Applications of New Ionic Liquids for Organic Transformations

by

Daniel J. Eyckens B. Biomed. Sc., B.Sc (Hons)

Submitted in fulfilment of the requirements for the degree of

Doctor of Philosophy

Deakin University

June, 2018

Acknowledgements

First, to my supervisor Luke Henderson. Thank you for everything you’ve

done for me past, present and future. For teaching and encouraging me,

and most of all the reassurance when the imposter syndrome strikes.

Thank you for reading, and re-reading my work and always having the

time to meet with me and assist, not just in the write up stage, but since I

began honours (almost 5 years).

Next, to my family. Only with your continued love and support throughout

my life have I been able to achieve what I have today. You have always

helped, encouraged, inspired and seen the best in me, even when I can’t

see it myself. Thank you Mum, Dad and Carly for everything you have

done, and no doubt will do, in the future. I would also like to thank my

grandparents for all the support you have given me and interest you have

shown. Making you proud means the world to me, and I hope I have done

that.

To my loving girlfriend Rory. You have been with me since before I started

this journey into postgraduate research. You have seen me at all the

highest highs and lowest lows, with all the levels of stress in between. And

yet you have stuck by me, supported me and always kept me grounded.

Thank you so much, I also could not have done this without you.

To all the housemates of Grayling Street, past and present, temporary

and permanent. Even those that do not pay rent (you know who you are).

Thank you for the endless nights of fun, relaxing, destressing and re-

stressing. You guys are all my family too and I appreciate all of you. You

made getting through this PhD fun, and are all my friends for life.

To the reader; good luck and be kind. I haven’t written a PhD Thesis

before, and I don’t intend to write another.

Thank you

Presentations and Publications

Directly from this work and covered in this thesis

1. Eyckens, D.J.; Brozinski, H.L.; Delaney, J.P.; Servinis, L.;

Naghashian, S.; Henderson, L.C., (2016). “Ion-Tagged

Prolinamide Organocatalysts for Direct Aldol Reaction On-

Water.” Catal. Lett., 146(1): 212-219. IF: 2.80, citations: 3

2. Eyckens, D.J.; Champion, M.E.; Fox, B.L.; Yoganantharajah, P.;

Gibert, Y.;Welton, T.; Henderson, L.C., (2016). “Solvate Ionic

Liquids as Reaction Media for Electrocyclic Transformations.”

Eur. J. Org. Chem., 5: 913-917, IF: 2.83, citations: 11

3. Eyckens, D.J.; Demir. B.; Walsh. T.; Welton, T.; Henderson,

L.C., (2016). “Determination of Kamlet-Taft parameters for

selected solvate ionic liquids.” Phys. Chem. Chem. Phys.,

18(19): 13153-13157. IF: 4.12, citations: 11

4. Eyckens, D. J. and L. C. Henderson (2017). "Synthesis of α-

aminophosphonates using solvate ionic liquids." RSC

Advances 7(45): 27900-27904. IF: 3.11, citations: 2

5. Stanfield, M. K., Stojcevski, F., Hendlmeier, A. J., Varley, R. J.,

Eyckens, D. J., Henderson, L. C. (2018). “Phosphorus based

α-amino acid mimetic for enhanced flame retardance in an

epoxy resin.” Aust. J. Chem., available online.

Other contributions by the author

6. Yoganantharajah, P.; Eyckens, D.J.; Pedrina, J.L.; Henderson,

L.C.; Gibert, Y., (2016). “A study on acute toxicity and solvent

capacity of solvate ionic liquids in vivo using a zebrafish

model (Danio rerio).” New J. Chem., 40(8): 6599-6603. IF:

3.27, citations: 2 (selected for cover)

7. Eyckens, D. J., Servinis, L., Scheffler, C., Wölfel, E., Demir, B.,

Walsh, T. R., Henderson, L. C., (2018). "Synergistic interfacial

effects of ionic liquids as sizing agents and surface modified

carbon fibers." J. Mater. Chem. A 6(10): 4504-4514. IF: 8.87,

citations: 0

8. Arnold, C. L., Beggs, K. M., Eyckens, D. J., Stojcevski, F.,

Servinis, L., Henderson, L. C., (2018). "Enhancing interfacial

shear strength viasurface grafting of carbon fibers using the

Kolbe decarboxylation reaction." Compos. Sci. Technol. 159:

135-141. IF: 4.87, citations: 0

9. Yoganantharajah, P., Ray, A. P., Eyckens, D. J., Henderson, L.

C., Gibert, Y. (2018). "Comparison of solvate ionic liquids and

DMSO as an in vivo delivery and storage media for small

molecular therapeutics." BMC Biotechnology 18(1): 32. IF:

2.87, citations: 0.

10. Eyckens, D. J., Stojcevski, F., Hendlemeier, A. J., Arnold, C. L.,

Randall, J. D., Perus, M. D., Servinis, L., Gengenbach, T. R.,

Demir, B., Walsh, T. R., Henderson, L. C., (2018). “An

efficient high-throughput grafting procedure for enhancing

carbon fibre-to-matrix interactions in composites.” Chem. Eng.

J., 353: 373-380. IF: 6.74, citations: 1.

Conference Presentations and Posters

Oral Presentation: “Exploration of the Physical Properties of New

Solvate Ionic Liquids” at the 7th Australasian Symposium on

Ionic Liquids, Newcastle, New South Wales, Australia, 2016.

Poster Presentation: “Solvate Ionic Liquids as Green Alternatives for

Molecular Solvents” at the Royal Australian Chemical Institute

Centenary Congress, Melbourne, Victoria, Australia, 2017.

Poster Presentation: “Solvate Ionic Liquids for Organic

Transformations” at the Royal Australian Chemical Institute

Centenary Congress, Melbourne, Victoria, Australia, 2017.

Poster Presentation: “Solvate Ionic Liquids as Green Alternatives for

Molecular Solvents” at the 255th American Chemical Society

National Meeting, New Orleans, Louisiana, United States of

America, 2018.

i

Abstract

This project evaluates solvate ionic liquids (the solvation of lithium

bis(trifluoromethanesulfonyl)imide in either triglyme or tetraglyme, denoted

by [Li(G3)]TFSI and [Li(G4)]TFSI, respectively) for their application as

strongly coordinating solvents in organic chemistry. The Kamlet-Taft

parameters ([Li(G3)]TFSI: α = 1.32, β = 0.41, π* = 0.942, ETN = 1.028;

[Li(G4)]TFSI: α = 1.35, β = 0.37, π* = 0.910, ETN = 1.033) and the

Gutmann Acceptor Numbers ([Li(G3)]TFSI and [Li(G4)]TFSI: AN = 26.5)

for both of the solvents were determined.

These solvate ionic liquids were also examined in comparison to a similar

solvent; 5.0 M Lithium Perchlorate in Diethyl Ether (LPDE), which held

prominence in the literature in the early 1990s and was eminently suitably

for electrocyclization reactions, e.g. the Diels-Alder reaction. The reports

of 5.0 M LPDE’s successful organic transformations will be used as a

guide to determine the capabilities of the [Li(G3)]TFSI and [Li(G4)]TFSI

solvate ILs. Performing the Diels-Alder reaction in the SILs achieved

excellent yields (up to 81%) in only 30 minutes, representing 93%

reduction in time. The [2+2] cycloaddition cascade formation of dienes

was also achieved to good success (up to 70%).

The Kabachnik-Fields reaction (nucleophilic attack of a phosphite on an in

situ formed imine) for the synthesis of α-aminophosphonates was also

investigated in these SILs. A range of analogues (19 compounds) with

varying substituents, at the aryl amine and aryl aldehyde, were produced

in only 5 minutes at room temperature, with excellent yields (up to 96%).

Also synthesised were bis-adducts of α-aminophosphonates in high yield

(up to 64%), in the same conditions. Included in this range of bis-α-

aminophosphonates is an asymmetric variant.

The facile formation of α-aminophosphonates led to a brief investigation

into their use as flame retardants. A common diarylamine epoxy cross-

linker, 4,4’-diaminodiphenylmethane, was converted to a mono-α-

aminophosphonate and incorporated into a thermoset resin at very low

ii

phosphorus percentages. It was found that a decrease in both the time

taken for a burning resin sample to self-extinguish (60 seconds to 24

seconds), and the mass loss from burning (28% less) compared to control

samples was observed.

Finally, the design, synthesis and evaluation of an ion-tagged

organocatalyst was completed. The proline-based catalyst was

synthesised in 6 steps, with an overall yield of 29% and tested for its

ability to catalyse the aldol reaction, with good success (up to 96%

conversion, dr (anti:syn) = 96:4, er = 92:8). The catalyst was also

examined for its effect on the nitro-Michael reaction using

nitrovinylstyrenes, proving its broad scope with good conversion and dr,

but suffered in er (up to 95% conversion, dr (anti:syn) = 91.9, er = 65:35).

This project served to determine the effect on reaction outcomes when

using ionic liquids either as solvents or catalysts. The success of this work

has resulted in several publications, as well as others that in preparation.

iii

Abbreviations and Acronyms

13C NMR Carbon-13 Nuclear Magnetic Resonance 1H NMR Proton Nuclear Magnetic Resonance

Chemical shift

Boc tert-butoxycarbonyl

Bn Benzyl

DMAP N,N-Dimethylaminopyridine

DMF N,N-Dimethylformamide

DMSO-d6 Deuterated Dimethyl Sulfoxide

EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et Ethyl

Et3N Triethylamine

EtOAc Ethyl Acetate

EtOH Ethanol

g Grams

[Li(G3)]TFSI Solvated lithium bis((trifluoromethyl)sulfonyl)imide in triethylene glycol dimethyl ether (triglyme)

[Li(G4)]TFSI Solvated lithium bis((trifluoromethyl)sulfonyl)imide in tetraethylene glycol dimethyl ether (tetraglyme)

h Hours

Hz Hertz

HRMS High Resolution Mass Spectroscopy

IR Infrared

J Coupling constant

LiTFSI Lithium bis((trifluoromethyl)sulfonyl)imide

m/z Mass to charge ratio

MeOH Methanol

mg Milligram

min Minutes

iv

mp Melting Point

MW Microwave Irradiation

nBu normal-butyl

NMR Nuclear Magnetic Resonance

PET Petroleum spirits (40-60 C)

Ph Phenyl

pH Potential of hydrogen

ppm Parts per million

rt Room temperature

tBu tert-butyl

Tetraglyme Tetraethylene glycol dimethyl ether

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMS Trimethylsilane

Triglyme Triethylene glycol dimethyl ether

v

Table of Contents

– General Introduction and Thesis Overview ........................... 1

Background ........................................................................................... 1

Research aims and objectives .............................................................. 3

Thesis outline ........................................................................................ 5

– Literature Review .................................................................. 7

Ionic Liquids .......................................................................................... 7

Preparation of Traditional Ionic Liquids ............................................ 10

Solvate Ionic Liquids ........................................................................... 14

Practical Considerations .................................................................. 19

Components of SILs ........................................................................ 19

Applications of SILs ......................................................................... 20

5.0 M Lithium Perchlorate in Diethyl Ether (LPDE) ............................. 25

Pericyclic reactions in 5.0 M LPDE .................................................. 26

Project Overview .................................................................................... 33

Aims .................................................................................................... 34

Project outcomes ................................................................................ 35

– Characterisation of SILs ..................................................... 37

Introduction ......................................................................................... 37

Kamlet-Taft Parameters ................................................................... 37

Gutmann Acceptor Number ............................................................. 40

Determining the Kamlet-Taft Parameters of SILs ................................ 43

α Values – Hydrogen Bond Donating Ability .................................... 43

β Values – Hydrogen Bond Accepting Ability ................................... 49

π* Values – Dipolarity/Polarizability ................................................. 52

vi

ET(30) and ETN – Solvent Polarity and Normalised Solvent Polarity53

Gutmann Acceptor Number ................................................................ 55

Application of Lewis Acidity of Solvate Ionic Liquids Electrocyclisation

Reactions ............................................................................................ 59

Diels–Alder Reactions ..................................................................... 59

[2+2] Cycloaddition Cascade formation of Dienes ........................... 62

Psuedo-Pinacol Rearrangement of Epoxides .................................. 63

Chapter Summary ............................................................................... 64

– Synthesis of α-Aminophosphonates in SILs ....................... 65

Introduction ......................................................................................... 65

Lithium Perchlorate-Assisted α-Aminophosphonate Synthesis ........ 68

Other Synthetic Methods to access α-Aminophosphonates ............ 72

Synthesis of α-Aminophosphonates in SILs ........................................ 77

Aniline Derivatives in the Kabachnik-Fields Reaction using SILs .... 80

Benzaldehyde Derivatives in the Kabachnik-Fields Reaction using

SILs ................................................................................................. 84

Synthesis of Bis-α-Aminophosphonates from Arylenediamines ....... 86

Application of an α-Aminophosphonate as a Flame Retardant ........... 90

Introduction ...................................................................................... 90

Flame retardance ............................................................................. 93

Compound Design ........................................................................... 94

Evaluation ........................................................................................ 95

Chapter Summary ............................................................................. 102

– Synthesis and Evaluation of an Ion-Tagged Organocatalyst

............................................................................................................. 105

Introduction ....................................................................................... 105

Chirality .......................................................................................... 105

Methods of inducing chirality ......................................................... 106

vii

Ion-Tagged Organocatalysts.......................................................... 109

Synthesis of an Ion-Tagged Organocatalyst ..................................... 114

Evaluation of 5.30 and 5.31 as Organocatalysts ............................... 118

Nitro-Michael Reaction .................................................................. 125

– Future Work (Solvate ILs) ................................................. 129

Physical Chemical Parameters ...................................................... 129

Synthetic Methods in SILs ............................................................. 129

Ion-Tagged Organocatalysis .......................................................... 130

Experimental ........................................................................................ 131

General Chemical Experimental ....................................................... 131

Preparation of Solvate Ionic Liquids .................................................. 132

Chapter 3 Experimental .................................................................... 133

Addition of dyes and preparation. .............................................. 133

Worked example for α and polarity measurements ................. 133

General procedure for the determination of Gutmann Acceptor

Number .......................................................................................... 136

Chemical Synthesis ....................................................................... 137

General Procedure for Diels-Alder reactions ................................. 137

General procedure for [2+2] reactions ........................................... 138

Chapter 4 Experimental .................................................................... 139

General preparation of α-aminophosphonates .............................. 139

Compound reports ......................................................................... 140

Chapter 5 Experimental .................................................................... 152

General Method for Catalyst Testing (Aldol) .................................. 156

Determination of reaction outcomes: conversion and diastereomeric

ratio ................................................................................................ 156

Determination of Reaction Outcomes: Enantiomeric Ratio. ........... 158

viii

DSC Results .................................................................................. 159

References ........................................................................................... 161

Published Works .................................................................................. 177

“If you do not know, ask.

You will be a fool for the moment, but a wise man for the rest of your life.”

~ Seneca the Younger

1

– General Introduction and Thesis Overview

Background

Synthetic organic chemistry deals with the manipulation of molecules on

an atomic. This may be the enhancement of therapeutic or medicinal

attributes,1 physical or material properties,2-3 fluorescence,4-7

conductivity,8-11 or combinations thereof. Many applications include the

augmentation of organic molecules into compounds that can effect greater

changes in other reaction pathways, the most relevant to this work is

organocatalysis.

In the modern world, chemistry is at the heart of a great many innovations

of technology. This includes methods of water purification,12 to highly

technological functions such as flexible Organic Light Emitting Diode

(OLED) screens.13 Although these outcomes are fantastic, the problem of

finding new avenues to manipulate molecular structure to effect these

changes is a persistent challenge.

