time.
130
Figure 3.6: The activity of 2.0 mol% H3PO4 during alkylation of anisole.
3.7.2 The evaluation of assisted acids as catalysts for the butylation of anisole
The previous studies showed that assisted acids (prepared by combining the lanthanide triflate
salts with mineral Brønsted acids) exhibit superior catalytic activity compared to individual Lewis
and Brønsted acids. Hence the ultimate objective was to eventually evaluate the catalytic
activity of assisted acids for the butylation of anisole. The first reaction was performed using the
La(OTf)3/H3PO4 assisted acid, Figure 3.7.
131
Figure 3.7: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by La(OTf)3/H3PO4 (0.8 mol%) at 100 ˚C, and stirred at 1000 rpm.
The La(OTf)3/H3PO4 acid exhibited excellent activity and quantitative conversion of anisole was
obtained within two hours. The catalyst was selective to three products, i.e. two mono-alkylated
products and a di-alkylated product, as was the case for the other catalysts. The two mono-
alkylated products were almost entirely converted into 2,4-di-tert-butylanisole by the end of the
reaction. Isobutylene oligomers (3.5 wt%) were also obtained when using this catalyst. The acid
combination has been proven once again to exhibit excellent activity, with total conversion of
intermediate products to 2,4-di-tert-butylanisole being noted. This is compared to inactive
La(OTf)3 and the low activity noted for H3PO4, when used individually as catalysts for this
process. The evaluation of other assisted acids was consequently performed, Figure 3.8.
132
Figure 3.8: Alkylation of anisole (560 mmol) with 1.5 bar isobutylene catalysed by Al(OTf)3/H3PO4 (0.8 mol%; 0.8 mol%) at 100 ˚C, and stirred at 1000 RPM.
Interestingly, Al(OTf)3 showed absolutely no activity as catalyst for the butylation of anisole on
its own, but when it is combined with H3PO4 it exhibited excellent activity, where almost all the
anisole was converted. Furthermore, both mono-butylated anisoles were almost converted to di-
tert-butylanisole, with 2-t-butylanisole consumed at a faster rate. It is, however, notable that the
rate of the reaction catalysed by La(OTf)3/H3PO4 is much higher than that of the reaction
catalysed by Al(OTf)3/H3PO4. Subsequently, another reaction catalysed by Gd(OTf)3/H3PO4 was
carried out, Figure 3.9.
133
Figure 3.9: Alkylation of anisole (560.01mmol) with 1.5 bar isobutylene catalysed by Gd(OTf)3/H3PO4 (0.8 wt%; 0.2 mol%) at 100 ˚C, and stirred at 1000 rpm.
This catalyst showed a much higher reaction rate than all other combined acid catalyst systems,
the starting material and intermediates were completely converted to the final product. The rate
of this experiment is comparable to that afforded by triflic acid.
3.8 Alkylation of diphenylether (DPE)
The alkylation of diphenyl ether (DPE) with olefins, alcohols and alkyl halides yields
commercially important products. There are numerous applications of alkylated DPE, including
its use as heat transfer fluids.276 Alkylated DPE can be used as a dielectric agent in
transformers as claimed on a patent of Westinghouse Electric Corporation.277 This patent
discloses the use of up to 99 wt% of mono-ethylated, mono-propylated, mono-butylated DPE
and up to 20 wt% dialkylated DPE as dielectric fluid in a capacitor.
Mobil Oil Corporation filed a patent278 on the use of alkylated DPE as lubricant fluid with
excellent low temperature viscometrics. The later patent pertains to the alkylation of DPE with
olefins such as 1-tetradecene, 1-dodecene and 1-octene in the presence of zeolite at 200 ˚C,
and the catalysts exhibited high selectivity to mono alkylated products. Coleman et al.279
134
disclosed a process where DPE was alkylated with alkyl halides, olefins and alcohols in the
presence of alkylation catalysts such as AlCl3, AlBr3, FeCl3, and heterogeneous catalysts. The
best results were obtained when using AlCl3. This patent claims that alkylation with alcohols is
favourable when using clay catalysts. The product mixture does not need to be separated, since
the mixture contains properties that are readily suited to be used as, for example, dielectric
agents in transformers, condensers and other electrical equipment or as plasticisers for
synthetic resins. The mixture has relatively low viscosity and freezing point compared to its
individual compounds; therefore mixtures are more valuable than individual products. The
mono-alkylated, di-alkylated and tri-alkylated products were reported in this invention.
In example 4 of this patent, alkylation of DPE with tertiary butyl chloride in the presence of AlCl3
using the reagents in a 1:1 mole ratio at 100 ˚C yielded three products: a liquid mono-tertiary-
butyl-DPE (26%) boiling at 150.5-152.5 ˚C (6 mmHg); a crystalline mono-tertiary-butyl-DPE
isomer (41%) boiling at 153.5-155.5 ˚C (6 mmHg), with a melting point of 54-54.5 ˚C and a liquid
di-tertiary-butyl-DPE (31%) boiling at 191.3 ˚C (6 mmHg). In example 7, diisobutylene was used
as an alkylating agent at 60 ˚C. The reaction produced four products: a crystalline mono-tertiary-
DPE, boiling point 154.5-159.3 ˚C (6 mmHg) and melting at 53.3-54 ˚C; mono-octyl-DPE boiling
at 184.5-185.5 ˚C (6 mmHg); a compound with empirical formula C24H34O, boiling at 218-223 ˚C
(6 mmHg) and a compound with empirical formula C38H42O, boiling at 229.5-239.5 ˚C (6 mmHg).
Phillips Petroleum Company filed a patent280 on the alkylation of DPE with isobutylene in the
presence of sulphuric acid as catalyst. Example 2 of this patent discloses alkylation of DPE with
isobutylene in the presence of AlCl3 at 60 ˚C and mole ratio of 4.2 of olefin to DPE. The product
distribution showed presence of 2% mono-alkylated, 41% di-alkylated and 20% tri-alkylated
products. The product mixture was a pale yellow oil with low viscosity. In another example,
where isobutylene was used (example 6) at 27 ˚C, with DPE to olefin mole ratio of 4.4, less than
1% mono-alkylated; about 19% di-alkylated and about 63% tri-alkylated products were obtained.
It has also been claimed that when the mole ratio of olefin to DPE is increased to 7.15, less than
1% mono-alkylated, 25%-di-alkylated and 57% tri-alkylated products were obtained.
The alkylation of DPE with α-dodecene to produce mono-alkylated DPE, which is a precursor for
synthesis of di-alkyl-DPE sulfonates (an important class of surfactant produced by Dow
Chemical Company under the trade name Dowfax®)281 catalysed by an ionic liquid (IL) has been
reported by Kou et al.282 The catalyst could not be recycled due to leaching of the active species
(Al2Cl7)-.
135
The alkylation of diphenyl ether with benzyl chloride was studied by Yadav et al.283 In this study,
sulfated zirconia was used as catalyst. The reaction was performed at 90 ˚C. This reaction
produced an isomeric mixture of ortho- and para-benzyl-diphenyl ether having a molecular
weight of 260 g/mol. The HCl generated in situ (by-product) does not take part as catalyst in the
reaction due to its low solubility in the reaction mixture. The other example, where the alkylation
of DPE with 1-decene in the presence of sulfated zirconia was carried out by Yadav et al. 284
(Scheme 3.11). Conversions of about 85% were obtained from the reaction, with high selectivity
to ortho- and para-mono-alkylated products.
When n= 0, m= 7 n= 1, m= 6 n= 2, m= 5 n= 3, m= 4
OH3C(CH2)7CH CH2
O
H3Cn(H2C) (CH2)mCH3
O
(CH2)nCH3
(CH2)mCH3
Sulfated zirconia
150 oC; 2hrs
3.33
3.34
3.35
Scheme 3.11: Alkylation of DPE with 1-decene
In the present study, t-butylation was pursued in order to evaluate the catalytic activity of
assisted acids for butylation of diphenyl ether with isobutylene. The alkylation of DPE was
performed using selected metal triflate salts, H3PO4 and assisted acid systems. The Lewis acids
evaluated included Zr(OTf)4, Al(OTf)3, La(OTf)3, and Gd(OTf)3, with only H3PO4 being evaluated
as a Brønsted acid. The alkylation of DPE with isobutene resulted in the formation of an oily
viscous mixture of products. The viscosity of the reaction mixture depends on the selectivity of
the catalyst used as well as on the extent of alkylation of the substrate. For example, if the
catalyst forms only mono-butylated compounds, the viscosity of the product mixture will be
lower than when the catalyst yields both mono- and di-butylated compounds. Furthermore, the
viscosity of the former product mixture will also be lower than when tri-butylated species are
formed. There were three major products identified from the study, i.e. two mono-butylated
diphenylether products and a di-alkylated-tert-butyl-phenoxy ether, a tri-alkylated phenoxy ether
136
and tetra-alkylated phenoxyether (which has to be confirmed with NMR spectroscopy). Up to
this stage we have not come across literature where the tetra-alkylated phenoxyether was
reported. The proposed structures of butylated DPE compounds are shown in Table 3.16.