It is therefore pertinent, to investigate new methods of accessing different

organic compounds. A great deal of organic synthesis requires dissolution

in a liquid medium to increase the molecule to molecule interactions and

facilitate reaction between them. Many solvents have been used to

achieve this, and the most relevant class of solvent to this project are ionic

liquids.

An ionic liquid is a non-aqueous liquid consisting entirely of ions.14 It is

comparable to heating sodium chloride (table salt) to its melting point (ca.

800 °C) when it becomes a liquid made of ions (not to be confused with

dissolving salt in water). The main difference between an ionic liquid and

the example given is that the melting point of an ionic liquid is often much

closer to room temperature, which makes performing reactions in them

much easier and safer than performing reactions in molten sodium

chloride.

2

As an extension on this, solvate ionic liquids (SILs) are comprised of a salt

and a glyme molecule whereby the glyme chelates the cation of the salt,

diffusing the positive charge over several atoms and preventing the close

association of the anion and the cation, causing the mixture to become a

liquid. In this way, SILs are pseudo-ionic liquids in that they incorporate

the glyme molecule that is not, in itself, ionic (Figure 1.1).

Figure 1.1 Structure of solvate ionic liquids (SILs); the cations [Li(G3)]+, [Li(G4)]+ and the anion bis(trifluoromethansulfonyl)imide (TFSI).

The question may then be raised as to whether the mixture is simply the

salt dissolved in glyme, or if it is a chelated structure. To that end, there

has been great investigation to determine that the mixture is the latter,15-16

and may be classed as a solvate ionic liquid.

The SILs that are the main focus of this thesis consist of the lithium

bis(trifluoromethanesulfonyl)imide salt and either triethylene glycol

dimethyl ether (triglyme, G3) or tetraethylene glycol dimethyl ether

(tetraglyme, G4). These components combine to give the SILs referred to

herein as [Li(G3)]TFSI and [Li(G4)]TFSI (Figure 1.1).

Although they have shown good application as electrolytes in batteries,15,

17-18 there was (before the initiation of this project) no representation in the

literature of organic reactions being attempted in these SILs. This project

will focus on the use of SILs as solvents to carry out organic

transformations.

There was, however, a similar solvent used in the late 1990s and early

2000s which was lithium perchlorate dissolved in diethyl ether (LPDE).19-23

Usually appearing at a concentration of 5.0 M, this solvent showed good

application for organic reactions, but fell out of favour due to poor handle-

ability and the potential for the perchlorate anion to explode when heated.

3

This solvent will be used as a point of comparison, and a guide for the

types of reactions that may be prove successful for the SILs.

The use of different solvents may drastically affect reaction outcomes.24-25

This project identifies the outcomes effected by SILs, whether it be

improvements in yield, ease of product isolation or reduction of reaction

times. To better understand this, the physical parameters of SILs are

explored, so they may be compared with other solvents.

An auxiliary study is also included in this thesis; an ion-tagged

organocatalyst which will be evaluated for its catalytic activity in Chapter

5.

The production and evaluation of ion-tagged organocatalysts served as a

transitional project at the beginning of this PhD as it was similar to the

author’s honours project (production of novel organocatalysts) and aided

by increasing familiarity with compounds bearing an ‘ionic liquid’ like

moiety (imidazolium), whilst examining the literature for the main aim of

the PhD (solvate ionic liquids). Interestingly, the ion-tagged

organocatalysts fulfilled the criteria to be classed as ionic liquids and

provided insight into how ionic liquids may affect reaction outcomes.

Research aims and objectives

The main focus of this thesis was to determine the adequacy of using

solvate ionic liquids as reaction media for organic transformations. Broad

criteria for an ‘improvement’ were enhanced reaction outcomes, such as

increases in yield of final products, reduction in time or temperature of the

reaction, and/or ease of isolation and purification of synthesised products.

To evaluate SILs as replacements for organic solvents, the physical

characteristics of each must initially be determined, so they may be

compared with other solvents. In this project, characterisation of the SILs

will take the form of determining their Kamlet-Taft parameters.26-29 These

parameters describe the hydrogen bonding donating (α), hydrogen

bonding accepting (β), polarizability (π*) and overall polarity (ENT). Further

characterisation will be achieved through the investigation of the Gutmann

4

Acceptor Number,30-31 which is an indication of the degree of Lewis acidity

possessed by a solvent.

Once the physical parameters are assessed, the application of SILs as

solvents for organic reactions will be undertaken. Most pertinent are those

reactions that have shown success in 5.0 M LPDE, namely Diels-Alder32

and Kabachnik-Fields33-34 reactions.

Other investigations into how an ionic tag may influence catalytic activity

and reaction outcomes include the synthesis and evaluation of ion-tagged

organocatalysts.

The following list is a brief description of the studies carried out to answer

the above research questions;

Chapter 3-4

Determine the Kamlet-Taft Parameters of [Li(G3)]TFSI,

[Li(G4)]TFSI, triglyme and tetraglyme. These identify the hydrogen

bond donating (α) and accepting (β) nature of a solvent, as well as

the polarity (ENT) and polarizability (π*).

Determination of the Gutmann Acceptor number (AN). This gives

an indication of the degree of Lewis acidity a solvent can exhibit,

which can greatly influence reaction outcomes.

Perform a pilot study of the application of these previous points to

an electrocyclic reaction; in this instance Diels-Alder cycloadditions.

Evaluate the outcomes of using these SILs to produce α-

aminophosphonates.

Application of an α-aminophosphonate as a flame retardant in an

epoxy resin.

Chapter 5

Determine and optimise the synthesis of an organocatalyst with an

ion tag.

5

Evaluation of the organocatalyst’s catalytic activity, including yield,

enantiomeric and diastereomeric ratios.

Thesis outline

This thesis begins with a review of the literature surrounding the use of

ionic liquids for organic transformations (Chapter 2). Identified here, is the

positive effects the use of ILs in organic chemistry, as well as the parallels

between traditional ionic liquids, and solvate ionic liquids. Also discussed

is a pseudo-solvate ionic liquid that has shown good use for organic

transformations; 5.0 M lithium perchlorate in diethyl ether (5.0 M LPDE).

Chapter 3 describes the identification of the Kamlet-Taft parameters of the

solvate ionic liquids, which categorise the hydrogen bond donating and

accepting properties, as well as the polarity and polarizability of the

solvents. This is followed by the investigation of the Gutmann Acceptor

number which gives an indication of the Lewis acidity exhibited by a

solvent. Finally, an application of the SILs in facilitating electrocyclic

reactions, including Diels Alder reactions.

Chapter 4 is an examination of the three-component, one-pot synthesis of

α-aminophosphonates in the SILs. These small, organic molecules are

structurally similar to α-amino acids and have diverse applications from

uses as medicinal compounds to agriculture. This chapter culminates in

the investigation of an epoxy resin curing agent containing an α-

aminophosphonate moiety to impart flame retardancy into the material.

Keeping in the theme of ion tagged compounds, Chapter 5 contains the

optimisation and synthesis of an ion-tagged organocatalyst which is then

evaluated for its catalytic activity.

6

7

– Literature Review

Ionic Liquids

In its simplest form, chemistry is a science of combining or altering

compounds by manipulating the conditions within which the compounds

interact. To that end, the most efficient method of perpetuating these

interactions is in a liquid medium, which can consist of almost any fluid,

though only a relative few are used as solvents.

Broadly, solvents fall into two categories; polar and non-polar, though

there is an almost infinite number of sub-categories. The use of water as a

solvent is very attractive due its non-toxic nature, high availability, low

cost, ease of handling, high boiling point, and polarity. Despite these

obvious advantages, the inherent problem that its employment as a

solvent immediately excludes the use of water-sensitive reactants and

reagents, and many organic compounds are not soluble in this medium.

This obstacle can be remedied by replacement of water with an organic

solvent. This may suffice, though at the typical sacrifice of an increase in

toxicity, cost and flammability, as well as a higher vapour pressure,

potentiating the loss of solvent if improperly sealed.

Ionic liquids (ILs) have been popularly used as a medium for organic

solvents for 20 years.14 Broadly, the term applies to a salt that is in a liquid

state under 100 °C, and many ionic liquids exist as liquids at room

temperature (room temperature ionic liquids, RTILs). A variety of ionic

liquids have been developed, including; protic, aprotic, organic or

inorganic.14, 35-37 ILs may be known by different synonyms including liquid

salts, liquid electrolytes, ionic fluids or molten salts. The latter is

sometimes regarded as less accurate due to potentially inciting the idea of

a highly corrosive, viscous, and high-melting matter,37 which is not always

the case for ionic liquids.

Ionic liquids are composed of a charge diffuse anion or cation, and

commonly both. These ‘soft’ charges cause the ions to associate poorly,

8

preventing them from existing as a solid. The most common cations in ILs

are alkylammoniums, alkylphosphoniums, N,N′-dialkylimidazoliums, and

N-alkylpyridinium species (Figure 2.1).14 Advantageous to these solvents

is the ability for their properties to be tailored, accessed by differing the

substituents, or the combination of anion and cation, altering the melting

point of such ILs from -14 °C to 87 °C, and manipulating the solubilities of

reactants, reagents, and products.38

Figure 2.1 Common cations of ionic liquids.

Despite the relatively recent increase in interest of ionic liquids from both

synthetic and material science perspectives, the first reported ionic liquid

was ethylammonium nitrate by Walden in 1914.39 ILs have found use in a

multitude of areas, including CO2 capture,40-41 electrolytes for batteries,18,

42-43 dissolution of lignin,44-45 and as solvents for chemical reactions.14, 36,

38

By far the most common ILs used in synthetic organic chemistry are

imidazolium-derived.14, 36-37 To note the nomenclature used, [Bmim]

represents 1-butyl-3-methylimidazolium (Figure 2.2), this holds true for

other varieties such as [Emim] which is 1-ethyl-3-methylimidazolium. The

anion of the ionic liquid is then written after the parenthesis; [Emim]Cl in

this case a chloride ion.

Figure 2.2 Example structure of an imidazolium-derived ionic liquid ([Bmim]) with ambiguous anion.

In contrast to the many utilitarian devices often found in nature, ionic

liquids are surprisingly uncommon. Only one example of an IL has been

found in nature, deriving from the combination of venoms of the fire ant

(2.1, Solenopsis invicta) and the tawny crazy ant (2.2, Nylanderia fulva).

9

When the latter is sprayed with the former’s venom, it grooms itself with its

own venom to detoxify.46 The protic ionic liquid formed (2.3) is due to the

protonation of S. invicta venom alkaloids (a Brønsted base) by formic acid

(a Brønsted acid) venom from N. fulva (Scheme 2.1).

Scheme 2.1 The naturally occurring protic ionic liquids 2.3, formed from the combination of ant-venoms from S. invicta (2.1) and N. fulva (2.2). Image credit: Alexander Wild.47-48

The formation of protic ionic liquids typically occurs in this fashion

(stoichiometric combination of a Brønsted acid and Brønsted base,

resulting in a salt with an exchangeable proton), which differs from aprotic

ionic liquids that are commonly formed through the quarternisation of a

tertiary amine.49-50

When considering the suitability of ionic liquids as replacements for

organic solvents, the following advantages must be considered:14, 35-36, 38

(1) They allow the dissolution of a wide range of organic and inorganic

compounds, often bringing reagents with varying solubilities into

the same phase.

(2) Intrinsic to their nature as liquids made entirely of ions, is their high

degree of polarity that may be coordinating or non-coordinating to

dissolved reagents. They absorb microwave irradiation very well

and so are excellent solvents for microwave-assisted reactions.

(3) Various ILs are immiscible with certain organic solvents allowing a

biphasic, polar and non-aqueous system, greatly simplifying the

purification or separation of compounds. Additionally, hydrophobic

ILs can be used with water to form biphasic solutions. This also

results in the easy recycling of the IL, through selective solvation.

10

(4) They exhibit negligible vapour pressure, enabling their use in

highly vacuous conditions, at high temperatures and removing the

containment issues of organic solvents as well as reducing the

concern for built up pressure.

These are all attractive features, and many reactions benefit from highly

polar solvents. This is a consequence of the stabilisation of high-energy

transition states that may be encountered in a given synthetic

transformation. ILs also serve to significantly extend the lifetimes of

reactive species, such as [RuCl6]-3 which is found to undergo deleterious

reactions with the reaction media, especially in aqueous solutions

(equation below), though also in molecular solvents.51

[ ] + ⇌ [ ( ) ] + ( ≥ 2)

This complex is stabilised due to the prevention of solvation or solvolysis

decomposition pathways by an ionic liquid consisting of AlCl3-[Emim]Cl.

This is coupled with the advantage of using this ionic liquid at room

temperature, which precludes the thermally promoted dissociation and

disproportionation reactions leading to degradation of complexes.52 This

was demonstrated when other attempts at stabilising these compounds

for electrochemical analysis included the use of molten LiCl-KCl at

450 °C.53 Interestingly, the AlCl3-[Emim]Cl ionic liquid has found other use

as an electrolyte for Al+ batteries,54 demonstrating the versatility of ionic

liquids.

Preparation of Traditional Ionic Liquids

Most traditional ILs can be obtained through the quarternization of an

amine or phosphane, with the anion dependent on the alkylating agent

used. Alkylammonium ionic liquids can be accessed through the reaction

of the appropriate alkyl halide with ammonia. A similar procedure is

applied in the case of imidazolium and pyridinium-based cations.55-56

These simple halogen-anion ionic liquids precede the new class of ionic

liquids, which incorporate more complex anion structures. The first of

these was obtained in 1992 through the metathesis of [Emim]I with AgBF4

11

in methanol to give [Emim]BF4 (Figure 2.3), which is both air and moisture

stable (though is hygroscopic, a flaw common to many ILs).57

Figure 2.3 The anion exchange of iodide for tetrafluoroborate to form the EmimBF4 ionic liquid (top) and common anions of ionic liquids (below).

In some cases, further anionic combinations may be accessed through an

anion exchange process, such as the treatment of [Emim]Cl with HPF6 or

KPF6 to yield the [Emim]PF6 ionic liquid.58 In addition to these

tetrafluoroborate and hexafluorophosphate anions, is the substitution of

thiocyanate, bis((trifluoromethyl)sulfonyl)amide, trifluoroacetate,

tris((trifluoromethyl)sulfonyl)-methanide, nonafluorobutanesulfonate, and

heptafluorobutanoate anions, all prepared through metathesis reactions

(Figure 2.3).59-61 The use of anion exchange reactions offers a simple

method in generating new cation/anion combinations, though this method

can suffer due to the potential contamination from the previous

halogens.62 Nevertheless, almost limitless combinations of cation and

anion pairs are possible, leading to the claim the ionic liquids are highly

tailorable to the desired purpose.

Some limitations do exist for this class of solvents, which include melting

points that, although under 100 °C, are substantially higher than room

12

temperature ([Bmim]Cl m.p. = = 70 °C). This may remove some

practicality for certain cation/anion combinations. One other limiting

aspect of imidazolium-based ILs is that they are essentially precursors to

N-Hetereocyclic Carbenes (NHCs).63 These carbenes are accessed by

removal of the acidic H2 proton by strong base and may be used as

ligands for a variety of metal complexes (Figure 2.4).

Figure 2.4 Formation of N-Heterocyclic Carbenes (NHC) by deprotonation of the H2 proton of an imidazolium salt.63

The Aldol reaction is one example of a reaction that may be less

accessible when using ILs as solvents. Most commonly base-catalysed,

this reaction consists of one carbon of a ketone or aldehyde adding to

another of a carbonyl to yield a β-hydroxycarbonyl compound (Figure 2.5).

The use of base to catalyse this reaction can result in the formation of

NHCs when imidazolium-based ILs are used, though these effects may be

suppressed in the presence of alcohols.36

Figure 2.5 Aldol reaction between cyclohexanone (2.4) and benzaldehyde (2.5).

Interestingly, the use of [Bmim]BF4 has effectively been used as a solvent

for the aldol reaction between propanal and 2-methylpentanal exhibited a

20% higher conversion to the α,β-unsaturated product, than purely

aqueous systems (catalytic NaOH used to reduce generation of NHCs).64

13

A common method of catalysing the aldol reaction is the use of a

secondary-amine-containing organocatalyst (often proline or proline-

based), which proceeds through an enamine pathway. The use of a chiral

organocatalyst confers chirality to the products and the first example of

this in an IL was a 30 mol% loading of proline in [Bmim]PF6 to catalyse

the reaction between various substituted benzaldehydes and acetone.65

The use of proline is interesting as it may be incorporated as the cation or

anion of the ionic liquid, serving as a solvent/catalyst combination. This

may be achieved through attachment of an ionic moiety to the proline

scaffold or the deprotonation of the carboxylic acid group.66-67 This latter

method has been shown to overreact to the second aldol reaction, though

this may be limited by the addition of water.66

One of the first reactions investigated for application in ILs was the Diels-

Alder reaction (described later in this chapter).68 Originally, water was

used as a solvent32 for this electrocyclic reaction though an alternative

was examined in the form of [EtNH3]NO3.68 This ionic liquid demonstrated

the ability to increase reaction rates and endo-selectivity for the reaction

between cyclopentadiene (2.7) and methyl acrylate (2.8, Figure 2.6),

though only in relation to non-polar molecular solvents.68 Water remained

superior, though it is recognized that the use of ILs may facilitate water

sensitive reagents otherwise unusable.

Figure 2.6 Diels-Alder reaction between cyclopentadiene (CPD, 2.7) and methyl acrylate (2.8) in ethylammonium nitrate ([EtNH3]NO3) ionic liquid.

It has been shown that these reactions show increased endo-selectivity

with increased hydrogen bond donation from the cation of the IL, and a

decrease with more hydrogen bond-accepting anions.69 Also, longer alkyl

chains of imidazolium salts may reduce selectivity due to steric effects.70

14

In terms of kinetics, higher viscosity of ionic liquids results in reduced

reaction rate, but this may be remedied by incorporating an organic

solvent to lower viscosity.71 Small amounts of water may be added to the

IL which has also been shown to improve reaction rates.72

A new class of ILs can be prepared by ‘softening’ a hard cation of an ion

pair that would normally exist as a solid at room temperature. These

particular ILs are referred to as solvate ILs and will be the main focus of

this project. For a more comprehensive exploration of ionic compounds

and their application please refer to the literature.14, 36-38, 73-74

Solvate Ionic Liquids

A recently reported75 class of ionic liquids known as solvate ionic liquids

(SILs) is an area of study in its infancy, though investigations into to the

field are rapidly increasing. Typically, they exist due to the diffusion of a

cationic charge via the sequestering of a hard cation, often in an ethereal

solvent.35 The most pertinent to this project is the dissolution of lithium

bis(trifluormethanesulfony)imide (LiTFSI) in either triethylene glycol

dimethyl ether or tetraethylene glycol dimethyl ether (triglyme/G3 or

tetraglyme/G4, respectively, Figure 2.7).

Figure 2.7 Simplified structure of Lithium in G3 ([Li(G3)]TFSI), G4 ([Li(G4)]TFSI), and the TFSI- anion.

The LiTFSI salt has been incorporated into polymer electrolytes for

batteries, with good success,76-79 and the addition of boric acid ester

monomers have assisted the solubility of the salt in these networks.80-81

Henderson et al. first identified and characterised the chelation of Li+ salts

in triglyme82 and tetraglyme,83 but the salts studied did not include LiTFSI.

Similar structures of Li+ cations with oligoether-containing structures were

investigated by Fujinama and Buzoujama84 which consisted of two

15

ethereal units and two electron withdrawing units attached to an aluminate

anionic centre (2.10) according to Scheme 2.2.

Scheme 2.2 Production of an aluminate-based lithium solvate salt.85

Comparatively, Shobukawa et al. demonstrated an analogous structure,

though with a borate anionic centre (2.11, Figure 2.8).85 The main

difference here is that the latter example was fully characterised as an

ionic liquid, and the former (aluminate solvate), was not formally

characterised, though was referred to as a liquid salt in the manuscript.84

Both structures exhibit similar glass transition states, far below 0 °C

(average Tg ≈ -50 °C across different length PEG groups) and the

reduction in Lewis basicity of the anionic component of these solvates

allow the Li+ cation to be chelated by the ethylene oxide.85

Figure 2.8 Borate-based solvate ionic liquid produced by Shobukawa et al.85

Although these examples are similar in concept to the solvate ionic liquids

explored in this thesis, Pappenfus et al. was the first to identify the

equimolar mixture of LiTFSI and tetraglyme as a room temperature

(solvate) ionic liquid.86 This was closely followed by the analysis of

different length glyme oligomers with lithium salts.87

The chelation of the lithium cation by the glyme molecule characterises

the mixture as a solvate ionic liquid, not just a concentrated solution, as

identified by Ueno et al.88 by exploring anion-dependent properties. It was

determined that a weakly Lewis basic anion (TFSI-type anions and ClO4)

16

was required to allow the glyme-Li+ chelation to dominate over the

competitive cation-anion. When anions of greater Lewis basicity were

employed, the result was concentrated solutions of salt in glyme (Table

2.1, entries with asterisks).

In contrast to the concentrated solutions, the solvate ILs showed high

thermal stability, high ionic conductivity, high viscosity, low volatility, low

flammability as well as a wide electrochemical window, similar to

traditional ILs.75, 88-89

Table 2.1, below, shows the difference in melting point and density of

equimolar mixtures of tri- or tetraglyme and lithium salts with a variety of

anions.

Table 2.1 Properties of a range glyme-lithium salt mixtures.

Entries in bold are those most relevant to this thesis. *denotes concentrated solutions, not solvate ILs. Abbreviations as follows: TFSI: bis(trifluormethansulfonyl)imide, FSI: bis(fluorosulfonyl)imide, OTf: trifluoromethylsulfonate, NO3: nitrate, TFA: trifluoroacetate, CTFSI: cyclic-TFSI derivative 1,2,3-dithiazolidine-4,4,5,5-tetrafluoro-1,1,3,3-tetraoxide, BETI: bis(pentafluoroethanesulfonyl)imide, ClO4: perchlorate, BF4: tetrafluoroborate. Adapted from Ueno et al.88

As may be seen in Table 2.1, altering the anion has large effects on both

melting point and density. The solvate ionic liquids explored in this thesis

Glyme-Li+ salt mixture Tm

(°C)

ρ

(g cm-3)

[Li(G3)]TFSI 23 1.42

[Li(G3)]FSI 56 1.36

[Li(G3)]OTf* 35 1.30

[Li(G3)]NO3* 27 1.18

[Li(G3)]TFA* n.d. 1.20

[Li(G4)]TFSI n.d. 1.40

[Li(G4)]CTFSI 28 1.40

[Li(G4)]FSI 23 1.32

[Li(G4)]BETI 23 1.46

[Li(G4)]ClO4 28 1.27

[Li(G4)]BF4 39 1.22

[Li(G4)]NO3* n.d. 1.17

[Li(G4)]TFA* n.d. 1.19

17

are in bold, and it is worth noting that although a melting point of 23 °C is

reported for [Li(G3)]TFSI, this is not consistent with the findings of the

authors’ observation. Also interesting to note, is the outcome that not all

lithium salts present as liquids in both tri- and tetraglyme, and may only

exist as such in one or the other with the alternative being a solid

complex. These combinations are not shown in Table 2.1, but an example

is [Li(G3)]ClO4 which is solid above 100 °C, whereas [Li(G4)]ClO4 has a

melting point of 28 °C.

Raman spectroscopy of LiTFSI in both triglyme and tetraglyme indicates a

very negligible percentage of free glyme in these equimolar mixtures

(Figure 2.9), which is to be expected of solvate ILs.16

Figure 2.9 Percentage of free glyme in equimolar mixtures of tri- or tetraglyme with various lithium salts.16

As identified previously, some combinations of lithium salt and glyme do

not result in solvate ionic liquids, only concentrated solutions, further

confirmed by the large percentage of free glyme (not-chelating) in those

examples.16

Both [Li(G3)]TFSI and [Li(G4)]TFSI satisfy the following criteria for solvate

ILs:90

(1) A solvate compound is formed between an ion and a ligand(s) in a

certain stoichiometric ratio (in this instance, 1:1).

0

10

20

30

40

50

60

70

80

90

100

% f

ree

glym

e

18

(2) Consist (almost) entirely of complex ions (solvates) and their

counter ions in the molten state.

(3) Show no physicochemical properties based on both pure ligands

and precursor salts under using conditions.

(4) Have a melting point below 100 ºC (which satisfies the criterion for

typical room temperature ILs).

(5) Have a negligible vapour pressure.

In relation to the third criterion, the equimolar mixture of LiTFSI and glyme

forgoes any evaporation due to the lithium chelation, an effect not present

when lesser concentrations of LiTFSI in glyme were assessed.90

Scheme 2.3 Addition of Lewis acid and Lewis base to give a solvate ionic liquid. Anion not shown.

The solvation occurs when the lone pairs on the oxygen atoms of the

ether moieties act as a Lewis base, donating electrons to the Lewis acid

(lithium) cation, chelating it (Scheme 2.3).82-83 This multidentate

sequestration enables the dissolution of alkali metals, such as LiTFSI or

lithium perchlorate (LiClO4). In the case of LiTFSI, electron density of the

nitrogen atom is attenuated due to the flanking strongly electron

withdrawing groups, heavily delocalising any anionic charge. This allows

the oligo-ether groups to coordinate the lithium cation. The combination of

these effects relieves the strong coulombic interactions of the naked

LiTFSI salt, reducing the previously high melting point (234–238 °C) to

below room-temperature.

Changing the glyme or anion combination can produce highly variable

results, exemplified by the crystal structure produced when LiClO4 is

dissolved in G3 (melting point = 103 °C) compared with the room-

temperature IL form when dissolved in G4.88 The greater the ionic

19

association of the salt in aprotic solvents, the less likely that chelation will

occur, supported by the previous example by the greater Lewis basicity

(association) of the anion ClO4- compared to TFSI-.91 Further to this,

employing a PF6- anion may catalyse the decomposition of polyethylene

oligomers to alkenes, HF and phosphorus containing products, according

to Scheme 2.4.92

Scheme 2.4 Mechanism of decomposition of Glyme-like groups (R2O) through reaction with the PF6 anion.

Practical Considerations

Many of the traditional ILs and indeed the solvate ILs, are both air and

moisture stable, though are often quite hygroscopic. Exposure to

atmospheric moisture, whether in an open reaction vessel, or through

inadequate storage, is enough to contaminate the solvent with trace

amounts of water. Depending on the desired outcome and reagents used

this may or may not be a problem, though it should be noted that some

reagents are deactivated by only trace amounts of water.62 It is therefore

recommended that these solvents are handled and stored under an inert

atmosphere (nitrogen or argon) to avoid any adventitious water

compromising the anhydrous nature of the solutes. The anionic character

associated with the IL may also dictate further special handling, as

perchlorates and organic nitrates are potentially explosive when dried

rigorously (under reduced pressure, or elevated temperature).

Components of SILs

The uncoordinated LiTFSI salt itself exists in a tetrahedrally coordinated

state, by four oxygens from four neighbouring anions (Figure 2.10).93 The

TFSI- anion, as a whole, has a near C2 geometry, as the sulfonyl moieties

have a distorted tetrahedral symmetry.94 The effect of the neighbouring

sulfur atoms in the S-N-S bond delocalises the charge from the nitrogen

20

atom, though does not necessarily reside on the sulfonyl oxygens, as may

have been suggested by simpler models.

Figure 2.10 Tetrahedral arrangement of LiTFSI salt. Pink = Li, green = F, yellow = S, black = C, blue = N. Top left shows the tetrahedrally bonded nature of the Li+ cation using dotted lines.93

As mentioned earlier, LiTFSI salt has seen great application as

electrolytes for batteries.76-78, 95-96 Though there is little representation in

the literature of the salt being used in terms of synthetic chemistry.

Various glymes as solvents have proven their use in their own right, with

examples including use as solvents in the preparation of biodiesel.97-98

They exhibit high boiling points, are miscible in both water and organic

solvents and offer a green alternative to traditional solvents due to being

largely chemically inert as well as maintaining high thermal stabilities,

relatively low vapour pressure and low toxicity. These desirable solvent

characteristics open a wide array of applications at which they excel,

including as a reaction media, extraction solvents, in gas purification, and

of course use in solvation of cations.16, 97, 99

Applications of SILs

Ionic liquids as reaction mediums for organic transformations are already

well-established in the literature, with many reviews available detailing

their use.14, 36, 38, 74 Further to this, ILs are typically used in conjunction

with microwave irradiation as they require much less energy to be heated

21

to a given temperature than traditional, molecular solvents (5-7 Watts

compared to 200 W).100 The same is true for solvate ionic liquids.

In addition to the use as solvents, is the ability to attach these ionic

moieties to organic scaffolds, such as organocatalysts.101-105 In doing so,

the desirable attributes of both ionic liquid and organocatalyst are

combined in one, convenient compound. This holds many benefits

including increasing the efficiency and recyclability of the organocatalyst

as well as altering the melting point of the compound. Ionic liquid tagged

organocatalysts will be presented in more detail in Chapter 5.

At the time of writing this thesis, only one study106 was present in the

literature (published during the course of the authors’ study, 2017) for the

application of these SILs in an organic reaction (excluding publications

stemming from this project).

Juaristi and co-workers report a highly efficient, and stereoselective

asymmetric aldol reaction when using (S)-proline in conjunction with

solvate ionic liquids (Table 2.2, below).106 The solvates explored are both

the [Li(G3)]TFSI and [Li(G4)]TFSI, as well as the perchlorate versions; the

[Li(G3)]ClO4 and [Li(G4)]ClO4. It should be noted that [Li(G3)]ClO4 is

reported as a solid (mp 103 °C),16, 88, 90, 106 and [Li(G4)]ClO4 is considered

a concentrated solution, rather than a solvate ionic liquid, due to the

excess of free glyme (~20%) in the system.16

Nevertheless, these particulars are of little consequence due to the

greater performance exhibited by the TFSI- anion varietals compared to

the ClO4- versions (Table 2.2). It was found that an equimolar mixture of

SIL and (S)-proline employed at 3 mol% with 1 equivalent of water was

the optimal conditions for the aldol reaction to take place, at ambient

temperature for 14 hours.106

22

Table 2.2 Evaluation of various SILs and blanks in the model aldol reaction.106

Entry SIL Yield (%)a dr (anti:syn)b er (anti)c

1 [Li(G3)]TFSI 94 94:6 98:2

2 [Li(G4)]TFSI 96 90:10 96:4

3 [Li(G3)]ClO4 84 93:7 98:2

4 [Li(G4)]ClO4 87 89:11 94:6

5d - 18 64:36 88:12

6 - 67 82:18 92:8 a Isolated yield. b Determined by 1H NMR spectroscopy from the crude reaction. c

Determined by HPLC with chiral stationary phase. d No water added, 24 h of reaction.