137
Table 3.16: Properties of the products obtained during alkylation of diphenylether
O 12
3
45
6
7
8
910
11
1213
14
1516
3.36
O123
5
6
7
89
10
11
1213
14
1516
4
3.37
O 1 2
34
5
6
7
8 9 10
11
12
13
1415
16
17
18
19
20
3.38
4-tert-butyl-phenylpheyl ether 2-tert-butyl-phenylphenylether 2,4-di-tert-butyl-phenylphenyl ether
1H NMR (400 MHz, CDCl3): δ=1.32 (s,
9H, H-6 to H-8); δ=6.92-7.34 (m, 9H,
ph).
1H NMR (400 MHz, CDCl3): δ=1.42 (s, 9H,
H-4, H-5 and H-6); δ=6.81-7.41 (m, 9H,
ph).
1H NMR (400 MHz, CDCl3): δ=1.23 (s, 9H, H-
3, H-5, H-6); δ=1.35 (s, 9H, H-10, H-11, H-12);
δ=6.60-7.41 (m, 8H, ph)
13C NMR (400 MHz, CDCl3): δ= 31.8
(C-6 to C-8); δ=34.5 (C-5); δ= 118.5
(C-2); δ= 118.7 (C-12 and C-16);
δ=123.1 (C-14); δ=126.8 (C-9 and C-
3); δ=129.8 (C-13 and C-15); δ=146.4
(C-4); δ=155.1 (C-1); δ=157.8 (C-11).
13C NMR (400 MHz, CDCl3): δ=30.4 (C-4
to C-6); δ=34.9 (C-2); δ= 118.9 (C-16 and
C-12); δ=120.3 (C-10); δ=122.8 (C-14):
δ=123.3 (C-8); δ=127.3 (C-7); δ=129.7 (C-
13 and C-15); δ=141.2 (C-2); δ=156.1 (C-
1); δ=158.0 (C-11)
13C NMR (400 MHz, CDCl3): 13C NMR (400
MHz, CDCl3): δ=30.3 (C-3, C-5, C-6); δ=31.7
(C-10, C-11, C-12); δ=34.6 (C-5); δ=35.0 (C-
9); δ=118.6 (C-16 and C-20); δ=119.7 (C-14);
δ=122.4 (C-13); δ=123.8 (C-7); δ=124.1 (C-
18); δ=129.6 (C-17, C-19); δ=140.0 (C-2);
δ=145.8 (C-8); δ=153.4 (C-1); δ=158.1 (C-15)
m/z (GC-MS): 226 (M+, 28%); 211 (M-
CH3, 100%); 195 (M-C2H6, 2%); 183
(M-C3H9, 6%); 91 (M-PhC3H9, 9%); 77
(M- OPhC3H9, 9%).
m/z (GC-MS): 226 (M+,59%); 211 (M- CH3,
100%); 195 (M- C2H6, 14%); 181 (M- C3H9,
13%); 133(M-C7H11, 15%); 91 (M-C10H12,
26%); 77 (M-OC10H12, 13%); 57 (M-
OC12H13, 9%)
m/z GC-MS: m/z (GC-MS): 282 (M+, 27%);
267 (M-CH3, 100%); 254 (M- C2H6, 2%); 211
(M- (C4H9), 2%); 91(M-OC14H22, 5%); 77 (M-
OC14H22, 4%); 57 (M-OC16H23, 14%)
Bp (760 tor): 307+/-11°C, a : 302-304
°C b
Bp (760 torr): 296+/-19 °C, a : 250-253°C b
Bp (°C@760 torr): 334+/-21°C, a : 339-342°C b
Mp: 54-55 °Ca: 53-55 °Cb
a Literature value, b Experimental value
138
The mono-alkylated product, (4-tert-butyl-phenylphenylether, 3.36), is a colourless crystalline
product with a boiling point of 302-304 ˚C, and 2-tert-butyl-phenylphenylether (3.37) is a
colourless free flowing liquid at room temperature, with a boiling point of 276-279 ˚C at
atmospheric pressure, while the di-alkylated product2,4-di-tert-butyl-phenylphenul ether, 3.38] is
also a colourless liquid at room temperature boiling at 339-342 ˚C at atmospheric pressure. A
highly vicious material left in the re-boiler was not purified any further due to instrument
limitations.
The initial reaction was performed in the presence of 0.14 mol% Zr(OTf)4 at 70 ˚C. The reaction
was stirred at 1200 rpm and at isobutylene pressure of 1.1 bar. It was expected that the reaction
would proceed rapidly, as in the case of the cresols and anisole, but surprisingly, it was slow.
Hence the experiment was allowed to proceed for 24 hrs. Over this period of time only 25%
conversion of DPE was achieved and the products were 16.8% and 3.3% of 3.36 and 3.37,
respectively. Only 2.9% of 3.38 and 1.9% and heavy products were obtained. Having observed
such low rates, it was decided to vary some reaction parameters with the aim of increasing the
rate of the reaction, Table 3.17.
Table 3.17: The variation of reaction parameters during butylation of DPE (0.36mol) in the presence of Zr(OTf)4.
Temp. (˚C)
[Cat.] mol%
Time (hours)
DPE conversion
(%)
Products distribution (%) Oligomers (wt%)
3.36 3.37 3.38 unknown
50 0.14 23 12.3 9.6 1.8 0.3 0.6 8.3
70 0.14 24 24.9 16.8 3.3 2.9 1.9 6.2
100 0.28 3.5 35.1 23.6 5.4 2.3 4.1 10.6
100 0.57 2 40.0 27 6.3 3.9 2.5 8.8
139
The results showed that an increase of the reaction temperature (50 ˚C to 100 ˚C) resulted in a
proportional increase of the reaction rate, as expected. Furthermore, increasing the catalyst
concentration at constant temperature (100 ˚C) yields an increase of the reaction rate. An
exotherm of approximately 6 ˚C was observed for the reaction performed at 100 ˚C. The overall
rate of DPE butylation was relatively slow, but the formation of mono-alkylated products,
especially (3.36) was fast in all instances. Hence, the evaluation of other metal triflates salts and
H3PO4 was performed at 100 ˚C, using 0.57 mol% catalysts concentration, Table 3.18.
Table 3.18: The results obtained during evaluation of other catalysts for butylation of DPE (0.57 mol%).
Catalyst
Time
(hours)
DPE conversion
(%)
Products distribution
(%)
(3.36) (3.37)
La(OTf)3 17 2.9 2.5 0.4
Al(OTf)3 7 0.6 0.5 0.1
Gd(OTf)3 6 1.4 1.2 0.2
H3PO4 7 0.7 0.6 0.1
The catalytic activities of the individual Lewis and Brønsted acid catalysts were extremely low
(Table 3.18) under the same conditions. Only two mono-alkylated products (3.36 and 3.37) were
obtained when using individual acids. Interestingly, Al(OTf)3 exhibited low activity for this
reaction, as was previously noted. However, the acid combinations of the metal triflates and
H3PO4 at a catalyst concentration of 0.57 mol% (Table 3.19) showed an altogether different
picture. A significant enhancement of reaction rate was observed when using the assisted acid
systems. The results obtained with these acids are comparable to those afforded when using
Zr(OTf)4. This is another example among several others in the present study showing activation
of one acid by the other. It is also noticeable that the amount of oligomers was lower compared
to the reaction catalysed by Zr(OTf)4.
140
Table 3.19: Results obtained during the evaluation of assisted acids for the butylation of DPE.
Catalyst Time
(hours)
DPE conversion (%)
Products distribution
(%)
Oligomers (wt%)
3.36 3.37 3.38 unknown
La(OTf)3/H3PO4 7 47.9 34.4 5.8 1.9 2.5 7.1
Gd(OTf)3/H3PO4 2 24.4 20.6 2.3 1.1 0.6 3.6
Al(OTf)3/H3PO4 5 34.3 26.1 3.3 0.8 3.6 6.5
3.9 Conclusions
Friedel-Crafts alkylation of m/p-cresol isomers
The study has shown that while Zr(OTf)4 is completely soluble in the reaction mixture of cresol
and isobutylene, its activity is comparable to that of less soluble Al(OTf)3 based on conversion of
cresols and selectivities to the di-alkylated products. Sc(OTf)3 gave high conversion of cresols to
mono-butylated products, some of which were further converted into di-butylated cresols. It was
noticeable that Sc(OTf)3 gave high selectivity to DBMC.
The metal triflate salts of the lanthanide series were proven to be inactive as catalysts for the
reaction under the set of conditions employed. The isobutylene oligomers obtained from the
reactions catalysed by aluminium and zirconium triflate salts are comparable. On the contrary,
Sc(OTf)3 afforded a relatively large amount of oligomers. The study showed aluminium triflate
could be recycled at least five times with no significant loss of catalytic activity, capitalising on
the low solubility of Al(OTf)3 in the reaction medium. Among the Brønsted acids evaluated,
H2SO4 gave some activity (although lower than that of Al- and Zr-triflate salts), while H3PO4 was
inactive.
The rate of the reaction was accelerated as the catalyst concentration was increased from 0.05
to 0.35 mol%, but these rate enhancements were mild. There was little or no further increase of
the reaction rate upon increasing the catalyst concentration to 0.8 mol%. At high catalyst
141
loadings (0.35 and 0.8 mol%), the selectivity to di-alkylated cresols is high due to high
conversion of the cresols and intermediate products (mono-alkylated cresols) to these products.