Employing [Li(G3)]TFSI with (S)-proline exhibits an excellent yield (94%),

dr (94:6) and er (98:2) in the aldol reaction between cyclohexanone 2.4

and 4-nitrobenzaldehyde 2.12 (Entry 1, Table 2.2). The yield is slightly

improved (96%) with the use of the tetraglyme counterpart, [Li(G4)]TFSI,

though both the diastereomeric ratio and enantiomeric ratio suffer (Entry

2, Table 2.2). This leads to the conclusion that, despite a slight reduction

yield, [Li(G3)]TFSI is the better performing SIL.

[Li(G3)]ClO4 gives the worst yield of all the additives (84%, Entry 3, Table

2.2), though does see an improvement in dr (93:7) when compared to

[Li(G4)]TFSI (90:10), and the same er as [Li(G3)]TFSI (98:2). This may

suggest some conformational benefit of the triglyme over the tetraglyme,

as [Li(G4)]ClO4 lead to worse dr and er, but a slight increase in yield

(87%, Entry 4, Table 2.2).

To give these results context, the reaction was repeated without the

addition of any SILs or water (Entry 5, Table 2.2). This instance shows, as

expected, the lowest yield (18%), diastereomeric and enantiomeric ratios

(64:36 and 88:12, respectively), and an increase in reaction time to 24

hours. Immediate improvement is observed with the addition of 1

23

equivalent of water, with higher yield (67%) and better dr and er (82:18

and 92:8, respectively, Entry 6, Table 2.2).

It is worth noting that the comparisons made here are of isolated yields

and not between conversions to product. This is pertinent in that isolated

yields are affected by conversion as well as isolation efficiency.

Unfortunately, conversion percentages were not reported.

The stereoselective advantage of [Li(G3)]TFSI in this aldol reaction is

proposed to be the formation of a supramolecular aggregate between the

SIL and (S)-proline (Figure 2.11).

Figure 2.11 Optimized structure of the (S)-proline-[Li(G3)]TFSI catalyst by ADFT, showing the supramolecular aggregate (aliphatic hydrogens not shown in simplified structure adapted from reference, right).106

This structure is supported by both 7Li NMR and IR spectroscopic

methods,106 and the transition state of the supramolecular ensemble

containing ketone, aldehyde, water and the (S)-proline-[Li(G3)]TFSI

complex is also modelled (Figure 2.12).

Figure 2.12 Supramolecular ensemble of cyclohexanone, benzaldehyde, water, (S)-proline and [Li(G3)]TFSI (aliphatic hydrogens not shown in simplified structure adapted from reference, right).106

The complex (Figure 2.12) shows the 1 equivalent of water acting as a

bridgehead between the carbonyls of the ketone and aldehyde.106 The

24

implication of benzaldehyde, rather than 4-nitrobenzaldehyde as used

throughout the majority of the study is not commented on.

The effect of [Li(G3)]TFSI in this aggregation is observed to be specific for

SILs, as a comparison is conducted with a traditional IL; [Bmim]PF6 and

one without any ionic species present.106 This is also explored in the

context of electron withdrawn, neutral and electron donating aldehydes

with cyclohexanone.

In every case examined, [Li(G3)]TFSI was the best performing example

with higher yields and diastereomeric and enantiomeric ratios. The best

results obtained of the three types aromatic aldehydes were those that are

electron withdrawn, as may be expected. Further demonstrating the

requirement for the SIL complex, is the poor result obtained when using

the lithium carboxylate of (S)-proline as the catalyst, or just the LiTFSI.

That work demonstrates the advantage of SILs in an organic

transformation, over a traditional IL ([Bmim]PF6), [Li(G3)]ClO4 or

[Li(G4)]ClO4. The latter proves the requirement for the solvation of the

lithium cation, as it has been defined as a concentrated solution.16

SILs as Electrolytes for Li+ ion Batteries

Solvate ionic liquids, particularly those containing Li+ salts, hold much

allure for battery production.15, 18, 89, 107-112 The ability to reduce the relative

safety concerns of using lithium electrolytes, whilst maintaining a high

ionic conductivity is very attractive. When this is coupled with the

negligible vapour pressure, the result is glyme-based electrolytes that can

be used in hermetically sealed devices, as well as those that are open to

the environment such as LiO2 batteries. Previously, solvate-like

electrolytes containing the LiTFSI salt could be reduced to as little as

51.4% of its original mass when left in a dry box, under a flow of argon at

25 °C in 11 days.92 This fact is remedied when the salt is chelated in the

triglyme or tetraglyme, reducing the vapour pressure to virtually non-

existent, and reducing (if not removing) the evaporation of the solvent.

The advantages exhibited by these solvate ILs, coupled with its high

thermal and electrochemical oxidative stabilities, wide potential window,

25

high ionic conductivity and high Li+ transference number, make these

solvents ideal candidates for use as battery electrolytes as observed in

the literature.75, 113

At the initiation of this project, no literature existed examining these SILs

in relation to their application in organic synthesis, and in that respect this

project is completely novel in its investigations. Despite this, there is a

similar solvent system that will be a point of comparison for this project.

5.0 M Lithium Perchlorate in Diethyl Ether (LPDE)

The closest relative to solvate ionic liquids in this work is 5.0 M lithium

perchlorate in diethyl ether (5.0 M LPDE, Figure 2.13), and similar to the

LiTFSI salt, the LiClO4 salt has been shown to be a good electrolyte for

battery systems.76, 114-119

Figure 2.13 Comparison of the [Li(G3)]TFSI, [Li(G4)]TFSI (left) and 5.0 M Lithium Perchlorate in Diethyl Ether (5.0 M LPDE, right). Simplified structures shown.

The use of an ethereal lithium perchlorate medium for organic

transformations, specifically Diels-Alder reactions, was first recommended

in 1986,120 though the first published example didn’t appear until 1991.121

From that point on, 5.0 M LPDE held prominence as an additive for

organic transformation in the literature until the early 2000s. It was

deemed too difficult to work with, as the production of this solvent required

the use of completely anhydrous reagents due to the hydrate of LiClO4

having no appreciable solubility in Et2O.122 The process often requires

multiple purification/drying procedures including heating (potentially

explosive) LiClO4 to 160 °C for up to 8 hours.123 Understandably, this

became quite tedious due to the high hygroscopicity of both reagents, the

danger associated with the explosive nature of perchlorates and high

26

flammability of Et2O. The persistent risk of explosion caused the solvent to

fall out of favour in the early 2000s.

The mechanism through which the 5.0 M LPDE accelerates organic

transformations has been a source of controversy. Grieco et al.121 and

Kumar124 attribute this to a high degree of internal pressure created by

solubilising LiClO4, and studies of [1,3]-sigmatropic rearrangements,125

ene,126 aldol,127 Michael,128 Mannich, [2+2] cycloadditions129 and Diels

Alder130 reactions have ensued to that end. Faita et al.131 stated that small

rate enhancements (up to 10 times) may be derived from internal

pressure, but much larger effects (102 to 105) are due to Lewis acid

activation. This is supported by the finding that [4+2]-cycloadditions

specifically benefit from a multi-activation process of both Lewis acid

activation and increased pressure.132

The notion of internal pressure influencing product selectivity was

disproved in the Diels-Alder reaction of (E)-1,3-pentadiene and methyl

acrylate, correlating the proposed benefits of this system to be derived

from the Lewis acidic nature of the lithium.133 This later explanation seems

to be agreed upon as more influential in the success of the reaction

medium’s application.131, 134-136

Being of such a similar construction as the solvate ionic liquids that are

the focus of this project (LiTFSI solvated in either triglyme or tetraglyme),

it is logical to explore the organic reactions that are already reported in 5.0

M LPDE, as a direct comparison. If the SILs in this project offer

comparable or better results as those seen in 5.0 M LPDE then these

SILs provide access to this class of catalysis again, without the limitations

of hygroscopic nature, potential explosion risk, and the added benefit of

ease of preparation and storage.

Pericyclic reactions in 5.0 M LPDE

Pericyclic reactions occur via a concerted process, involving a cyclic

transition state. Such reactions are immensely useful in terms of synthetic

chemistry. Pericyclic reaction types performed in 5.0 M LPDE include

27

[2+2] cycloadditions,129 [2+3] cycloadditions,137 [1,3]-sigmatropic

rearrangements of allyl vinyl ethers,125 ene reactions,138 as well as Diels-

Alder reactions. In the interest of remaining concise, only the later will be

explored in any real detail, though a thorough and broad review the uses

of 5.0 M LPDE provides detail on aforementioned reactions as well as

others.23

Diels-Alder reactions in 5.0 M LPDE

Diels-Alder reactions are [4+2] cycloadditions that increase the

complexity, or three dimensionality of a molecule. First reported in 1928,32

the Diels-Alder reaction has remained the first port of call for ring

formation. Despite the success of these reactions in organic synthesis,

some reagents are unable to be employed in this type of reaction due to

the requirement of an electron-rich diene and an electron-deficient

dienophile (Figure 2.14). This may be due to the reduced reactivities of

reagents, however this can be circumvented by increasing the reaction

temperature or pressure, the use of alternate solvents, or most relevant to

this report; the use of Lewis acid catalysts, the mechanism through which

5.0 M LPDE has been suggested to operate.

Figure 2.14 Example of Diels-Alder reaction between an electron-rich diene and an electron-deficient dienophile. EWG = electron-withdrawing group.

The methods of improving the outcome of this reaction do have their own

inherent drawbacks. Diels-Alder reactions are heavily governed by

reactant electronics and so Lewis acid catalysis can be employed to

achieve or enhance the desired electronics. High temperature may cause

cycloreversion, rather than the cycloaddition, and the possibility of side

reactions is also increased.139 Many investigations have been undertaken

to improve the conditions of Diels-Alder reactions, with advancement via

the application of 5.0 M LPDE as the solvent choice for both inter- and

intramolecular Diels-Alder reactions.

28

Intermolecular Diels-Alder reactions

Grieco et al.140 first reported the use of 5.0 M LPDE as a solvent to greatly

improve the outcome of typically difficult reagents to undertake this kind of

transformation (Scheme 2.5). This study involved the combination of

dienophiles and 1 equivalent of diene or azadiene (Scheme 2.5) at

ambient temperature and pressure, resulting in good yields and high

endo/exo ratio of the cycloadduct products.

Scheme 2.5 Diels-Alder reaction conducted in 5.0 M LPDE.140

The advantage of employing this reaction medium was first realised in the

[4+2] cycloaddition of ethyl acrylate 2.15 and cyclopentadiene 2.14, giving

a yield of 93% in only 5 hours (compared to up to 30 hours141) with an an

endo/exo ratio of 8:1 (Scheme 2.5). To give context to this result, an

identical reaction was carried out in water, giving 73% and only 4:1

endo/exo ratio. Controlling the three-dimensional geometry of the reaction

outcome of Diels-Alder reactions has been a challenge since their first

report and continues in the literature.142

The use of 5.0 M LPDE has shown marked improvement over non-

catalysed reactions. This is demonstrated by reduced reaction times

(Reaction A, Scheme 2.6) and improved yields (Reaction B, Scheme 2.6).

An exceptional example is the formation of 2.23, which, when conducted

in water results in a <20% yield in 24 hours (Reaction C, Scheme 2.6).

This poor result is decisively improved with the replacement of water with

5.0 M LPDE, increasing the yield to 80% in only 15 minutes.

29

Scheme 2.6 A series of reactions improved by the use of 5.0 M LPDE as a solvent and the comparison to previous reports. [a] Reported reaction.143 [b] Reported reaction.144 [c] Reported reaction.140

To further demonstrate the advantage of 5.0 M LPDE as a solvent, the

use of furans were investigated. Furans typically react poorly in Diels-

Alder reactions due to the stability afforded through the aromatic nature of

the compounds and often require pressures of 10–20 kbar to facilitate

cycloaddition.145 Dauben et al.146 reported the Diels-Alder reaction

between furan 2.24 and dienophile 2.25, requiring 1.2 equivalents of

furan, 6 hours and 15 kbar of pressure in dichloromethane giving 100%

conversion and 85:15 endo:exo selectivity. When conducted in 5.0 M

LPDE at ambient temperature and pressure, the reaction proceeded in 9.5

hours, delivered a 70% yield with the same stereochemical selectivity

(Scheme 2.7).

Scheme 2.7 Diels-Alder reaction of furan employing 5.0 M LPDE as the solvent.146

It should be noted, that despite the marginally increased reaction time (6

to 9.5 hours) and the slightly depressed yield, the absence of increased

pressure is a substantial advantage of this system over traditional

solvents, as this type of transformation becomes accessible to a wider

30

array of chemists. Furthermore, the original manuscript failed to report an

isolated yield for the reaction, only conversion by NMR, which is rarely

equal to the actual amount of product isolated. This is an important point

as the ease of isolation of desired products is paramount to obtain useful

amounts of compound.

Grieco et al.22 also demonstrated the ability of 5.0 M LPDE to enhance the

diastereofacial selectivity in the Diels-Alder reaction between maleic

anhydride and diene 2.27 observed in traditional organic solvents

(Scheme 2.8). The reaction proceeds in 3 hours, with a yield of 99% and

an endo:exo selectivity of 15.5:1 (2.28a:2.28b).

Scheme 2.8 Diels-Alder reaction demonstrating improved diastereofacial selectivity achieved by use of 5.0 M LPDE.22

Intramolecular Diels-Alder reactions

Similar to the intermolecular Diels-Alder transformations, the

intramolecular variety often require elevated temperature and/or pressure

coupled with extended reaction times to induce successful outcomes.147 In

addition to this, there is a persistent limitation being that intermolecular DA

reactions can still occur in these systems as a competing side reaction to

the desired internal annulation.

To demonstrate the benefit of using 5.0 M LPDE as the reaction medium,

Grieco et al.148 explored the use of 5.0 M LPDE to facilitate the

intramolecular Diels-Alder transformation of 2.29 to 2.30 (Table 2.3).

When using benzene, the reaction requires substantial heating (140 °C)

and 15 hours to obtain a mixture of 2.30a and 2.30b (2:1) though in good

yield of 84% (Entry 1, Table 2.3). An immediate improvement is observed

when the solvent is exchanged for 5.0 M LPDE. Though the reaction does

take a little longer (24 h compared to 15 h), the yield is excellent (95%),

31

with much lower temperature (25 °C) and an improved diastereomeric

preference for the cis product 2.30a (12:1, cis:trans, Entry 2, Table 2.3).

This increase in diastereoselectivity may be due to the reduction in

temperature compared to when benzene is used. The addition of 1.0

mol% camphorsulfonic acid proves further advantage, with even shorter

reaction time (4 h) again at 25 °C, with only the cis product 2.30a obtained

(Entry 3, Table 2.3). The only drawback is that the yield is reduced

compared to the previous example (78% down from 95%), though it is still

comparable to the original example of benzene, and the isolation of only

2.30a may be considered an excellent result.

Table 2.3 Intramolecular Diels-Alder reaction assisted by 5.0 M LPDE.148

Entry Solvent Time

(h)

Temperature

(°C)

2.30a:2.30b

(cis:trans)

Yield

(%)

1 Benzene 15 140 2:1 84

2 5.0 M LPDE 24 25 12:1 95

3 5.0 M LPDEa 4 25 1:0 78

a 1 mol% camphorsulfonic acid.

Replacement of diene 2.29 with the structurally similar 2.31 and

increasing the loading of CSA to 10 mol% results in a tricyclic structure

(2.32) in the same reaction time, although with slightly depressed yield

(64%).149 It can be seen from this comparison that the position of the

diene unit results in tandem diene migration – [4+2] cycloaddition.

32

Scheme 2.9 Intramolecular Diels-Alder reaction performed in 5.0 M LPDE using camphorsulphonic acid (CSA).149

The diversity of reactants positively affected by the use of 5.0 M LPDE is

further exemplified through the intramolecular Diels-Alder reaction of

nitrotriene 2.33.150 The reaction proceeds in 24 hours and at ambient

temperature with a respectable yield of 70% of only the anti-stereoisomer

(from endo selectivity). This outcome is derived from the reaction

proceeding only through the anti- conformation transition state, due to

both electronic and steric effects (Scheme 2.10).

Scheme 2.10 Intramolecular Diels-Alder reaction of a nitrotriene performed in 5.0 M LPDE.150

33

Project Overview

This project investigates the use of recently discovered solvate ionic

liquids (SILs) as potential replacements for molecular solvents in synthetic

organic reactions. These new SILs are obtained when dissolving an

equimolar amount of lithium bis(trifluoromethylsulfonyl)imide (LiTFSI) salt

in either triethylene glycol dimethyl ether (triglyme, G3) or tetraethylene

glycol dimethyl ether (tetraglyme, G4). The resulting complexation of the

lithium cation by either the triglyme or tetraglyme compounds are referred

to as [Li(G3)]TFSI or [Li(G4)]TFSI, respectively.

Previously, these ionic liquids have only been established in the literature

as electrolytes for batteries15, 17, 42-43, 151-152 and no evidence of use in

organic chemistry was present when this project commenced.

The expanse of organic reactions that may be attempted in these solvents

is broad. However, this can be reduced by first determining the basic

characteristics of these solvents such as the hydrogen-bond donating and

accepting abilities, polarity and Lewis acid attributes they may possess.

Once these qualities were assessed, this new solvent system was

grouped among traditional solvents and even compared to traditional ionic

liquids.

Although there have been no examples in the literature of these new

solvate ILs in organic reactions, previous success with 5.0 M lithium

perchlorate in diethyl ether (5.0 M LPDE) will be used as a guide. First

finding use in the early 1990s,140 this medium was used to effect a wide

range of organic transformations, with great success.23 Organic

transformations performed in this solvent were achieved at lower

temperatures, lower pressures and in shorter reaction times than

previously published, and in some cases greater yields. The 5.0 M LPDE

has a very similar structure to SILs; both are chelated salts (to some

degree in the case of 5.0 M LPDE) in an ethereal solvent, and have a

charge diffuse cation. The major difference between these solvents is the

anion group, which incidentally is the main reason for the discontinued

34

use of 5.0 M LPDE, due to the highly explosive nature of the perchlorate

moiety, and practical limitations handling this material (hygroscopicity,

precipitation, etc.).

The combination of the solvent parameters and the literature examples of

organic reactions performed in 5.0 M LPDE, served as a guide to

advocate reactions that were most likely to benefit from these solvents.

This project also involved the design, synthesis and evaluation of an ion-

tagged organocatalyst, based on the trans-4-hydroxy-(S)-proline scaffold.

The ability to catalyse the asymmetric aldol reaction in a variety of

solvents, and across a range of substrates was used as a point of

comparison to previously published examples. To explore the diversity of

application, a second reaction system was evaluated, the 1,4-Michael

addition. Further to this, the effect of the anion on catalytic activity was

examined, as will the potential of recycling the catalyst.

Aims

1. Determine solvent descriptors (solvation abilities, Kamlet-Taft

parameters, Gutmann Acceptor Numbers) for solvate ILs and their

constituents at room temperature.

2. Establish the ability of the [Li(G3)]TFSI and [Li(G4)]TFSI ionic

liquids as a reaction media for organic transformations using 5.0 M

LPDE as a guide. This will take the form of Diels-Alder

electrocyclisations and the synthesis of α-aminophosphonates.

3. Design and synthesise an ion-tagged organocatalyst, based on the

trans-4-hydroxy-(S)-proline scaffold.

4. Evaluate this catalyst in a variety of reaction conditions and types,

as well as the effect of the anionic component of the imidazolium

tag on catalytic activity.

35

Project outcomes

Successful completion of this project resulted in the identification and

reporting of the basic characteristics of a new solvent system for organic

transformations. This has impact on the chemistry community by exposing

the application of a green alternative to many harsh solvent choices

currently available, including 5.0 M lithium perchlorate in diethyl ether

(LPDE) and its associated safety concerns. The organic reactions

assessed in the SILs were guided by the previous success of 5.0 M

LPDE, which had a significant impact in terms of synthetic chemistry and

the great improvement on reaction conditions and outcomes, despite the

dangers associated with its use. It was also the aim of this project to

scope beyond previous reactions, proving the solvate ILs to be an

invaluable resource.

This work with solvate ionic liquids led directly to 3 publications,153-155 and

one under review at the time of submission. Multiple subsequent

publications have also stemmed from this project, and the work of the

author, though are not featured in this thesis. Thgese include one on the

toxicity of these SILs in zebrafish,156 and their application for drug storage

and delivery for this same species.157 Another publication investigates the

use of [Li(G3)]TFSI as a potential sizing agent for carbon fibres in

composites.158

Another outcome of this project was the concise synthesis of an ion-

tagged organocatalyst, which was tested in a range of reaction conditions.

It was found to have good catalytic activity, and demonstrated to catalyse

the asymmetric aldol reaction as well as 1,4-Michael addition. The effect

of the anion on catalytic activity was evaluated, with the PF6- anion

proving to be advantageous. This work also resulted in a publication.159

36

37

– Characterisation of SILs

Introduction

Solvents are typically used for a specific purpose due to their individual

properties, whether they be organic, or inorganic. This is also true for ILs

which are commonly referred to as task-specific which are able to be

tailored for a given requirement.14 In light of this, it is pertinent to examine

the properties of solvents, including polarity/polarizability, hydrogen

bonding ability, and Lewis acidity. In determining these characteristics, the

new solvent can be grouped, somewhat arbitrarily, with similar solvents

which may suggest potentially suitable applications. The methods and

parameters of determining these characteristics are outlined in the

following.

Kamlet-Taft Parameters

Sometimes referred to as solvatochromic parameters, the Kamlet-Taft

parameters are determined spectrophotometrically via the addition of

different dyes to solvents and subsequent UV-visible spectroscopy.26 The

scale is based on linear solvation energy relationships (LSER) consisting

of three complimentary solvent characteristics. These are the hydrogen-

bond donating and accepting abilities (α and β values, respectively) and

polarity/polarizability (π* values). Also determined is the ET(30) (solvent

polarity and the ETN (normalised against water solvent polarity) from

Reichardt’s dye.

This technique has previously been employed in molecular solvents,26-28

in non-aqueous binary mixtures of organic solvents,160 as well as for ionic

liquids.161-163 In addition to the key characteristics that can be investigated

through this technique, is the reactivity of anionic nucleophiles in ionic

liquids.164 All solvents must be appropriately anhydrous when employing

this techniques, to reduce any convolution of results.

38

Details regarding the calculation, acquisition and analysis of each these

values will be provided in the Results and Discussion section of this

chapter.

One especially pertinent example is present in the literature relative to the

work presented here, though was published during the author’s

candidature (June, 2016), and after the work described in this chapter was

already published by the author (April, 2016).

Dolan et al.165 examined the Kamlet-Taft parameters of solvate ionic

liquids of varied anions and ethereal units. The glycols were either

triglyme (G3), tetraglyme (G4), triethylene glycol (E3) or tetraethylene

glycol (E4). These last two glycols (E3 and E4) are effectively the same as

the glymes, though terminate at each end with alcohol moieties, rather

than methyl ethers. These glycols are stated to be explored to determine

the effect of acidic protons on the solvent properties of SILs.165 The suite

of SILs consisted of lithium salts with anions as follows; TFSI-, BETI-, OTf-,

NO3-, and TFA-.

It is worth noting at this point, that of all the glyme and anion combinations

examined in that work, only 4 are confirmed solvate ionic liquids ([Li(G3

and G4)]TFSI, and [Li(G4)]BETI, [Li(G3)]BETI is technically a SIL, though

has a melting point of 74 °C).88 All others, as discussed earlier in this

thesis, are described as concentrated solutions (or poor SILs, though the

former term is more accurate).16 Triethylene (E3) and tetraethylene glycol

(E4) have not been investigated in relation to solvate ionic liquids.

Considering this, and in the interest of brevity, only those that are reported

SILs (and their glycol counter parts), will be discussed here.

The dyes used to determine the Kamlet-Taft parameters are traditionally

N,N-diethyl-4-nitroaniline, 4-nitroaniline and Reichardt’s dye (described in

greater detail later in this chapter). Burgess’ dye may be used in place

Reichardt’s dye, if the latter is not sufficiently soluble in the given solvent,

as was the case for Dolan et al., except for the glyme and glycol solvents

(values in parenthesis are from Reichardt’s dye, Table 3.1).165

39

Table 3.1 Kamlet -Taft parameters of selected solvate ionic liquids by Dolan et al.165

Solvent α β π*

G3 0.16 (0.10) 0.62 0.74

G4 -0.17 (0.03) 0.72 0.68

E3 0.54 (0.57) 0.70 0.90

E4 0.38 (0.49) 0.66 0.96

[Li(G3)]TFSI 1.03 0.30 0.96

[Li(G4)]TFSI 0.77 0.24 0.92

[Li(E3)]TFSI 0.91 0.29 1.22

[Li(E4)]TFSI 1.06 0.28 1.09

[Li(G3)]BETI 0.88 0.32 0.84

[Li(G4)]BETI 0.80 0.36 0.86

[Li(E3)]BETI 1.16 0.21 1.18

[Li(E4)]BETI 0.94 0.20 1.07

Values in parenthesis are determined by Reichardt’s dye.

Looking first at the α values (hydrogen bond donating), the tri- and

tetraglyme exhibit negligible values, as is anticipated judging from their

structures and lack of acidic protons. There is a marked increase in

hydrogen bond acidity when examining the glycol solvents E3 and E4,

which is due to the absence of the terminal methyl groups in these

structures compared to those of the glymes.

An unexpected result is the high α values for the SILs in all glyme and

glycols. This is attributed to the Lewis acidity of the chelated lithium

cation, which was echoed in the findings of the author’s research, and

confirmed with molecular dynamics (discussed later in this chapter).

Interestingly, there does not seem to be a compounding effect of the

Lewis acidity (pseudo-hydrogen bond donating) of lithium and the acidic

protons of the glycol solvents E3 and E4.

40

The β values (hydrogen bond accepting ability) of the solvents also

demonstrated the effect of chelation of lithium by the glyme/glycol units, in

that the observed values of the SILs are comparatively lower than those of

the glyme/glycol solvents on their own. This reduced hydrogen bond

accepting ability of the solvents is caused by the electrons of the ethereal

oxygens being engaged with the lithium, and therefore unavailable for

other hydrogen bonding entities. Again, these results are similar to those

found in the author’s research.

Finally, the π* (pi-star) values (polarity/polarizability) are the ability of the

solvent to stabilise charge or become polarised. It would then follow that

ionic compounds, like SILs, should have higher values than the solvating

solvents themselves, which is consistent with the findings above, as well

as the author’s own research.

Discussed in this chapter is a description of the method of determining the

Kamlet-Taft parameters, as well as the findings and conclusions of these

results. The values presented by Dolan et al.165 are slightly different than

those found in this work, though this due to the use of different dyes, and

the somewhat arbitrary nature of this method. Nonetheless, the trends

observed are the same.

Gutmann Acceptor Number

Further to the polarity and hydrogen bonding abilities of these solvate ILs,

is the potential of the lithium cation, attenuated as it is, to act as a Lewis

acid (LA). A Lewis acid is a chemical entity able to accept electrons from

an electron donor (Lewis base), often an ionic or positively charged

species, and the combination of both results in a Lewis adduct.166 Many

organic reactions are promoted by incorporating a Lewis acid species,

often added to a reaction mixture, not intrinsic to the solvent. Coordination

with electron-rich oxygen of a functional group may serve to increase the

probability of nucleophilic attack in the proximate atoms (alpha or beta

carbons, Scheme 3.1).167

41

Scheme 3.1 Activation of the β carbon via Lewis acid activation by AlCl3.167

The degree of Lewis acidity may be quantitatively measured though the

determination of the Gutmann Acceptor Number. First described by Mayer

et al. in 1975,30 this method employs 31P NMR to monitor the change in

chemical shift of the phosphorus atom in the Lewis base triethylphosphine

oxide (Et3P=O) in relation to solvents of differing Lewis acidity (Figure

3.1). Triethylphosphine oxide is used as the alkyl groups promote

solubility in a wide range of solvents.

Figure 3.1 Interaction of a Lewis acid (LA) with triethylphosphine oxide (Et3P=O).

The equation for the calculation of AN is derived from the scale proposed

by Mayer et al. with heptane (non-Lewis acidic) as zero and antimony

pentachloride in 1,2-dichloroethane (DCE, strongly Lewis acidic) as 100.30

Solvents may then be ranked on this scale by taking the corrected value

(relative to heptane) over the corrected value of antimony pentachloride in

DCE (δ42.58) and multiplying by 100. This is equivalent to multiplying the

original corrected value by 2.348 (Equation 3.1).

=∆ ( )

∆ ( ∙ )× 100 =

∆ ( )

42.58× 100 = ∆ × 2.348 (3.1)

The electron pair of the oxygen of the oxygen-phosphorus bond donates

to the Lewis acid, thereby reducing the bond order of the phosphorus-

oxygen double bond. This results in increasing the dipole moment (its δ+

charge), and alters the chemical shift of the phosphorus atom, shifting it

downfield (to the left) in the 31P NMR spectra. The magnitude of shift in

42

the 31P spectra caused by the Lewis acid is proportional to the Lewis acid

strength.

The Lewis acid:Lewis base ratio is 3:1 (LA to Et3PO) to ensure complete

saturation of the P=O bond, and a non-Lewis acid solvent (heptane)

serves as the ‘zero’ from which the change in ppm of other solvents are

measured against. This methodology has been employed in relation to

many compounds of different molecular character, including solvents and

individual compounds (Table 3.2).168-172

Table 3.2 Gutmann Acceptor Numbers of different Lewis Acids.168-172

Lewis Acid Gutmann Acceptor Number

Hexane 0

Acetone 12.5

Methanol 41.3

AlCl3 87

TiCl4 70

SnCl4 59

As mentioned earlier, the effect of the glyme attenuating the otherwise

hard lithium cation is a factor in causing the resulting complex to exist in a

liquid state at low temperatures. This also serves to soften the Lewis

acidity of the now charge-diffuse cation, which has been shown to benefit

some organic reactions such as the Baeyer-Villiger oxidation of ketones to

esters or lactones.173 A similar effect is seen in molecular compounds

through the addition of electron-withdrawing or donating groups to

increase or decrease Lewis acidity respectively.171-172 Additionally, similar

studies have demonstrated this ability to tune acidity in ionic liquids.174

43

Determining the Kamlet-Taft Parameters of SILs

α Values – Hydrogen Bond Donating Ability

The hydrogen bond donating ability of a solvent is an important aspect

when establishing the types of reactions or applications that may be

suited to that solvent. The method of determining a solvents α value in

relation to the Kamlet-Taft parameters requires the use of two dyes with

contrasting hydrogen bond abilities; Reichardt’s Dye and p-nitroanisole

(Figure 3.2). These dyes were used as they are the most commonly used

in the literature,26-28 and no solubility issues were found with SILs in this

project.