A significant enhancement of the reaction rate was achieved by the assisted acid systems
compared to individual acids, although the activity of assisted acids is relatively lower than that
of the triflate salts of aluminium and zirconium. The acid combination of Al(OTf)3 and H3PO4
gave similar results to those afforded by Al(OTf)3 on its own, hence there was assisted acidity
occurring. The combination of SPA and La(OTf)3 yielded a superior assisted solid acid catalyst.
This catalyst could be recycled four times, without being completely deactivated.
Friedel-Crafts alkylation of anisole and diphenyl ether
Among the Lewis acids evaluated, only Zr(OTf)4 gave high activity, while the lanthanide triflate
salts were inactive, as was Al(OTf)3. Three products were obtained, i.e. 2-tert-butyl anisole, 4-
tert-butylanisole and 2,4-di-tert-butyl anisole. The Brønsted acids (H3PO4 and HOTf) evaluated
in the study exhibited diverse activity for butylation of anisole, with triflic acid giving a higher
reaction rate than H3PO4. The assisted acids prepared by combining the inactive Lewis acids
with a mildly active Brønsted acid (H3PO4) showed a significant enhancement of the reaction
rate.
The metal triflate salts [Al(OTf)3, La(OTf)3 and Gd(OTf)3] that were evaluated for the butylation
of DPE with isobutylene were inactive, with the exception of Zr(OTf)4. The mineral Brønsted acid
(H3PO4) was also shown to be inactive for this reaction. However, the combination of the metal
triflate salts with H3PO4 gave good activity, indicating that the acid combination is catalytically
active. The butylation reaction of DPE with isobutylene was slow compared to that of cresol and
anisole. During alkylation reaction of DPE, three products were successfully isolated (2-tert-
butyl DPE, 4-tert-butyl DPE and 2,4-di-tert-butyl DPE).
The study has thus shown that some metal triflate Lewis acids can catalyse the Friedel-Crafts
alkylation reactions effectively as individual catalysts, especially Zr(OTf)4 and Al(OTf)3. The
study has also revealed that some individual Brønsted acids and metal triflate Lewis acids may
be inactive as catalysts for the reaction, but when these acids are used concurrently, superior
activity prevailed indicating a synergistic attribute of the acid combinations.
142
CHAPTER 4 Synthesis of Chromans
This chapter will discuss the results obtained during the evaluation of assisted acid catalysts for
the synthesis of chroman compounds via the reaction of dienes with phenolic substrates.
4.1 Introduction
Benzopyran is a bicyclic organic compound that results from the fusion of a benzene ring to a
heterocyclic pyran ring. Benzopyran systems exist in many instances as natural products, some
of which exhibit biological activity.285 For example, a class of such compounds called
benzotripyrans has recently been found to inhibit HIV.286 Dihydrobenzopyran (chroman) is also
found in vitamin E, its derivatives,287 and flavanoids.288 The most common and straightforward
way of preparing these compounds is via a cyclocoupling reaction of phenol derivatives with
1,3-dienes in the presence of Lewis or Brønsted acids (Scheme 4.1).
OH
R
acid catalyst
O
R4.1
4.2
4.3
R = CH3, Ph, tert-butyl
Scheme 4.1: Addition of 2-methyl-1,3-diene to a phenol derivative.
The catalysts used in such reactions may be homogeneous or heterogeneous acids. 289, 290 High
temperatures are commonly needed, and low to moderate yields of products are reported.
Considerable research efforts have been focussed on obtaining catalyst systems that are
efficient (high activity and selectivity) under mild reaction conditions.291 Among the acids
reported to promote these reactions is H3PO4.292 Youn et al.293 have reported the use of AgOTf
(5 mol%) as catalyst for sequential addition and cyclisation of phenols with dienes and proposed
mechanism shown in Scheme 4.2.
143
Ag+
OH
R
Ag
OH
R
H+
H+
OH
Ag
R
Ag+
O
Ag
H
R
O
AgR
[Ag+]
Scheme 4.2: Proposed mechanism for AgOTf catalysed synthesis of chromans.
The superior activity of assisted acids prompted us to further evaluate these acids for the
synthesis of chomans via the reaction of dienes with phenolic compounds. The synthesis of
chromans involves the alkylation reaction of a phenolic compound followed by the etherification
reaction to form a cyclic benzofuran or benzopyran. It is mentioned in the literature that such
reactions normally require high temperatures and large amounts of catalysts to occur. Having
observed the high activity of the assisted acids for hydroalkoxylation of olefins and Friedel-
Crafts alkylation reactions, it was decided to apply these catalysts systems to the synthesis of
the bicyclic materials.
144
4.2 Reaction of phenol with 2-methyl-1,3-butadiene (isoprene)
The very first reaction involved alkylation of phenolic compounds with isoprene in the presence
of the La(OTf)3/H3PO4 assisted acid. The reaction was performed in a 300 mL autoclave reactor
fitted with a gas entrainment stirrer. In the first reaction, p-cresol, isoprene and catalyst (0.1
mol%) were weighed directly into the reactor vessel according to Scheme 4.3. Prior to heating
the reactor to the operating temperature, a significant exotherm was evident, i.e. the reaction
temperature increased from room temperature up to 220 °C. This strong exotherm was clearly
demonstrative of a vigorous reaction which self-initiated even at ambient temperature, and
indicated that perhaps the reactants should be added sequentially and possibly slowly, the one
to the other.
[La(OTf)3/H3PO4]
OH O
4.4 4.5
4.2
Scheme 4.3: Preparation of 2,2,6-trimethylchroman catalysed by La(OTf)3/H3PO4
Having observed such a large exotherm, the subsequent reactions were performed in a glass
reactor setup (round bottom flask fitted with a reflux condenser and equipped with magnetic
stirrer) for the ease of controlling the reaction temperature. In this experiment, the catalyst and
the p-cresol were weighed into a round bottom flask. The olefin (isoprene) was added drop-
wise, while stirring the reaction mixture, and using an ice bath to control the reaction
temperature. The reaction was allowed to proceed for the next 6 hours, and thereafter a sample
was taken and treated with sodium bicarbonate before it was injected into a gas chromatograph
coupled to an FID detector.
The GC results showed the presence of a product peak (79%), which was substantiated with
GC-MS analysis. The product was purified using a Kugelrohr distillation setup, and the sample
was analysed using NMR spectroscopy, and was found to correspond to the desired 2,2,6-
trimethylchoman. The 1HNMR spectrum showed a singlet peak at δ = 1.21 ppm, intergrating for
6 protons of the two methyls on the pyran ring. The triplet peak at δ =1.64 -1.67 ppm,
intergrating for two protons correspond to -CH2- of the pyran ring furtherst from the benzene
145
ring, The singlet at δ = 2.13 ppm, intergrating for 3 protons is due to the methyl on the para-
position of the benzene ring. The second triplet peak at δ = 2.50-2.65 ppm integrating for two
protons is corresponds to the -CH2- of the pyran ring closest to the benzene ring, while the
multiplet peak at δ =6.57-6.78 ppm is ascribed to the protons of the benzene ring. The 13CNMR
spectrum showed 11 peaks instead of 12 and this is because, the two methyl peaks bonded to a
quaternary carbon at δ = 73.88 ppm are chemically equivalent with δ = 26.86 ppm. The 13C
signal of the methyl on the benzene ring appeared at δ =20.48 ppm, while those of the aromatic
ring appeared at δ =120.57-151.77 ppm.
Having obtained good catalytic activity from La(OTf)3/H3PO4 during the reaction of p-cresol with
isoprene, it was decided to evaluate various phenolic compounds in reactions with isoprene
(Table 4.1). In the current study, the reaction of isoprene with hydroquinone yielded two
isomeric products (4.8 and 4.9), with an overall yield of 84%.. The isoprene molecules were
added on both hydroxyl groups of hydroquinone (Scheme 4.4), thereafter cyclising to form
tricyclic products. In the literature, it has been reported that only 68% of 4.7 forms290 upon using
Amberlyst 15 as catalyst. The initial interpretation of these results is that the Amberlyst 15
system provides a catalyst that is less active and more selective for the monosubstituted
product, while the present catalyst is more active leading to the two disubstituted products. In
another report, 294 the condensation of hydroquinone with isoprene in the presence of ortho-
phosphoric acid yielded three products (4.7, 4.8 and 4.9). Consequently, it can be concluded
that the distribution of the products obtained from this reaction is dependent to some extent on
the activity of the catalyst employed.
In the current study, purification of the isomers was performed using column chromatography
techniques with hexane/ethyl acetate (solvent system 100:1) and using alumina as the
stationary phase. The GC-MS analysis of these compounds gave a molecular ion or parent ion
with overall m/z = 246 (which corresponds to the molar mass of each of the two isomers). The
NMR characterisation technique was useful during characterisation of 4.8 and 4.9. The isomer
4.8 showed, beside other signals,a singlet peak for the aromatic protons at δ =6.58 ppm and
integrating for two protons (H-14 and H-15), while the 4.9 isomer exhibited a singlet peak at δ =
6.49 ppm and also integrating for two protons (H-7 and H-15). However, a clear distinction
between the two isomers could not be made based on the 1HNMR spectra as noted by the
splitting pattern of the aromatic ring protons H-7, H-14 and H-15. The 13CNMR spectra of the
two isomers are similar, hence there was no clear differences in the chemical shifts of the two
146
isomers. Nevertheless, the number of peaks on the spectrum corresponds to the quantity of
carbon atoms in the compounds.