Figure 3.2 Dyes used in calculating α values of solvents; Reichardt's Dye and p-nitroanisole.

The dyes are separately dissolved in sub-millimolar concentration in

solvents that are unable to provide hydrogen bonds. In this case the

solvents are tetrahydrofuran (THF), dimethylformamide (DMF), 1,2-

dichloroethane (DCE), and ethyl acetate (EtOAc). From here, the samples

are spectroscopically analysed using UV-Vis Spectroscopy to determine

the wavelength at which maximum absorbance is achieved (vmax). This

value, in nanometers, is then converted to kiloKaisers according to

Worked Example 3.1 (data shown in Table 3.3).

1 = 1000 If = 400 = 400 × 10

1400 × 10

= 2 500 000

2 500 000 100

= 25 000 = 25 ∴ 400 = 25

44

Worked Example 3.1 Unit conversion from nanometers (nm) to kiloKaisers (kK).

Measurement of these dyes in solvents previously mentioned gave the

values presented in Table 3.3, which agreed very well with the literature

values (in grey).

Table 3.3 Wavelength of maximum absorbance of dyes in a variety of solvents, conversion of units to kiloKaiser (kK) and comparison to literature values.168-172

Solvent

Dyes

Reichardt's Dye p-nitroanisole

vmax kK Lit. (kK) vmax kK Lit. (kK)

THF 762.80 13.11 13.08 305.33 32.75 32.79

DMF 659.07 15.17 15.31 313.67 31.88 32.05

DCE 691.00 14.47 14.65 310.13 32.24 32.36

EtOAC 746.40 13.40 13.32 303.13 32.99 32.79

MeOH 518.67 19.28 19.04 305.60 32.72 32.79

[Li(G3)]TFSI 446.60 22.39 312.40 32.01

[Li(G4)]TFSI 445.47 22.45 311.73 32.08

[Bmim]TFSI 573.93 17.42 308.20 32.45

Triglyme 706.87 14.15 308.93 32.37

Tetraglyme 716.33 13.96 309.13 32.35

These values for each of the dyes are plotted against each other and a

line of best fit generated Graph 3.1, a representation of non-hydrogen

bonding solvents and their predicted absorbance. With this data obtained,

a measurement of a solvent with a strong hydrogen bond donating ability

(in this project, methanol; MeOH) is carried out according to the same

method, and subsequently plotted on the same graph. As can be seen

from Graph 3.1, MeOH falls far from this line, due to it being a very strong

hydrogen bond donor. The magnitude of the deviation from this line is

proportional to the hydrogen bond donating capacity, α.

Up to this point, all data has correlates very well with the reported

literature values, which is confirmation of the technique and methods

being used. This data point is then used as a reference to determine the

amount of hydrogen bond donating ability of the desired solvent relative to

45

MeOH. This is done by calculating the distance of the data point of MeOH

from the line generated by the non-hydrogen bonding solvents using its

equation, and comparing the distance of an unknown to this value.

Conducting the same measurements with the [Li(G3)]TFSI, [Li(G4]TFSI,

[Bmim]TFSI and the two glymes themselves found the maximum

absorbance of each (Table 3.3), and the subsequent plotting on Graph

3.1.

Graph 3.1 Distribution of absorbance data in relation to Reichardt's dye and p-nitroanisole in kiloKaisers (kK).

The α values were determined for both [Li(G3)]TFSI and [Li(G4)]TFSI

ionic liquids, as well as the tri- and tetraglymes on their own (Table 3.4).

Determination of the α value of a common ionic liquid [Bmim]TFSI was

carried out, to compare the values of the ionic liquids, as well as to ensure

correct technique was used by comparison to literature values. The anion

was kept consistent to increase the comparability of the ionic liquids’

Kamlet-Taft parameters.

y = -1.8225x + 73.208R² = 0.9016

10.00

12.00

14.00

16.00

18.00

20.00

22.00

24.00

26.00

31.50 32.00 32.50 33.00

Reic

hard

t's D

ye (k

K)

p-nitroanisole (kK)

Solvents

MeOH

[Li(G3)]TFSI

[Li(G4)]TFSI

[Bmim]TFSI

Triglyme

Tetraglyme

~ 5.7 kK

~ 7.7 kK ~ 7.5 kK

46

Table 3.4 α values of solvents.

Entry Solvent ΔkK values α value

1 MeOH 5.71 1.00

2 [Li(G3)]TFSI 7.52 1.32

3 [Li(G4)]TFSI 7.70 1.35

4 Triglyme -0.07 -0.01

5 Tetraglyme -0.29 -0.05

6 [Bmim]TFSI 3.35 0.55[a]

[a]Literature value = 0.61164, 175

Methanol is given the arbitrary value of 1.00 (Entry 1, Table 3.4) as this is

the standard against which the others are measured. The two solvate ILs,

[Li(G3)]TFSI and [Li(G4)]TFSI (Entry 2 & 3, Table 3.4), have α values of

1.32 and 1.35, respectively. They exhibit greater hydrogen bonding ability

than that of MeOH, despite the absence of acidic protons. This initially

was a source of confusion, and multiple attempts were made to improve

the measurement, all with the same result. The consistency of the result,

along with some other methods (detailed below) revealed the possibility of

the lithium cation acting as a surrogate proton donor, thus giving the

strongly positive result. The hydrogen bond donating ability of these ILs is

due to their Lewis acidity, which is essentially is the ability of a species to

accept electrons, much like a hydrogen bond, but stronger. This result

was supported by molecular dynamics simulation carried out by

collaborator Professor Tiffany Walsh (Figure 3.3).

The molecular dynamics simulation supports the hypothesis of the ability

of the chelated lithium to interact with Reichardt’s Dye, giving the apparent

high value for apparent hydrogen bond donation. Not shown is the

tetraglyme unit, for the sake of clarity. In short, the solvated Li+ cation is

behaving similar to the hydrogen of a protic solvent bearing a δ+ partial

charge.

47

Figure 3.3 Typical configuration predicted for the dye—Li+ complex, showing additional coordination of three oxygen atoms provided by two TFSI molecules, taken from the [Li(G4)]TFSI liquid simulation. Remainder of the liquid not shown for clarity. Cyan=carbon, white=hydrogen, blue=nitrogen, red=oxygen, green=fluorine, yellow=sulphur and purple=Li+ (simplified structure shown on right).

The two glymes, G3 and G4 registered almost-zero α values, as they

have no acidic protons and this result was expected (Entry 4 & 5, Table

3.4). It also further supported the large α values of the solvate ILs as there

would be negligible hydrogen bond donation contributed from the glymes.

The slightly negative values of the glymes is due to the position of the line

generated from the other solvents, and is of no consequence to the α

value. Finally, [Bmim]TFSI represents the hydrogen bond donating ability

of a traditional IL as a reference for the solvate ILs, and is a little over half

as hydrogen bond donating as MeOH (Entry 6, Table 3.4). This may be

due to the cationic charge in part, as is the case with the solvate ILs, and

the actual acidity of hydrogens on the backbone of imidazolium unit. This

was also compared with previously published Kamlet-Taft values for

[Bmim]TFSI and was in good agreement (within 0.06), giving confidence

in these results.

48

To confirm the values obtained in the initial α measurements, a second

set of measurements were taken using another non-hydrogen bond

accepting dye; N,N-diethyl-4-nitroaniline (Figure 3.4) and plotted (Graph

3.2). Reichardt’s dye was still used as the hydrogen bond accepting dye

and the same methodology employed to generate the second set of α

values, which should echo the first. The results of the secondary α values

are shown in Table 3.5.

Graph 3.2 Distribution of absorbance data in relation to Reichardt's dye and N,N-diethyl-4-nitroaniline in kiloKaisers (kK).

Figure 3.4 The dye; N,N-diethyl-4-nitroaniline.

y = -1.8128x + 59.868R² = 0.9504

12.00

14.00

16.00

18.00

20.00

22.00

24.00

23.00 24.00 25.00 26.00 27.00 28.00

Reic

hard

t's D

ye (k

K)

N,N-diethyl-4-nitroaniline (kK)

Solvents

MeOH

[Li(G3)]TFSI

[Li(G4)]TFSI

[Bmim]TFSI

Triglyme

Tetraglyme

5.14 kK

7.05 kK 6.79 kK

49

Table 3.5 α2 values generated through the use of a second, non-hydrogen bond accepting dye, N,N-diethyl-4-nitroaniline.

Entry Solvent ΔkK

values α1 value[a] α2 value

1 MeOH 5.14 1.00 1.00

2 [Li(G3)]TFSI 6.79 1.32 1.32

3 [Li(G4)]TFSI 7.05 1.35 1.37

4 Triglyme 0.29 -0.01 0.06

5 Tetraglyme -0.03 -0.05 -0.01

[a]Determined earlier with Reichardt’s Dye and p-nitroanisole

Again, methanol is given the value of 1.00 as the standard to compare

against (Entry 1, Table 3.5). Comparison of the first and second sets of α

values for [Li(G3)]TFSI and [Li(G4)]TFSI (Entry 2 & 3, Table 3.5

compared to Entry 2 & 3, Table 3.4) reveals almost identical α values.

This is certainly true of the α values of [Li(G3)]TFSI, with the small

exception of [Li(G4)]TFSI as the α value increasing from 1.35 to 1.37.

Considering how many variables are present in the conversion of units,

the use of solvents and the arbitrary nature of the line of best fit, this small

deviation can be considered irrelevant. A similar situation can be seen in

the case of the second set of α values for the glymes, where a small

deviation of +0.07 and +0.04 is observed for the tri- and tetraglyme,

respectively (Entry 4 & 5, Table 3.5). As mentioned earlier, this may be

due to a number of factors, and should generally be regarded as

negligible. With a high degree of confidence in these data, the focus then

turned to determining the β value for these solvents.

β Values – Hydrogen Bond Accepting Ability

The practical and numerical method of calculating the β values of a

solvent is almost identical to that of the α values, with a few minor

differences. As β values are representative of the hydrogen bond

accepting ability of the solvent, the dyes required and the solvents used to

generate the baseline must reflect this. The dyes used are 4-nitroaniline

and N,N-diethyl-4-nitroaniline due to the prevalence in the literature.26-28

50

In addition to the difference in dyes used, the solvents required for the

baseline calculation must show no hydrogen bond accepting abilities;

heptane, toluene, 1,2-dichloroethane (DCE), and dichloromethane (DCM).

Hexamethylphosphorylamide (HMPA) serves as the strongly hydrogen

bond accepting solvent, though is quite toxic. To circumvent using this, β

values of the unknown solvents may be made relative dimethylsulfoxide

(DMSO), which is equal to 0.743 when compared to HMPA. Again, the

absorbance was determined through UV-Vis spectroscopy and the value

converted to kiloKaiser, showing strong correlation to the literature values

(Table 3.6), before plotting the dyes against each other and a line of best

fit generated (Graph 3.3).

Table 3.6 Wavelength of maximum absorbance of dyes in a variety of solvents, conversion of units to kiloKaiser (kK) and comparison to literature values.

Solvent

Dyes

p-nitroaniline N,N-diethyl-4-nitroaniline

vmax kK Lit. (kK) vmax kK Lit. (kK)

Heptane 319.73 31.28 31.30 360.73 27.72 27.71

Toluene 338.60 29.53 29.41 386.87 25.85 25.87

DCE 352.47 28.37 28.37 399.27 25.05 25.06

DCM 349.13 28.64 28.65 399.87 25.01 24.96

DMSO 388.40 25.75 25.71 413.00 24.21 24.30

[Li(G3)]TFSI 368.80 27.11 409.53 24.42

[Li(G4)]TFSI 366.20 27.31 407.67 24.53

[Bmim]TFSI 366.80 27.26 411.00 24.33

Triglyme 370.07 27.02 394.00 25.38

Tetraglyme 371.20 26.94 395.13 25.31

51

Graph 3.3 Distribution of absorbance data in relation to p-nitroaniline and N,N-diethyl-4-nitroaniline in kiloKaisers (kK).

Consistent with findings from the α values, the absorbance of the

baseline-solvents was supported by literature values. The calculation of β

values is performed in the same manner as the α values, which is

determining the distance of the DMSO data point from the line, and

comparing the other solvents to this. The β values are shown in Table 3.7.

Table 3.7 β values of solvents.

Entry Solvent ΔkK Values β value

1 DMSO 1.98 0.743

2 [Li(G3)]TFSI 0.82 0.307

3 [Li(G4)]TFSI 0.74 0.278

4 Triglyme 1.90 0.713

5 Tetraglyme 1.90 0.716

6 [Bmim]TFSI 0.58 0.218[a]

[a]Literature value = 0.24164, 175

As with MeOH, DMSO is given the arbitrary β value of 1.00 (Entry 1,

Table 3.7) to give context to the β values of the other solvents tested.

Both [Li(G3)]TFSI and [Li(G4)]TFSI exhibit a little over a third of the

hydrogen bond accepting ability of DMSO, with β values of 0.41 and 0.37,

respectively (Entry 2 & 3, Table 3.7). This is due to two factors, the

y = 1.0245x + 2.9158R2 = 0.9859

24.00

25.00

26.00

27.00

28.00

29.00

30.00

31.00

32.00

23.00 24.00 25.00 26.00 27.00 28.00

p-ni

troa

nilin

e (k

K)

N,N-diethyl-4-nitroaniline (kK)

Solvents

DMSO

[Li(G3)]TFSI

[Li(G4)]TFSI

[Bmim]TFSI

Triglyme

Tetraglyme

1.90 kK

1.98 kK

52

oxygen atoms of the glyme molecule, as well as from the TFSI anion. In

contrast, the two glyme molecules display hydrogen bond accepting

abilities, almost equal to that of DMSO, 0.96 (Entry 4 & 5, Table 3.7). The

vast difference between the glyme molecules and solvate ILs can be

attributed to the chelation of the lithium cation in the IL, reducing the

availability of the glyme-oxygen atoms to participate in hydrogen bonding.

As both the tri- and tetraglymes are essentially the same molecule, only

with one ethylene unit differing them, it expected that they should have

near-identical β values, which is the case. [Bmim]TFSI demonstrated a β

value of 0.29 (Entry 6, Table 3.7), smaller than that of both solvate ILs, yet

there is an absence of hydrogen bond accepting sites on the cation,

suggesting the involvement of the anion. This supports the comparatively

increased β values of the solvate ILs being derived from the collaborative

effort of the glyme-chelated cation and the TFSI anion accepting hydrogen

bonds.

π* Values – Dipolarity/Polarizability

The most ambiguous of the Kamlet-Taft parameters, the π* scale relates

to the dipolarity/polarizability of a solvent and is so named as it is derived

from and best correlates solvatochromic effects on p π* and π π*

electronic spectral transitions.26 It is the ability of a solvent to stabilise a

charge or dipole. Therefore, it is a measurement of differential stabilization

of the more polar excited state with respect to the ground state of the dye.

The change in the absorption maximum of the dye is induced by the local

electric field generated by the solvent. An improved model from Welton et

al.176 for calculating π* from data obtained measuring N,N-diethyl-4-

nitroaniline is shown in Equation 3.2.162

∗ =−

−4.12(3.2)

The scale is then normalised from heptane (π*= 0.000) to DMSO (π* =

1.000) and the data is shown in Table 3.8.