O
O
O
O
OH
OH
O
OH
H+
4.6 4.74.8 4.9
78
15
14
15
4.2
Scheme 4.4: Reaction of isoprene with hydroquinone in the presence of La(OTf)3/H3PO4
During the reaction of phenol with isoprene, the major product formed is a chroman (4.10). Four
minor product peaks were also present on the GC trace, although the minor peaks were not fully
characterised in the current study. In a publication by Dewhirst and Rust,295 it is reported that
the reaction of phenol with isoprene in the presence of aluminium phenoxide yields the products
(4.10-4.14) presented in Scheme 4.5. Furthermore, Dewhirst and Rust also reported that
bisphenol is formed at higher temperatures (>100 °C) in the presence of aluminium phenoxide.
These by-products correspond to the C-alkylation reactions of phenol with isoprene forming
ortho-, para-, and ortho-/para- alkylated phenol as well as the p-alkylated chroman products.
The average combined yield reported by Dewhirst and Rust was 70%, with the product
districution ratio of 4.10:4.12:4.13:4.14 = 0.38:0.25:0.24:0.13
147
4.10 4.12
4.13 4.14
O
O
OH
OH
Scheme 4.5: Products obtained from the reaction of phenol and isoprene.
The Brønsted acid (H3PO4) catalysed reaction of isoprene with phenol was also reported by
Bader and Bean.296 In their study, six products were obtained including the alcohols which were
formed via partial hydration of ortho- and para-alkylated phenols. In the current study, it is
proposed that the carbocation that is formed via protonation of the diene by the acid undergoes
nucleophillic attack by the OH group of a phenol, followed by [3,3] sigmatropic rearrangement to
form ortho-alkylated phenol intermediate, which is consequently followed by cyclisation via the
tertiary carbocation to form the ether product as shown by the porposed mechanism in Scheme
4.6.
148
OH
R
H+ O
OH
H+
OH
-H+
R
RR
O
R
-H+
Scheme 4.6: Proposed mechanism for preparation of chroman using Brønsted acid.
The various chromans obtained in the present study during the reaction of different phenols with
isoprene are presented in Table 4.1. During the reactions of 2-tert-butyl-4-methylphenol and 2-
tert-butylphenol and naphthol with isoprene, high yields of the corresponding chroman products
(4.17, 4.19 and 4.21) were isolated.
149
Table 4.1: Reaction of various phenols (2.1 mmol) with isoprene (7.0 mmol) in the presence of assisted acid La(OTf)3/H3PO4.
Entry ROH Product Yield (%)
1
OH
4.15
O
4.10
53
2
OH
4.4
O
4.5
74
3
OH
4.16
O
4.17
81
4
OH
4.18
O
4.19
83
5
OH
4.20
O
4.21
92
150
6
OH
OH4.6
O
O
O
O
4.8 4.9
84
The reaction of phenol with isoprene gave a relatively low yield (53%) of the corresponding
chroman, due to the formation of several by-products, while p-cresols yielded 74% of the
chroman derivative (4.5). All the other substrates gave large quantities of the chroman products
(>80%), the highest yield being 92% afforded from the reaction of 2-naphthol with isoprene.
4.3 Reaction of phenols with 2,3-dimethyl-1,3-butadiene
The reaction of substituted phenols with 2,3-dimethyl-1,3-butadiene was also performed using
La(OTf)3/H3PO4 as catalyst. In these reactions a 1:1 mole ratio of phenolic substrate to the olefin
was used, and the olefin was added drop-wise, into the reaction mixture via an addition funnel.
Here, too, all reactions were also exothermic. The separation of isomers was conducted using
column chromatography. The solvent system used was hexane/ethyl acetate (100:1 v/v)
mixture. The reaction of each phenol with the diene yielded two isomers (Table 4.2), the first
isomer consisting of 5-membered chiral cyclic ether, while the second isomer consists of six-
membered cyclic ether.
The results obtained from the reaction of phenolic substrates with 2,3-dimethyl-1,3-butadiene
instead of isoprene are completely distinct. This is due to the fact that isoprene can form a tert-
carbocation on only one carbon atom, whereas 2,3-dimethyl-1,3-butadiene can form tert-
carbocations on two carbon centres, and hence the reactivity of 2,3-dimethyl-1,3-butadiene is
relatively high. For all the reactions, the GC-MS analysis confirmed the presence of two isomer
peaks. For example, the compounds 4.21 and 4.22 gave an m/z=190, corresponding to the
molecular ion. The 1HNMR spectrum of 4.21 showed only one doublet peak at δ = 1.00 ppm,
integrating for three protons which corresponds to a single methyl group attached to the pyran
ring, while two singlet peaks at δ = 1.14 and 1.36 ppm corresponding to the two methyl groups
of the pyran ring were also present. Furthermore, a sextet peak at δ = 1.85-1.94 ppm for a
151
single proton next to the -CH2- on the pyran ring. On the other hand, 4.22 showed two doublet
peaks at δ = 0.93 ppm and at δ = 0.99 ppm, corresponding to the methyl groups of the isopropyl
substituent of the furan ring. A singlet reasonating at δ = 1.33 ppm, which correspond to the
methyl functional group of the furan ring, was also noted and a septet at δ = 1.96-2.02 ppm was
indicative of a proton on the isopropyl substituent. These unique characteristics of the isomers
in entry1 are common for the other isomers in entries 2 and 3, except that the chemical shifts
are different.
A possible mechanism for the formation of 4.21 and 4.24 is shown in Scheme 4.7. The initial
step in this mechanism involves the protonation of the olefin, yielding a tertiary carbocation,
followed by the nucleophillic addition of the carbocation to the ortho-position of p-cresol, forming
an olefinic substrate (which is still likely to react further), Thus, the tert-olefinic cresol substrate
get protonated and form a carbocationic fuctional group. Both positions of the olefinic fuctional
group forms tert-carbocations after being protonated. As a result, the reaction of the hydroxyl
functional groups of cresol with carbocations, lead to the formation of two products, i.e. a five-
membered ring (4.22) and a six-membered ring (4.21) chroman isomers. The isomer consisting
with a five membered ring is chiral. The chromans 4.23 and 4.24, 4.25 and 4.26 in Table 4.2 are
formed via the same mechanistic pathway as 4.21 and 4.24.
152
H+
OH
OH
H+
OH
O O
(4.21) (4.22)
OH
-H+-H+
Scheme 4.7: Brønsted acid catalysed preparation of chroman.
The reaction of phenolic substrates with 2,3-dimethyl-1,3-butadiene also gave high quantities of
the corresponding chromans in all cases. It was noticeable that 2-tert-butyl phenol gave a
relatively low yield (73%) as compared to other substrates, but this remains a respectable yield.
The latter could be attributed to the fact that this compound is activated for further alkylation on
the para-position, which may lead to the formation of p-alkylated 2-tert-butylphenol by-product
or possibly by dealkylation of the t-butyl group leading to by-products..
153
Table 4.2: Reaction of substituted phenols with 2,3-dimethyl-1,3-butadiene.
Entry ROH Products Overall yield (%)
1
OH
4.4
O
4.21
O
4.22
87 (4:1)
2
OH
4.16
O
4.23
O
4.24
93 (1:1.7)
3
OH
4.18
O
4.25
O
4.26
73 (1:1.5)
The six membered ring isomer (4.21) in entry 1 is formed favourably compared to that with furan
ring (4.22), while in entry 2 and 3, the isomers with furan rings are formed in a slight excess.
This could be due to the fact that tert-butyl groups on the benzene ring increases the steric
hindrance, thereby favouring more distally positioned bulk. These results hint at the possibility of
rapid migration of the carbocation between the two tertiary centres caused by facile1,2-H shift.
This is possible and would probably arise because of the anticipated energy
compatibility/equivalence between the two carbocations. Here, product development control
154
may be determinative in the outcome of the reaction, arising from a late transition state
according to Hammond postulate.297
4.4 Conclusions
The study has shown that the assisted acids system such as La(OTf)3/H3PO4 can catalyse the
condensation of phenols and butadienes efficiently in one-pot transformations. Furthermore, the
catalyst was able to promote the reactions at room temperature.
The reaction of phenol with isoprene gave relatively low yields, due to the formation of by-
products, while the condensation of hydroquinone with isoprene yielded two product isomers.
The tert-butylated phenols reacted effectively with isoprene, giving high yields of the chroman
products.
The reaction of 1,3-dimethyl-2,3-butadiene with various phenolic substrates gave two chroman
isomers (five-membered dihydrobenzofurans and six-membered chromans), the products being
chiral but racemic. In all instances high yields were obtained. It may be an interesting future
project to determine if the latter set of products may be prepared in an enantioselective fashion
in the presence of chiral Lewis/Brønsted acid pairs. It will further be a useful part of the study to
see if selectivity for the chroman or dihydrofuran may be enhanced.
155
CHAPTER 5 Experimental Protocol
This chapter describes the experimental protocols, analytical techniques and the reactor set-ups
employed when performing varous experiments
5.1 General protocol for preparation of ethers
The etherification reactions were carried out in a 300 mL autoclave stainless steel reactor
equipped with gas entrainment stirrer. The reagents (methanol and an olefin) were weighed
directly into the reactor. The reactor was then assembled and heated up to the operating
temperature, while stirring at 1000 rpm. Upon reaching the operating temperature, the catalyst
dissolved in methanol was introduced into the reactor using a sample bomb or pressurised
stainless steel vessel (6 bar N2). The reaction was monitored over time from the addition of the
catalyst, with samples taken and analysed in a gas chromatograph (GC). The reactor setup is
shown in Figure 5.1.
Catalyst preparation and addition: The required amount of catalyst was weighed in a glass
beaker, and dissolved in 5 g of methanol. The catalyst solution was then transferred into a 50 ml
stainless steel sample bomb using a syringe. Finally, the vessel was pressurised with N2 (6 bar).
While the reactor was being heated to the operating temperature, one end of the catalyst vessel
was connected onto the reactor inlet, upon reaching the operating temperature, the catalyst was
introduced into the reactor by first opening the outlet valve of the samples bomb followed by
opening the inlet valve of the reactor to allow all the catalyst contents to empty into the reactor.
Example: Methanol (56.03 g; 1900 mmol), and 2M2B (11.02 g; 150 mmol) were weighed into
the reactor. The reactor was assembled and heated up to the operating temperature (100 °C).
At 100 °C, the addition of Al(OTf)3 (0.08 g; 0.17 mmol) dissolved in methanol (5 g; 156 mmol)
was performed.
156
Figure 5.1: Reactor set-up used for etherification of alcohols and olefins
5.1.1 Reagents
The reagents (Table 5.1) used during the etherification reactions were obtained from different
sources. The isoprene used in these reactions was 95% purity, and was further purified by
flashing it through a column packed with activated alumina. After this step, the purity was found
to be 99% (as analysed in GC). The impurities were identified by GC-MS to as C10 cyclic
compounds. All the other reagents were used as obtained from the supplier. The
methylenecyclopentene used was obtained from a mixture of primary and secondary olefins. All
the metal triflate salts were obtained from Sigma-Aldrich except zirconium and aluminium
triflates, which were obtained from Sasol (Germany). The Brønsted acids were also obtained
from Aldrich, with high purity i.e. >98%.
NV: Non return valve
PI: Pressure indicator
PT: Temperature indicator
SIC: Stirrer control
S: Sampling line
M: stirrer mottor
~: Bursting disc
157
Table 5.1: Reagents used during etherification reaction of olefins and alcohols
Reagent Supplier Purity (%)
Methanol Aldrich 99
2M2B Saarchem 99
Isoprene Aldrich 99
Styrene Saarchem 99
1-hexene Sasol 99
methylenecyclopentene Sasol 22
Tert-amylalcohol Saarchem 99
Ethanol Saarchem 99
n-Butanol Aldrich 99
Lanthanide triflates Aldrich 99+
Zr(OTf)4 and Al(OTf)3 Sasol 99+
5.1.2 Purification of ethers
The purification of ether products was performed in an Aldershaw distillation set-up (Figure 5.2).
The reaction mixture was transferred from the stainless steel reactor into a 500 mL round
bottom flask and the glass beads were added to avoid spluttering and create smooth boiling of
the reaction mixture. A 15-plate Aldershaw column was fitted onto the round bottom flask. A
condenser was also fitted on top of the column and the distillation set up was assembled to
completion. The reflux timer was used to control the rate of sample reflux and sample
withdrawal. A heating mantle was used to supply heat to the reaction mixture and the
thermocouples were used to monitor the temperature changes and tap-water was used as a
coolant which was circulated in the condenser.
158
Figure 5.2: Experimental set-up for the purification of ethers.
159
5.1.3 Gas chromatography analysis
The samples were analysed in using a 5890 Agilent gas chromatography connected to a PC
equipped with Class-VP software for recording the integration of chromatograms. The free fatty
acid (FFAP) column with length of 50 m, internal diameter of 0.2 mm was utilised. The
temperature limits of this column are between 60 and 250 °C. The GC programme was set to
run for 15 minutes, and the flame ionisation detector was used for detection of the reaction
components. The GC programme is shown in (Table 5.2).
Table 5.2: GC operating conditions during analysis of the etherification reaction mixture.
Parameter Condition
Carrier gas Hydrogen
Initial Temperature 60 °C
Initial time 5 min.
Temperature ramping rate 6 °C/min.
Final temperature 240 °C
Final time 5 min.
Injector temperature 250 °C
Detector temperature 250 °C
5.1.4 NMR analysis
The NMR analysis was used to confirm the nature of the ethers or products obtained from the
reactions. The analysis was carried out using a Varian 400 MHz NMR, the spectra were
recorded in deuterated chloroform (CDCl3) at room temperature with TMS as an internal
standard. The chemical shifts are reported in parts per million (ppm) and the coupling constants
(J) in Hertz. Tert-amyl alcohol was characterised using an authentic sample obtained from
Saarchem.
160
Characterisation of tert-amyl-ether
O21
4
5
3
1H NMR (400 MHz, CDCl3): σ = 0.79-0.83 (t, 3H, J=7.5 Hz, H-3); 1.07 (s, 6H, H-4); 1.41-1.47 (q,
2H, J=7.3, H-2); 3.11(s, 3H, J=0, H-5)
13C NMR (400 MHz, CDCl3): σ = 8.06 (C-3); 24.5 (C-4); 32.1 (C-2); 48.9 (C-5); 74.5 (C-1).
Characterisation of 1,1-dimethyl-2-propenyl methyl ether
O2
1
3
4
5
1H NMR (400 MHz, CDCl3): σ = 1.26 (s, 6H, H-4); 3.20 (s, 3H, H-5); 5.10-5.16 (m, 2H,H-1);
5.76-5.84 (m, 1H, H-2)
13C NMR (400 MHz, CDCl3): σ = 24.5 (C-4); 49.5 (C-5); 74.28 (C-3); 113.0 (C-1); 142.5 (C-2)
m/z (GC-MS): (M+,2%); (M-CH3, 100%); 73 (M-C2H6, 30%); 55 (M-OC2H6), 51%); 41 (M-OC3H9,
37%); 27 (M-OC4H9), 9%).
Characterisation of 2-methyl-3-butenyl methyl ether
O12
345
6
1H NMR (400 MHz, CDCl3): σ=1.59 (s, 3H, H-5); 1.66 (s, 3H, H-6); 3.21 (s, 3H, H-1); 3.80-3.81
(d, 2H, J=7.1, H-2); 5.23-5.72 (t, 1H, J=6.8, H-3)
13C NMR (400 MHz, CDCl3): σ= 17.6 (C-6); 25.66 (C-5); 57.4 (C-1); 68.6 (C-2); 121.5 (C-3);
136.6 (C-4)
161
m/z (GC-MS): 100 (M+,14%); 85 (M-CH3, 100%); 69 (M-OCH3, 14%); 55 (M-OC2H6), 29%); 41
(M-OC3H9, 32%); 29 (M-OC4H9, 9%).
Characterisation of 1,3-dimethoxy-3-methylbutane
O O1 2
3
4
5
67
1H NMR (400 MHz, CDCl3): σ= 1.17 (s, 6H, H-3 and H-4); 1.77-1.80 (t, 2H, J=7.3, H-5); 3.19 (s,
3H, H-1); 3.32 (s, 3H, H-7); 3.44-3.47 (t, 2H, J=7.3, H-6)
13C NMR (400 MHz, CDCl3): σ= 25.3 (C-3 and C-4); 39.4 (C-5); 49.4 (C-1); 58.5 (C-7); 67.0 (C-
5); 74.1 (C-2)
Characterisation of 1-methoxy-1-methylbenzene
8
9
O 12
3
45
67
1H NMR (400 MHz, CDCl3): σ=1.59-1.57 (d, 3H, J=6.6 Hz, H-2); 3.32 (s, 3H, H-7); 4.34-4.39 (q,
1H, J=6.35, H-1); 7.30-7.44 (m, 5H, H-5 to H-8)
13C NMR (400 MHz, CDCl3): σ= 23.9 (C-2); 56.7 C-3); 80.0 (C-1); 126.3 (C-6 and C-8); 127.6
(C-7); 128.6 (C-5 and C-9); 143.7 (C-4)
m/z (GC-MS): 136 (M+, 3%); 121 (M-CH3, 100%); 105 (M-OCH3, 23%); 91 (M-OC2H6, 13%); 77
(M-OC3H7, 24%); 28 (M-OC5H10), 26%).