53

Table 3.8 π* values of solvents.

Entry Solvent π*

1 DMSO 1.000

2 [Li(G3)]TFSI 0.942

3 [Li(G4)]TFSI 0.910

4 Triglyme 0.667

5 Tetraglyme 0.688

6 [Bmim]TFSI 0.966

As DMSO is used to normalise the π* scale against, it has been included

as a reference for the other solvents (Entry 1, Table 3.8). [Li(G3)]TFSI and

[Li(G4)]TFSI have π* values of 0.942 and 0.910 (Entry 2 & 3, Table 3.8),

both very close to that of DMSO, due to their ability to stabilise charge,

resultant of their high polarity. Both the glymes have similar π* values to

each other with 0.667 and 0.688 for both the tri- and tetraglymes

respectively (Entry 4 & 5, Table 3.8). This is to be expected, as well as the

depressed result when compared to the solvate ILs due to the decreased

polarity of the solvent. [Bmim]TFSI exhibits a π* value closer to that of

DMSO than the solvate ILs with 0.966 (Entry 6, Table 3.8), which reflects

the similarity of the solvents in relation to the high polarity and the anion.

ET(30) and ETN – Solvent Polarity and Normalised Solvent Polarity

The determination of the ET(30) and the ETN (solvent polarity and

normalised solvent polarity, respectively) does not require any further

measurements, only calculations using the data already obtained. The

solvent polarity, ET(30), is referred to as such due to the betaine

(Reichardt’s Dye) in the original report simply being the 30th dye

investigated. This parameter is calculated using the maximum absorption

of Reichardt’s Dye in the solvent which is then substituted into Equation

3.3.162, 177

54

(30)( ) =28591

( )(3.3)

The ET(30) gives no real context to the polarity of the solvent, so it is

therefore necessary to normalise this value on a scale of trimethylsilane

(TMS, least polar, ETN = 0.000) to water (most polar, ET

N = 1.000). This is

accomplished using Equation 3.4.162, 177

=( ) − ( )( ) − ( )

=( ) − 30.7

32.4(3.4)

The results of these calculations are summarised in Table 3.9.

Table 3.9 The ET(30) (solvent polarity) and ETN (normalised solvent polarity) of solvents.

Entry Solvent ET(30) ETN

1 Water 63.1 1.000

2 [Li(G3)]TFSI 64.0 1.028

3 [Li(G4)]TFSI 64.2 1.033

4 Triglyme 40.4 0.301

5 Tetraglyme 39.9 0.284

6 [Bmim]TFSI 49.8 0.590

The ETN gives a relative scale of the polarity of solvents compared to water

as the most polar, ETN = 1.000 (Entry 1, Table 3.9). [Li(G3)]TFSI and

[Li(G4)]TFSI have ETN values of 1.028 and 1.033 (Entry 2 & 3, Table 3.9),

greater than that of water. Given the nature of ionic liquids comprising

entirely of ions, it is not unexpected that they would have a high degree of

polarity. This is due to the full cationic and anionic charges present in the

IL, rather than the dipole moment experienced by water. The tri- and

tetraglyme compounds are both around a third of the polarity of water with

ETN values of 0.301 and 0.284, respectively (Entry 4 & 5, Table 3.9). These

ethereal solvents are expected to have a degree of polarity associated

55

with them, due to the electronegativity of the oxygen atoms, and

decreased ETN values compared to the solvate ILs is due to the absence of

ions. [Bmim]TFSI has a markedly reduced ETN value compared to the

solvate ILs, with 0.590 (Entry 6, Table 3.9), which is consistent with the

higher α and β values of the solvate ILs.

This work was collated and is featured in a publication in Physical

Chemistry Chemical Physics:

Eyckens, D.J.; Demir. B.; Walsh. T.; Welton, T.; Henderson, L.C., (2016).

“Determination of Kamlet-Taft parameters for selected solvate ionic

liquids.” Phys. Chem. Chem. Phys., 18(19): 13153-13157. IF: 4.12,

citations: 11

Gutmann Acceptor Number

Given the presumed Lewis acid effects of the solvate ILs promoting higher

α values in the Kamlet-Taft parameters, and the confirmation of this effect

with molecular dynamics, it is necessary to look at this characteristic

directly.

The Gutmann Acceptor Number is a measurement of the Lewis acidity of

a solvent. It requires the use of 31P NMR and measures the interaction of

the desired solvent and a Lewis base, either triethylphosphine oxide

(Et3PO) or triphenylphosphine oxide (Ph3PO) (Figure 3.5) in a 3:1 ratio

(solvent:base) dissolved in deuterated benzene. Triethylphosphine is most

commonly used in the literature.

Figure 3.5 Lewis bases used for determining the Gutmann Acceptor Numbers (AN) of a solvent.

The Acceptor Number (AN) is determined by monitoring the shift of the

phosphorus atom when introduced to a Lewis acid by polarisation of the

56

P=O bond (Figure 3.6). The greater the strength of the Lewis acid, the

more positive the phosphorus atom becomes, shifting the resonance of

that atom in the 31P NMR spectrum downfield (to the left).

P

O

O

O O

OLi+

P

O

O

OO

O Li+

Figure 3.6 Interaction of [Li(G3)]+ as a Lewis acid with a Lewis base, either triphenylphosphine oxide or triethylphosphine oxide.

In order to accurately ascertain the degree of shift of the phosphorus

resonance, the Lewis base must first be measured in relation to a non-

Lewis acidic solvent, as a control measurement (n-heptane was used in

this case). A comparison of heptane and the two solvate ILs with Ph3PO is

shown below (Figure 3.7). The external reference used was 0.0485 M

triphenylphosphate in acetone-d6.

Figure 3.7 Overlayed 31P NMR spectra of [Li(G3)]TFSI, [Li(G4)]TFSI and n-heptane in relation to triphenylphosphine oxide demonstrating the shift resultant from different solvents. (0.0485 M triphenylphosphate used as external reference in acetone-d6).

n-heptane

57

The above example shows the difference in chemical shift (Δδ) of Ph3PO

when combined with different solvents. Measurements using Ph3PO were

conducted with [Li(G3)]TFSI and [Li(G3)]TFSI and n-heptane (Table 3.10),

to get a broad idea of whether these ILs were Lewis acidic, and to ensure

correct technique while waiting for the Et3P=O to be delivered (which was

on back order). It is worth noting that the difference in chemical shift

between Ph3PO and Et3PO is substantial, and due to both steric and

electrochemical effects of the aromatic rings. This is why Et3PO is the

preferred analyte of choice. Once available, conducting the

measurements with Et3PO requires a simple calculation to be applied to

the change in resonance compared to n-heptane (Δδ) (Figure 3.8).

Figure 3.8 Interaction of Et3P=O with a Lewis acid (LA) and the method of calculation.

The Acceptor Numbers of solvents are summarised in Table 3.10.

Table 3.10 Δδ of solvents and determination of Acceptor Number (AN)

Entry Lewis Acid Ph3PO Et3PO

AN δ(31P) Δδ(31P) δ(31P) Δδ(31P)

1 None 29.12 – 46.88 – –

2 n-heptane 29.21 0.00 46.66 0.00 0.00

3 LiTFSI (salt) – – 64.48 17.82 41.84

4 [Li(G3)]TFSI 31.85 2.64 57.96 11.30 26.53

5 [Li(G4)]TFSI 31.76 2.55 57.96 11.30 26.53

6 Triglyme – – 46.76 0.10 0.24

7 Tetraglyme – – 46.75 0.09 0.21

8 [Bmim]TFSI – – 51.68,

47.94 5.07, 1.30 11.90,

3.10

58

It was of interest to determine the AN of the naked LiTFSI salt, to quantify

the effect chelation had on the lithium cation. The salt, exhibited an

Acceptor Number of 41.84 (Entry 3, Table 3.10), almost double that of the

solvate ILs. Lithium has been shown to be a strong Lewis acid, often used

as an additive for organic reactions, so in the non-chelated form, it is

logical to expect this increase in Lewis acidity. [Li(G3)]TFSI and

[Li(G4)]TFSI demonstrated identical AN with 26.53 each (Entry 4 & 5,

Table 3.10). This represents the effect of chelation, as the lithium cation is

not as free to interact with the Lewis base, the effect may be due to a

combination of electronic and steric effects. The tri- and tetraglyme

molecules showed very low AN with 0.24 and 0.21, respectively (Entry 6 &

7, Table 3.10). The negligible Lewis acidity exhibited by these

compounds, is to be expected due to the absence of electron-accepting

functional groups. [Bmim]TFSI shows reduced Lewis acidity when

compared to the solvate ILs with AN values of 11.90 and 3.10 (Entry 8,

Table 3.10). This is due to the nature of the cation, as Lewis acids are

typically metal-based and the amine cation is not as efficient at accepting

electrons. Presumably, the observed Lewis acidity of [Bmim]TFSI is

dominated by hydrogen-bonding effects between the phosphine oxide and

the acidic hydrogen atom at C2, and the pair at C4/C5 on the imidazolium

ring (Figure 3.9), giving the two values.

Figure 3.9 Acidic protons of [Bmim]TFSI shown in red.

It should be noted that the Acceptor Number of 5.0 M LPDE was

attempted, though it was not able to be accurately assessed due to the

instant precipitation of the lithium perchlorate once added to the non-

ethereal NMR solvent.

59

Application of Lewis Acidity of Solvate Ionic Liquids

Electrocyclisation Reactions

Given the physical chemical analysis of these solvate ionic liquids and the

results therein, their effect on organic transformations remained to be

determined.

Diels–Alder Reactions

In an effort to recreate the success of 5.0 M LPDE and utilise the Lewis

acidity, [Li(G3)]TFSI and [Li(G4)]TFSI were both assessed in their

application as solvents for Diels–Alder reactions. The [4+2] cycloadditions

of a series of solvents are summarised in Table 3.11. The limitation of not

being able to heat 5.0 M LPDE due to potential explosion is not relevant to

the solvate ILs, and thus this fact was exploited during reaction

optimisation.

Table 3.11 Diels–Alder reactions in solvate ionic liquids.

Entry Solvent Time Temp. (°C)[a]

Yield (%)[b]

1 5.0 M LPDE 7 h r.t. 94[c]

2 [Bmim] PF6 2 h 80[d] 96[e]

3 [Li(G3)]TFSI 10 min 100 48

4 [Li(G4)]TFSI 10 min 100 78

5 [Li(G3)]TFSI 30 min 100 73

6 [Li(G4)]TFSI 30 min 100 81

[a] Microwave irradiation. [b] Isolated yield. [c] Reported yield.140 [d] No microwave irradiation. [e] Reported yield.178

The Diels–Alder reaction between isoprene and 3.3 is reported to proceed

well at ambient temperature in 5.0 M LPDE (94% in 7 h, Entry 1, Table

3.11).140 It has also been shown to be successful in [Bmim]PF6, with the

60

addition of heat (96% in 2 h, Entry 2, Table 3.11).178 The reported

conditions for the Diels–Alder reaction in ionic liquids use 5 equivalents of

the diene, and this was kept consistent in this study to allow for greater

comparison. However, isoprene was observed to be only sparingly soluble

in the solvate ILs, forming a biphasic solution when added to the reaction

vessel. This suggests that a much lower effective concentration was

required to complete these reactions than in the instances of other ionic

liquids, meaning fewer equivalents may have been able to be used to

produce the same result. After 10 min at 100 °C in [Li(G3)]TFSI, diene 3.4

was obtained in a moderate, 48% isolated yield (Entry 3, Table 3.11). In

contrast, the same conditions in [Li(G4)]TFSI proceeded markedly better,

giving a 78% isolated yield (Entry 4, Table 3.11) within the 10 minute

timeframe. Extending the reaction time to 30 min (Entry 5 & 6, Table 3.11)

gave improved yields for both [Li(G3)]TFSI and [Li(G4)]TFSI (73% and

81%, respectively). This demonstrated the advantages of being able to

heat these solvate ILs without limitation (such as those outlined for 5.0 M

LPDE) as part of an optimisation process.

Table 3.12 Diels–Alder reactions in solvate ionic liquids.

Entry Reactant Solvent Time Temp. (°C)[a]

Yield (%)[b]

1 3.5a CHCl3 20 min 100 <5

2 3.5a [Li(G3)]TFSI 20 min 100 73[c]

3 3.5a [Li(G4)]TFSI 20 min 100 21[c]

4 3.5a [Li(G3)]TFSI 16 h r.t. 0

5 3.5b CHCl3 20 min 100 45

6 3.5b [Li(G3)]TFSI 20 min 100 74

7 3.5b [Li(G4)]TFSI 20 min 100 65

[a] Microwave irradiation. [b] Isolated yield. [c] Only trans product isolated.

61

The Diels–Alder reaction between isoprene and dimethyl maleate (3.5a)

or dimethyl fumarate (3.5b) was also investigated. Previous reports179 of

the Diels–Alder reaction between dimethyl maleate (3.5a) and isoprene

required the use of extremely high temperatures to obtain good yields (cf.

195 °C and 66%, respectively). Attempting the reaction in a molecular

solvent (chloroform) proved the difficult nature of this reaction when only

traces of the desired product 3.6 obtained (Entry 1, Table 3.12) despite

relatively high temperatures. Employing [Li(G3)]TFSI and [Li(G4)]TFSI

(Entry 2 & 3, Table 3.12) showed greater promise, with isolated yields of

73% and 21%, respectively. Despite this, it was found that the isolated

product was 3.6b, possessing the trans configuration of the esters and not

the expected cis transfiguration of 3.6a. This is unusual as

stereochemistry is typically retained throughout the Diels-Alder reaction,

and it was concluded that while the product 3.6a may form initially, it is

possible for this product to convert to the more thermodynamically stable

3.6b (Figure 3.10).

Figure 3.10 Epimerisation of Diels-Alder adduct.

This epimerization is presumed to be due to the higher temperature

employed in this reaction. The dramatic reduction in yield in [Li(G4)]TFSI

is unknown, but may be due to a slightly different solubility of isoprene in

this IL compared to the [Li(G3)]TFSI variation.

This reaction was then repeated with 3.5a at room temperature in

[Li(G3)]TFSI overnight (Entry 4, Table 3.12) to minimise possible

epimerization. Unfortunately, the reaction was unsuccessful and only

starting material 3.5a was isolated.

Dimethyl fumurate (3.5b) was then employed as the dienophile, and a

much less pronounced improvement in yield was obtained in the solvate

ILs, when compared to the molecular solvent (Entry 5, Table 3.12 vs.

62

Entry 6 & 7, Table 3.12). When compared to previous reports180 however

(cf. 36 h, 70 °C), the reaction required considerably less time to occur.

[2+2] Cycloaddition Cascade formation of Dienes

Another electrocyclisation reaction attempted in the solvate ILs was the

[2+2] reaction of dimethyl ketene (3.7) (generated in situ from isobutyryl

chloride) and (E)-cinnamaldehyde (3.8) giving 3.9 after CO2 extrusion.

This reaction is reported not to proceed in the absence of LiClO4 and has

been reported in 5.0 M LPDE, therefore is an obvious choice to compare

the application of the solvate ILs.

Table 3.13 Comparison of solvents in [2+2] cascade formation of dienes.

Entry Solvent Time (h) Temp. (°C) Yield (%)[a]

1 CHCl3 6 r.t. < 5

2 5.0 M LPDE 6 r.t. ~ 20

3 [Li(G3)]TFSI 6 r.t. 56

4 [Li(G4)]TFSI 6 r.t. 41

6[b] [Li(G3)]TFSI 6 r.t. 60

7 [Li(G3)]TFSI 6[c] 80 70

[a] Isolated yield. [b] Activated molecular sieves (100 mg) were used throughout the reaction. [c] The reaction mixture was heated for the finally hour of the specified time.