162
Characterisation of 1-methoxy-1-methylcyclopentane
O1 23
6
7
5
4
1H NMR (400 MHz, CDCl3): σ= 1.18 (s, 3H, H-3); 1.32-1.38 (m, 2H, H-4); 1.46-1.56 (m, 2H, H-
7); 1.60-1.68 (m, 2H, H-5); 1.71-1.79 (m, 2H, H-6); 3.11 (s, 3H, H-1)
13C NMR (400 MHz, CDCl3): σ= 22.7 (C-3); 23.9 (C-5 and C-6); 37.8 (C-4 and C-7); 50.0 (C-1);
84.7 (C-2)
m/z (GC-MS): 114 (M+, 13%); 99 (M-CH3), 19%); 85 (M-OCH3, 100%); 72 (M-OC2H6, 47%); 55
(M-OC3H6, 26%); 43 (M-OC4H8), 15%).
163
5.2 General protocol for alkylation of phenolic compounds
The butylation reactions were performed in a 300 mL autoclave reactor equipped with a heating
mantle, gas entrainment stirrer, bursting disc, dip-tube and several valves (Figure 5.3).
Figure 5.3: The experimental set-up for the butylation of phenolic compounds
The isobutylene from the cylinder was allowed to pass through a regulator (locked at 2 bar), via
a heat exchanger (70 °C) to ensure that isobutylene passes through the mass flow meter
(coriolis) was in the gas phase. The isobutylene was heated again to 70 °C (to avoid cooling the
reaction mixture when the olefin wa introduced) before it entered the reactor via a dip-tube (also
used for taking samples). A non return valve located after HV2 was installed to avoid any back
pressure. The cooling coil to which the tap water was circulated for maintaining the reaction
temperature was also installed. This was because butylation reactions of some phenolic
compounds such as cresols are exothermic. The reactor was equipped with bursting disc and
depressurising valves to vent any unnecessary pressure build up.
164
Butylation reaction example: A mixture of meta- and para-cresol (60.0g; 554.9 mmol) together
with a catalyst Zr(OTf)4 (0.61g; 0.89 mmol) were weighed directly onto the reactor. The reactor
was assembled and heated up to the operating temperature (70 °C) while stirring at 1200 rpm.
When the temperature of 70 °C is attained, the isobutylene is allowed to flow into the reactor
and the reaction was allowed to proceed over a period of 60 minutes and taking samples over
fixed time intervals. The isobutylene cylinder was then closed, but, the reaction was allowed to
proceed for another 60 minutes (post run) with residual isobutylene already in the reactor. After
120 minutes of the total reaction time, the reactor was cooled down, followed by venting out any
residual isobutylene that may be present and finally pouring out the reaction mixture and
cleaning the reactor.
Reagents
The reagents used during alkylation reactions were obtained from various suppliers, Table
5.3.The Lewis acids and Brønsted acids used as catalysts for these reactions were obtained
from the suppliers specified in Table 5.1
Table 5.2.
Table 5.3: Reagents used during alkylation or butylation of phenolic compounds
Reagent Supplier Purity (%)
m/p-Cresol Sasol ≥99
Anisole Sigma-Aldrich 99.5
Diphenylether Sigma-Aldrich 99.8
isobutylene Air Liquide 99.9
Purification and analysis of butylated products
The purification of the products obtained during alkylation of anisole and DPE was performed in
the same set-up used to purify ether products in Figure 5.2.
165
Analytical techniques for characterisation of the reaction products.
The authentic samples obtained from Sigma Aldrich were used as standards during
characterisation of the products obtained from the reaction of cresols with isobutylene. The
products obtained from the reactions where anisole and DPE were used as substrates and were
characterised using GC, GC-MS and NMR techniques after purification.
GC analysis: The analysis of the reaction mixtures was performed in a 6890 Shimadzu gas
chromatography. A DB-1 capillary column with length of 20.0 m, internal diameter of 100 μm
and film thickness of 0.10μm was used at constant pressure. The program was set to run for 20
minutes. The flame ionisation detector (FID) was used for detection of reaction products. The
GC analysis conditions are shown in Table 5.4.
Table 5.4: Analysis conditions of the butylated compounds
Parameter Condition
Carrier gas Hydrogen
Initial Temperature 100 °C
Initial time 0 min.
Temperature ramping rate 10 °C/min.
Final temperature 290 °C
Final time 0 min.
Injector temperature 250 °C
Detector temperature 300 °C
166
NMR and GC-MS analysis
The reaction of anisole with isobutylene afforded two mono-butylated products (2-tert-
butylanisole and 4-tert-butylanisol) and one di-butylated anisole (2,6-di-tert-butyl anisole)
Characterisation of 2-tert-butylanisole
O1
23
4
56
7
89
10
11
1H NMR (400 MHz, CDCl3): δ=1.38 (s, 9H, H-5,H-6 and H-7); δ=3.80 (s,3H, H-1); δ=6.82-6.94
(m, 2H, J=7.6 H-9 and H-10); δ=7.13-7.19 (d,1H, J=9.8, H-8); δ=7.23-7.26 (d, 1H; J=9.5, H-11)
13CNMR (400 MHz, CDCl3): δ=30.0 (C-5, C-6 and C-7); δ=34.9 (C-4); δ=55.1 (C-1); δ=111.9 (C-
11); δ=120.8 (C-9); δ=127.0 (C-10); 138.4 (C-3); δ=158.8 (C-2)
m/z (GC-MS): 164 (M+, 27%); 149 (M-CH3, 100%); 134 (M-C2H6, 5%); 121 (M-C3H9, 51%); 105
(M-C4H9); 91 (M-C5H12, 35%); 77 (M-OC5H12, 10%).
Characterisation of 4-tert-butylanisole
1
23
456
7
8
9
10
11
O
1H NMR (400 MHz, CDCl3): δ=1.28 (s, 9H, H-7,H-8 and H-9); δ=3.71 (s,3H, H-1); δ=6.80-6.83
(d, 2H, J=8.8, H-4 and H-10); δ=7.26-7.29 (d, 2H, J=8.8, H-3 and H-11)
13C NMR (400 MHz, CDCl3): δ=31.9 (C7-9); δ=34.3 (C-6); δ=55.7 (C-1); δ=113 (C-11 and C-13);
δ=126.6 (C-4 and c-10); δ=143.3 (C-5); δ=157.8 (C-2)
167
m/z (GC-MS): 164 (M+, 15%); 149 (M-CH3, 100%); 133 (M-C2H6, 3%); 121 (M-C3H9, 27%); 109
(M-C4H9, 13%); 91 (M-C5H12, 10%); 77 (M-OC5H12), 8%).
Characterisation of 2,4-di-tert-butylanisole
O1
23
4
56
7
8910
11
1213
14
15
1H NMR (400 MHz, CDCl3): δ=1.30 (s, 9H, H-11,H-12 and H-13); δ=1.39 (s, 9H, H-5, H-6 and
H-7); δ=3.78 (s,3H, H-1); δ=6.18-6.83 (d, 1H, J=8.6 H-14); δ=7.15-7.19 (m,1H, J=6.1, H-8);
δ=7.31-7.32 (d,1H, J=2.4, H-15)
13C NMR (400 MHz, CDCl3): δ=29.8 (C-5, C-6 and C-7); δ=31.8 (C-11, C-12 and C-13); δ=34.5
(C-4); δ=35.3 (C-10); δ=55.3 (C-1); δ=111.2 (C-15); δ=123.5 (C-8); δ=124.3 (C-14); δ=137.6 (C-
3); 142.5 (C-9); δ=156.4 (C-2).
m/z (GC-MS): 220 (M+, 20%); 205 (M-CH3, 100%); 189 (M-C2H6, 2%); 175 (M-C3H9, 4%);
147(M-C5H12, 3%); 105 (M-C8H18, 2%); 91 (M-C9H21, 2%); 57 (M-OC11H23, 9%)
The Friedel-Crafts reaction of DPE with isobutylene yielded two mono-alkylated products, one
di-alkylated product as well as one tri-alkylated product. The heavy products with high viscosity
were also obtained. The NMR data of the alkylated DPE products is shown below.
168
Characterisation of 1-tert-butyl-2-diphenylether (2-tert-butyl-DPE)
O123
5
6
7
89
10
11
1213
14
1516
4
1H NMR (400 MHz, CDCl3): δ=1.42 (s, 9H, H-4, H-5 and H-6); δ=6.81-7.41 (m, 9H, ph).
13C NMR (400 MHz, CDCl3): δ=30.4 (C-4 to C-6); δ=34.9 (C-2); δ= 118.9 (C-16 and C-12);
δ=120.3 (C-10); δ=122.8 (C-14): δ=123.3 (C-8); δ=127.3 (C-7); δ=129.7 (C-13 and C-15);
δ=141.2 (C-2); δ=156.1 (C-1); δ=158.0 (C-11)
m/z (GC-MS): 226 (M+,59%); 211 (M-CH3, 100%); 195 (M-C2H6, 14%); 181 (M-C3H9, 13%);
133(M-C7H11, 15%); 91 (M-C10H12, 26%); 77 (M-OC10H12, 13%); 57 (M-OC12H13, 9%)
Synthesis of 1-tert-butyl-2-diphenylether (2-tert-butyl-DPE)
O 12
3
45
6
7
8
910
11
1213
14
1516
1H NMR (400 MHz, CDCl3): δ=1.32 (s, 9H, H-6 to H-8); δ=6.92-7.34 (m, 9H, ph).
13C NMR (400 MHz, CDCl3): δ= 31.8 (C-6 to C-8); δ=34.5 (C-5); δ= 118.5 (C-2); δ= 118.7 (C-12
and C-16); δ=123.1 (C-14); δ=126.8 (C-9 and C-3); δ=129.8 (C-13 and C-15); δ=146.4 (C-4);
δ=155.1 (C-1); δ=157.8 (C-11).
m/z (GC-MS): 226 (M+, 28%); 211 (M- CH3, 100%); 195 (M-C2H6, 2%); 183 (M-C3H9, 6%); 91
(M-PhC3H9, 9%); 77 (M- OPhC3H9, 9%).
169
Characterisation of 2,4-di-tert-butyl-phenylpheyl ether
O 1 2
34
5
6
7
8 9 10
11
12
13
1415
16
17
18
19
20
1H NMR (400 MHz, CDCl3): δ=1.23 (s, 9H, H-3, H-5, H-6); δ=1.35 (s, 9H, H-10, H-11, H-12);
δ=6.60-7.41 (m, 8H, ph)
13C NMR (400 MHz, CDCl3): δ=30.3 (C-3, C-4, C-6); δ=31.7 (C-10, C-11, C-12); δ=34.6 (C-5);
δ=35.0 (C-9); δ=118.6 (C-16 and C-20); δ=119.7 (C-14); δ=122.4 (C-13); δ=123.8 (C-7);
δ=124.1 (C-18); δ=129.6 (C-17, C-19); δ=140.0 (C-2); δ=145.8 (C-8); δ=153.4 (C-1); δ=158.1
(C-15)
m/z GC-MS: m/z (GC-MS): 282 (M+, 27%); 267 (M-CH3, 100%); 254 (M-C2H6, 2%); 211 (M-
(C4H9), 2%); 91(M-OC14H22, 5%); 77 (M-OC14H22, 4%); 57 (M-OC16H23, 14%)
5.3 General protocol for synthesis of chromans
The synthesis of chromanes was performed in a 250 mL three-neck round bottom flask fitted
with a reflux condenser and equipped with a magnetic stirrer. The reactions were performed at
room temperature, under atmospheric pressure. During the synthesis of chromanes, all
reagents were used as obtained from the suppliers.
Example: p-cresol (30 g; 280 mmol) and the assisted acid [La(OTf)3/H3PO4] (0.1602 g; 0.27
mmol/ 0.0482 g; 0.490 mmol) were weighed directly into the flask, followed by assembling the
reaction set-up. Subsequently, an addition funnel containing isoprene (30.53 g; 448.97 mmol)
was inserted and the olefin (isoprene) was added drop-wise into the flask, while stirring the
reaction mixture. When the reaction temperature started to increase, a cooling bath containing
ice cold water was periodically inserted to maintain the reaction mixture at room temperature.
170
The purification of some of the compounds was performed using column chromatographic
techniques, loaded with activated, neutral alumina and using hexane: ethylacetate solvent
system in a ratio of 9:1(v/v). Some of the compounds were further purified in a Kugelrhor
distillation set up shown in Figure 5.4. The chromanes were characterised using GC-MS and
NMR spectroscopy
Figure 5.4: Kugelrhor distillation setup used for purification of chromans.
171
Characterisation of 8-tert-butyl-2,2-dimethylchroman
O
12
3
4
56
78
9
101112
1314
15
1H NMR (400 MHz, CDCl3): δ=1.48 (s, 6H, H-1 and H-3); δ=1.59 (s, 9H, H-12 to H-14); δ=1.88-
1.92 (t, 2H, H-4); δ=2.90-2.93 (t, 2H, H-5); δ=6.85-7.23 (m, 3H, Ph)
13C NMR (400 MHz, CDCl3): δ=23.2 (C-5); δ=27.0 (C-12 to C-14); δ=30.1 (C-4); δ=34.9 (C-11);
δ=74.0 (C-2); δ=118.9 (C-8); δ=121.1 (C-6); δ=124.5 (C-9); δ=127.6 (C-7); δ=137.9 (C-15);
δ=152.6 (C-10)
m/z (GC-MS): 218 (M+, 36%); 203 (M-CH3, 58%); 163 (M-C4H9, 34%); 147 (M-C5H12, 100%);
119(M-OC6H15, 11%); 91 (M-OC8H17, 13%); 77 (M-OC9H19, 7%)
Characterisation of 8-tert-butyl-2,2,6-trimethylchroman
O
12
3
4
56
78
9
101112
1314
15
16
1H NMR (400 MHz, CDCl3): δ=1.22 (s, 6H, H-1 and H-3); δ=1.27 (s, 9H, H-12 to H-14); δ=1.61-
1.64 (t, 2H, H-4); δ=2.13 (s, 3H, H-16); δ=2.61-2.64 (t, 2H, H-5); δ=6.16 (s, 1H, H-9); 6.80 (s,
1H, H-7)
13C NMR (400 MHz, CDCl3): δ=20.8 (C-16); δ=23.1 (C-5); δ=26.9 (C-1 and C-3); δ=29.2 (C-12
to C-14); δ=32.8 (C-4); δ=34.7 (C-11); δ=73.6 (C-2); δ=120.6 (C-6); δ=125.3 (C-9); δ=127.6 (C-
172
7); δ=127.8 (C-8); δ=137.6 (C-10); δ=150.3 (C-15)
m/z (GC-MS): 232 (M+, 49%); 217 (M-CH3, 41%); 190 (M-C3H9, 1%); 177 (M-C4H9, 35%); 161
(M-C3H12, 100%); 133 (M-C5H18, 9%); 105 (M-OC6H18, 7%); 91 (M-OC7H20, 9%);77 (M-OC8H22,
5%);
Characterisation of 2,2,6-trimethylchroman
O
12
3
4
56
78
9
10
11
12
1H NMR (400 MHz, CDCl3): δ=1.21 (s, 6H, H-1 and H-3); δ=1.64-1.68 (t, 2H, J=6.8, H-4);
δ=2.14 (s, 3H, H-12); δ=2.60-2.63 (t, 2H, J=6.8, H-5); δ=6.57-6.78 (m, 3H, H-7,H-9 and H-10)
13C NMR (400 MHz, CDCl3): δ=20.5 (C-12); δ=22.5 (C-5); δ=26.9 (C-1 and C-3); δ=33.0 (C-4);
δ=73.9 (C-2); δ=117.0 (C-10); δ=120.6 (C-6); δ=127.9 (C-7); δ=128.7 (C-9); δ=129.8 (C-8);
δ=151.8 (C-11)
m/z (GC-MS): 176 (M+, 55%); 161 (M-CH3, 33%); 147 (M-C2H6, 8%); 133 (M-C3H9, 8%); 121(M-
OC3H9, 100%); 105 (M-OC4H9, 8%); 91 (M-OC5H11, 26%); 77 (M+-OC6H13, 10%)
173
Characterisation of 2,2-dimethylchroman
11O
12
3
4
56
78
9
10
1H NMR (400 MHz, CDCl3): δ=1.32 (s, 6H,H-1 and H-3); δ=1.77-1.80 (t, 2H, J=6.8, H-4);
δ=2.75-2.78 (t, 2H,J=6.8, H-5); δ=6.76-7.09 (m, 4H, H-7 to H-10)
13C NMR (400 MHz, CDCl3): δ=22.7 (C-5); δ=27.2 (C-1 and C-3); δ=33.1 (C-4); δ=74.3 (C-2);
δ=117.5 (C-10); δ=119.8 (C-8); δ=121.1 (C-6); 127.6 (C-7); δ=129.6 (C-9); δ=154.3 (C-11)
m/z (GC-MS): 162 (M+,55%); 147 (M-CH3, 54%); 133 (M-C2H6, 11%); 119 (M-OC2H6, 11%); 107
(M-OC3H6, 100%); 91 (M-OC3H8, 16%); 77 (M-OC4H10, 18%)
Characterisation of 2,2-dimethyl-3.4-dihydro-2H-benzochomene
O
12
3
4
56
78
910
11
1213
14
1H-NMR (400 MHz, CDCl3): δ=1.42 (s, 6H,H-1 and H-3); δ=1.88-1.91 (t, 2H, J=7.0, H-4);
δ=2.86-2.89 (t, 2H, J=6.6, H-5); δ=7.13-7.74 (m, 6H, H-7 to H-13)
174
Characterisation of 3,3,8,8-tetramethyl-1,2,3,8,9,10-hexahydopyrano[3,2-f]chromene
O
O
12
3
4
567
8
9
101112
1314
1516
1H NMR (400 MHz, CDCl3): δ=1.30 (s, 12H,H-1,H-3,H-11 and H-9); δ=1.78-1.82 (t, 4H, J=6.8,
H-4 and H-12); δ=2.54-2.58 (t, 4H,J=6.8, H-5 and H-13); δ=6.58 (s, 2H, H-7 and H-15)
13C NMR (400 MHz, CDCl3): δ=20.4 (C-4 and C-12); δ=26.8 (C-1,C-3,C-9 and C-11); δ=33.1 (C-
5 and C-13); δ=72.7 (C-2 and C-10); δ=116.2 (C-7 and C-15); δ=119.2 (C-6 and C-14); δ=147.2
(C-8 and C-16)
m/z (GC-MS): 246 (M+, 36%); 231 (M-CH3, 5%); 191 (M-C4H12, 77%); 175 (M-OC4H12, 19%);
161(M-O2C4H12, 13%); 147 (M-O2C5H12, 10%); 133 (M-O2C6H12, 4%); 121 (M-O2C7H14, 5%); 91
(M-O2C9H18, 10%); 77 (M-O2C10H20, 9%)
175
Characterisation of 2,2,7,7-tetramethyl-2,3,4,7,8,9-hexahydropyrano[2,3-g]chromene
13
11
128
9
14
1516
12
3
4
56
7
10
O
O
1H NMR (400 MHz, CDCl3): δ=1.30 (s, 12H; H-1, H-3, H-10 and H-12); δ=1.73-1.77 (t, 4H,
J=6.8, H-4 and H-9); δ=2.67-2.71 (t, 4H, J=6.8, H-5 and H-8); δ=6.49 (s, 2H, H-14 and H-15)
13C NMR (400 MHz, CDCl3): δ=22.4 (C-5 and C-8); δ=27.1 (C-1; C-3;C-10 and C-12 ); δ=32.9
(C-4 and C-9); δ=73.6 (C-2 and C-11); δ=116.6 (C-14 and C-15); δ=119.9 (C-6 and C-7);
δ=147.2 (C-13 and C-16)
m/z (GC-MS): 246 (M+, 100%); 231 (M-CH3, 3%); 191 (M-C4H12, 74%); 175 (M-OC4H12, 21%);
161(M-O2C4H12, 14%); 147 (M-O2C5H12, 13%); 133 (M-O2C6H12, 4%); 121 (M-O2C7H14, 5%); 91
(M-O2C9H18, 20%); 77 (M-O2C10H20, 8%)
176
Characterisation of 2,2,3,6-tertramethylchroman
O
1 2 3
4 5
67
89
10
11
1213
1H NMR (400 MHz, CDCl3): δ= 0.91-0.93 (d, 3H,J=6.8, H-5); δ=1.07 (s, 3H, H-3); δ=1.28 (s, 3H, H-
1); δ=1.70-1.87 (m, 1H, H-4); δ=2.16 (s, 3H, H-10); δ=2.31-2.66 (m, 2H, H-6); δ=6.59-6.81 (m, 3H,
H-Ph).
13C NMR (400 MHz, CDCl3): δ=15.8 (C-5); δ=19.1 (C-10); δ=19.5 (C-4); δ=26.4 (C-3); δ=30.1 (C-
1); δ=34.6 (C-6); δ=90.9 (C-2); δ=115.7 (C-12); δ=120.2 (C-7); δ=126.8 (C-8); δ=127.7 (C-9);
δ=128.6 (C-11); δ=150.4 (C-13)
m/z (GC-MS): 190 (M+, 30%); 176 (M-CH3, 55%); 161 (M-C2H6, 9%); 147 (M-C3H9, 66 %);133 (M-
C4H12, 7%); 121 (M-OC4H12,100%); 105 (M-OC5H12, 6%); 91 (M-OC7H13), 25%); 77 (M-OC8H15,
11%)
177
Characterisation of 2-isoporpyl-2,5-dimethyl-2,3-dihydro-1-benzofuran
O
1
2
34
5
6
78
9
10
11
1213
1H NMR (400 MHz, CDCl3): δ= 0.93-0.94 (d,3H,J=6.8,H-3); δ=0.98-1.00 (d, 3H, J=6.8, H-1);
δ=1.33 (s, 3H, H-5); δ=1.96-2.02 (q, 1H, J=6.8, H-2); δ=2.26 (s, 3H, H-10); δ=2.73-3.12 (m, 2H,
H-6) and δ=6.61 (m, 3H, H-Ph).
13C NMR (400 MHz, CDCl3): δ=17.4 (C-1 and C-3); δ=20.8 (C-10); δ=23.3 (C-5); δ=37.3 (C-2);
δ=38.8 (C-6); δ=91.7 (C-4): δ=108.9 (C-12); δ=125.7 (C-8); δ=127.0 (C-7); δ=128.4 (C-11);
δ=129.2 (C-9); δ=157.2 (C-13).
m/z (GC-MS): 190 (M+, 37%); 175 (M-CH3, 10%); 161 (M-C2H6, 5%); 147 (M-C3H9, 100%); 133
(M-C4H12, 7%); 121 (M-C5H15), 46%); 105 (M-OC5H15, 7%); 91 (M-OC6H15, 15%); 77(M-OC7H18,
6%).
178
Characterisation of 8-tert-butyl-2,2,3,6-tetramethylchroman
O4
12
3
5
67
89
10
11
12
1314
1516
17
1H NMR (400 MHz, CDCl3): δ=0.98-0.99 (d,3H,J=6.8,H-4); δ= 1.15 (s,3H,H-1); δ=1.37 (s, 9H,H-
14 to H-16); δ=1.40 (s,3H,H-3); δ=1.77-1.86 (m, 2H,H-6); δ=2,24 (s,3H,H-10); δ=6.63 (s, 1H, H-
8) and δ=6.71 (s, 1H,H-11)
13C NMR (400 MHz, CDCl3): δ=16.6 (C4); δ=20.0 (C-10); δ= 20.9 (C-3); δ=27.6 (C-1); δ=29.9
(C-14 to C-16); δ= 31.7 (C-13); δ=34.7 (C-6); δ=35.4 (C-5); δ=90.6 (C-2); δ=121.5 (C-7);
δ=125.1 (C-11); δ=127.6 (C-8); δ=1338.0 (C-9 and C-12); δ=150.0 (C-17)
m/z (GC-MS): 246 (M+, 50%); 231 (M-CH3, 23%); 217 (M-C2H6, 1%); 203 (M-C3H9, 24%); 189
(M-C4H9, 3%); 177 (M-C3H12, 71%); 161 (M-C4H15, 100%); 147 (M-C5H18, 23%); 133 (M-C6H21,
14%); 121 (M-OC6H21, 10%) ; (105 (M-OC7H21, 9%); 91 (M-OC8H23, 15%); 77 (M-OC9H25, 15%)
179
Characterisation of 7-tert-butyl-2-isopropyl-2,5-dimethyl-2,3-dihydro-1-benzofuran
O
1
23
4
5
67
8
910
11
1214
1516
1713
1H NMR (400 MHz, CDCl3): δ= 0.94-0.95 (d,3H,J= 6.84,H-1); δ= 0.99-1.01 (d, 3H,J=6.6, H-3);
δ=1.30 (s,3H, H-5); δ=1.34 (s,9H,H-14 to H-16); δ=1.95-2.02 (q, 1H,J=6.84, H-2); δ=2.27 (s, 3H,
H-10); δ=2.96-3.08 (m,2H, H-6); δ=6.80 (s,1H, H-11); δ=6.85 (s, 1H,H-8)
13C NMR (400 MHz, CDCl3): δ= 17.5 (C-1 and C-3); δ=21.1 (C-10); δ=23.4 (C-4); δ=29.0 (C-14,
C-15 and C-16); δ=34.0 (C-2); δ=37.0 (C-6); δ=38.9 (C-13); 90.6 (C-5); δ=123.2 (C-11);
δ=125.0 (C-8); δ=127.2 (C-9); δ= 128.5 (C-7); δ= 132.1 (C-12); δ=154.9 (C-17)
m/z (GC-MS): 246 (M+, 60%); 231(M-CH3, 16%); 203 (M-C3H9, 50%); 177 (M-C3H12, 21%); 161
(M-C4H15, 100%); 147 (M-C5H18, 51%); 133 (M-C6H21, 14%); 91(M-OC8H23, 14%); 77(M-OC9H25,
7%)
Synthesis of 7-tert-butyl-2-isopropyl-2,methyl-2,3-dihydro-1-benzofuran
1
2
56
7
8
910
11
1213
1415
16O 3
4
1H NMR (400 MHz, CDCl3): δ= 0.95-0.96 (d,3H,J= 6.8,H-1); δ= 1.00-1.02 (d, 3H,J=6.84, H-3);
δ=1.32 (s,3H, H-4); δ=1.97-2.04 (q, 1H,J=6.8, H-2); δ=2.38-3.12 (m,2H, H-6); δ=6.72-7.05
(m,3H, H8-H10).
180
13C NMR (400 MHz, CDCl3): δ= 17.5 (C-4); δ=21.6 (C-2); δ=23.2 (C-6); δ=29.4 (C-13 to C-15);
δ=34.0 (C-12); δ=37.2 (C-1); δ=38.9 (C-3); δ=90.6 (C-5); δ=119.3 (C-9); δ=122.9 (C-8); δ=124.3
(C-10); δ= 127.4 (C-7); δ= 132.5 (C-11); δ=157.2 (C-16).
m/z (GC-MS): 232 (M+, 49%); 217 (M-CH3, 16%); 189 (M-C3H9, 74%); 173 (M-C4H9, 7%); 163
(M-C5H12, 15%); 147 (M-C6H15, 100%); 133 (M-C7H15, 29%); 119 (M-C8H18, 14%); 105 (M-
OC8H18, 9%); 91 (M-OC9H18, 19%); 77 (M-OC10H20, 9%).
181
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