Conducting the reaction in chloroform resulted in trace amounts of product

formed, as was expected (Entry 1, Table 3.13). When repeating the

literature conditions,19 the high yield (95%) originally reported in 5.0 M

LPDE was unable to be reproduced (Entry 2, Table 3.13). Employing

freshly prepared 5.0 M LPDE, from extensively dried LiClO4 and diethyl

ether, saw highly variable yields at best. The yield of 3.9 in 5.0 M LPDE

varied between 5–40%, with <20% being typical for repeated attempts.

Despite the complete consumption of the aldehyde 3.8, a complex mixture

of products was typically observed in the 1H NMR spectrum of the crude

mixture.

63

The complete consumption of the aldehyde 3.8 was also observed in the 1H NMR spectra of crude mixtures of the reactions carried out in

[Li(G3)]TFSI and [Li(G4)]TFSI, though the isolated yields were greatly

improved; 56% and 41%, respectively (Entry 3 & 4, Table 3.13). It was

hypothesised that atmospheric water may be affecting the reaction

outcomes. In an attempt to remedy this and improve yields, 4 Å molecular

sieves were added to the reaction in [Li(G4)]TFSI to remove adventitious

water, improving the yield to 60% (Entry 6, Table 3.13). Further to this,

heating for the final hour of the reaction to 80 °C in [Li(G3)]TFSI increased

the yield to 70% (Entry 7, Table 3.13).

These reactions highlight the ease with which these SILs can be handled.

The use of molecular sieves and heated using 5.0 M LPDE is not

possible, due to precipitation of lithium perchlorate if taken out of inert

atmosphere, and again the limitations of heating in this system.

Psuedo-Pinacol Rearrangement of Epoxides

5.0 M LPDE is also reported to greatly accelerate the pseudo-pinacol

rearrangement of styrene oxide (3.10).181 When this same rearrangement

was attempted in the [Li(G3)]TFSI and [Li(G4)]TFSI solvate ILs, only

starting material was observed in the 1H NMR spectrum of the crude

material. This same result was achieved through extended reaction times.

Scheme 3.2 Attempted rearrangement of styrene oxide 3.10 with solvate ionic liquids.

This outcome is attributed to the reduced availability of the lithium cation

to interact with the epoxide and act as a Lewis acid. It is thought to be due

to the relative strength of chelation by the glyme molecules being greater

than that of the diethyl ether coordination to the lithium cationic species in

5.0 M LPDE. Consistent with the Gutmann Acceptor Number

64

measurements of the uncoordinated LiTFSI salt as the diethyl ether

stabilised lithium ion would not be as well chelated and thus be more

available for participated in Lewis acid promoted reactions.

This work was collated and is featured in a publication in the European

Journal of Organic Chemistry:

Eyckens, D.J.; Champion, M.E.; Fox, B.L.; Yoganantharajah, P.; Gibert,

Y.;Welton, T.; Henderson, L.C., (2016). “Solvate Ionic Liquids as Reaction

Media for Electrocyclic Transformations.” Eur. J. Org. Chem., 5: 913-917,

IF: 2.83, citations: 11

Chapter Summary

The work described in this chapter saw the determination of the Kamlet-

Taft parameters for both [Li(G3)]TFSI (α=1.32, β=0.31, π*=0.94, ETN=1.03)

and [Li(G4)]TFSI (α=1.35, β=0.28, π*=0.91, ETN=1.03) solvate ionic liquids.

Work published since165 the initial publication154 (from this study) has

shown good correlation with the conclusions of this project and serves to

support the original findings.

The Gutmann Acceptor Number was also investigated, found to be 26.5

for each of the SILs, demonstrating the Lewis acidity inherent to the

solvents. This was experimentally tested by the application of the SILs as

the medium for Diels-Alder reactions, with the comparison to a similar,

previously popular solvent 5.0 M LPDE and was shown to have good

success.

The work shown is this chapter resulted in 2 peer-reviewed publications.

65

– Synthesis of α-Aminophosphonates in SILs

Introduction

Given the previous success in exploiting the Lewis acid properties of the

solvate ionic liquids to enhance reaction outcomes, the synthesis of α-

aminophosphonates was identified as a new avenue to assess. Previous

work by Heydari et al.182 had shown the suitability of using 5.0 M lithium

perchlorate in diethyl ether (LPDE) in this reaction. Thus, providing a point

of comparison to the similar solvate ionic liquids of this project. α-

Aminophosphonates are small, phosphorus containing molecules,

structurally analogous to naturally occurring α-amino acids (Figure 4.1).

H2N

R

OH

O

H2N P

R

OH

O

OH

-amino acid -aminophosphonate

Figure 4.1 Structural similarity between an α-amino acid and an α-aminophosphonate.

Replacement of the carbonyl component of the amino acid with

phosphorus has been shown to inhibit enzymes of receptors to which the

natural amino acids bind.183 This lays the foundation for α-

aminophosphonates to have medicinal or therapeutic applications.

These compounds are typically accessed via the Kabachnik-Fields

reaction, discovered independently by both Martin Izrailevich Kabachnik33

and Ellis Fields34 in 1952. The reaction proceeds through condensing an

amine 4.1 with an aldehyde 4.2 (either in situ or preformed), before

reaction with a phosphonate (Figure 4.2).

66

Figure 4.2 Proposed mechanism of imine condensation with a phosphite diester for the Kabachnik-Fields reaction.184 Simplified for interpretation.

The phosphite diester exists as a mixture of phosphonate and phosphite

(Figure 4.2), with the predominant form being the former, though this may

be influenced by the basicity of the solvent.185-186 Given this tautomerism,

the mechanism of formation of α-aminophosphonates may follow one of

two options.184 The first is a four-membered transition state of the

phosphonate with the imine (Pathway A, Figure 4.2), and the second is

the five-membered transition state, resembling nucleophilic attack

(Pathway B, Figure 4.2). In either event the resulting product 4.5 is the

same. One other possibility exists for the three-component mixture of

aldehyde, amine and phosphonate. This is the reaction of the aldehyde

(4.7) and phosphonate (4.6) according to the reversible Abramov reaction

to form an α-hydroxyphosphonate (4.8, Figure 4.3).187

Figure 4.3 The reversible Abramov reaction between a phosphonate (4.6) and an aldehyde (4.7) to an α-hydroxyphosphonate (4.8).

This product may then be transformed to the α-aminophosphonate, if the

amine is basic enough (pKa > 6, as described in the literature, shown

below), but may revert to the two starting materials before taking the imine

pathway.183 The use of 31P NMR to study the basicity of amines relative to

67

diethyl phosphite indicates that more basic amines may operate through

the α-hydroxyphosphonate pathway.188 When the imine of

cyclohexylamine and benzaldehyde (i.e. 4.9) is preformed, and introduced

to a dialkyl phosphite, no α-aminophosphonate is observed (Scheme

4.1).188

Scheme 4.1 Formation of α-aminophosphonates via the α-hydroxyphosphonate pathway when employing amines more basic than aniline.188

In contrast, combining the aldehyde with the phosphite and a catalytic

amount of cyclohexylamine gave only α-hydroxyphosphonate product.

Increasing the amount of amine in the system was proportional to the

amount of observed α-aminophosphonate 4.10, and finally, replacing

cyclohexylamine with aniline (less basic) gave no α-hydroxyphosphonate

4.12. These effects may be influenced by nature of the aldehyde (electron

withdrawing versus donating), but it is a point of interest that the

mechanism may be altered with different reactants.

Fields’ original paper34 described the exclusive production of α-

aminophosphonates through the addition of an aldehyde to a stirring

mixture of neat amine and phosphite diester. It was also stated that

reversal of reactant order to addition of the amine to a mixture of aldehyde

and phosphite would result in a mixture of compounds. These early

reactions, whilst robust, often required heating and due to the neat

conditions of the reaction, would also require large scale reactions,

typically multi-gram. Performing these reactions in a solvent, would allow

68

for smaller quantities of reactant to be used and increase handle ability,

but would also suffer from a reduction in reaction rate, affecting reaction

times and yields.

Lithium Perchlorate-Assisted α-Aminophosphonate Synthesis

The use of lithium perchlorate in diethyl ether has been shown to facilitate

the production of α-aminophosphonates, with good success, especially in

the face of an array of catalysts and method discussed later in this

chapter.

The un-solvated lithium perchlorate salt has effectively catalysed the

formation of α-aminophosphonates in solvent-free conditions in 40

minutes at room temperature (Scheme 4.2), but required 2 equivalents of

LiClO4, is a much higher loading than is commonly used for catalysts(ca.

1-10 mol%).20

Scheme 4.2 Formation of α-aminophosphonate 4.16 catalysed by LiClO4 in neat conditions.20

It is worth noting that although the reaction takes place without the use of

traditional solvents, the excess of aniline 4.14 may serve to appreciably

solubilise the reactants and lithium perchlorate. Also, α-

aminophosphonate 4.16 is produced using trimethyl phosphite (4.15),

which less common, as most studies use dialkyl- or diphenyl phosphites,

perhaps due to sterics or reactivity.182, 189-190

The acquisition of the desired product is isolated via simple work up of

dissolution in dichloromethane, causing the precipitation of LiClO4 which

is then filtered and may be reactivated by heating to 160 °C in vacuo. The

organic phase is then washed with water, dried with MgSO4 and residual

solvent removed under reduced pressure. Final products were then

subjected to column chromatography if required.

69

Azizi et al.20 explored the scope of this reaction in regards to substituent

effects of the aldehyde component, and extends to testing secondary

amines, also to good success (Scheme 4.3).

Scheme 4.3 Formation of α-aminophosphonate 4.18 catalysed by LiClO4 using neat reaction conditions, using a secondary amine 4.17.20

The use of secondary amines, when condensed with the aldehyde

generates a highly reactive iminium intermediate which may be stabilised

by LiClO4.20 The authors also state that due to the rapid formation of the

iminium salts in the presence of LiClO4, no α-hydroxyphosphonate by-

products are observed at the conclusion of the reaction.20

The preferred solvent of comparison to the solvate ionic liquids explored

throughout this project is the 5.0 M LPDE, of which there is one report as

to the affect this pseudo-solvate ionic liquid has on α-aminophosphonation

by Heydari et al. (Figure 4.4).182

Figure 4.4 α-Aminophosphonate synthesis in 5.0 M Lithium Perchlorate in Diethyl Ether (LPDE).182

The production of α-aminophosphonate 4.21 in excellent yields of up to

99%, occurs in only 10 minutes at room temperature. When compared to

the previous example of the solvent-free LiClO4 salt (synthesis of 4.18,

Scheme 4.3), this is a significant reduction in reaction time (40 minutes to

10 minutes), whilst the yields are higher (78% to 90%). This may be

assisted by dissolution of the reaction mixture in a solvent, facilitating

greater interaction with the Lewis acid. It should be noted that in the case

70

of the LiClO4, solvent-free synthetic method, trimethyl phosphite was

used, whereas dimethyl phosphite was used by Heydari et al.182

Nonetheless, these are exceedingly mild conditions, and employ the

exclusive use of secondary amines. The formation of the iminium cation

(as mentioned previously) may be positively influenced by the Lewis

acidity of the lithium cation and stabilised by the perchlorate anion,

causing the subsequent nucleophilic attack of the phosphite to be rapid.

The reported work up for these reactions states that the addition of water

to the reaction mixture, before extraction into dichloromethane, drying with

NaSO4 and the removal of excess solvent under reduced pressure. These

crude products were then purified by either; recrystallisation, distillation,

flash chromatography or HPLC.

Heydari et al. continues with the examination of 1,3-asymmetric induction

in chiral phosphonates using (R)-(+) α-methylbenzylamine 4.23 and a

range of aldehydes, in quite different conditions to those mentioned

above, though this did not depreciate yields (Figure 4.5).20

The authors do not elaborate on the reason for the changed reaction

conditions to −15 °C for 30 minutes (compared to room temperature for 40

minutes), or most interestingly, the use of a 2.0 M solution of LPDE rather

than 5.0 M LPDE.182

Figure 4.5 Synthesis of chiral α-aminophosphonates using 2.0 M LPDE by Heydari et al.182

Although these results do demonstrate excellent yields for the examples

shown, the diastereomeric ratio may be a product of the steric bulk of the

R1 groups, rather than any role played by the solvent. This follows from

71

the chelation or association of diethyl ether molecules with the lithium

cation being highly dynamic, with many equivalents of diethyl ether

molecules competing for access to the cation. This would, in theory,

severely limit any stereoselective influence of the solvent. To give context

to these findings, a relevant example from the literature follows (Figure

4.6).

Figure 4.6 Synthesis of chiral α-aminophosphonates in neat conditions by Ordoñez et al.191

Ordeñez et al. achieved very similar, albeit slightly depressed

diastereomeric ratios compared to LPDE without the use of any

solvents.191 This demonstrates the lack of stereochemical enrichment

induced by LPDE, as the diastereomeric outcomes are seemingly largely

derived from the substrates used.

That study by Ordeñez exhibits only slightly lower yields in the same

reaction, without the use of solvent or catalysts, but did so in greatly

extended times compared to 2.0 M LPDE (5-8 hours compared to 30

minutes) and required a significant increase in temperature via heating to

80 °C (Figure 4.6).191 Despite the similarity of diastereoselectivity, this

comparison exemplifies the substantial improvement observed when

performing these sorts of reactions in highly polar, Lewis acidic solvents.

The ability of the lithium cation of the 5.0 M LPDE to act as a Lewis acid,

is strongly replicated in the solvated lithium of the solvate ionic liquids

featured it this work, lending themselves to be utilised as potential

solvents for the Kabachnik-Fields reaction. As previously stated, the

attractiveness of lithium perchlorate in any concentration in diethyl ether

as a possible solvent is severely detracted from when considering the

72

labour-intensive nature of its production. Not only must the lithium

perchlorate and diethyl ether be arduously and thoroughly dried prior to

combination, once combined, possess extreme hygroscopicity that, if

unchecked, will lead to the LiClO4 precipitating from the solution.

Furthermore, the above reactions showed no thermal assistance,

presumably due to problems with the perchlorate anion and handling.

These limitations are overcome by the lithium

bis(trifluoromethanesulfonyl)imide based solvate ILs, as the parent salt

does not exhibit the explosive characteristic of lithium perchlorate, nor the

glymes the low boiling point of diethyl ether. Additionally, the solvate ionic

liquid product is simply dried under strong vacuum and heating (~120 °C)

for a few hours to afford the anhydrous solvent.

Other Synthetic Methods to access α-Aminophosphonates

Alternative synthetic methods including increased temperature and/or

pressure, or the use of catalysts have been investigated to access these

therapeutically significant compounds. An extensive array of heavy metal

catalysts have been investigated in the literature, including; ytterbium,192

hafnium,193 silver,194 copper,195 zinc,196 titanium,197 nickel,198

molybdenum,199 cerium,189 antimony,200 gallium,201 and iron.202 Some

selected examples appear in Table 4.1, below. Aspects of these methods

that may deter their use is the difficulty in purification, potential toxicity, the

inherent expense of purchase, and disposal. Some interesting examples

of different types of catalysts include cellulose-SO3H203 and carbon

nanotube supported imidazolium salt-based ionic liquids (Entry 6 and 7,

Table 4.1).204

73

Table 4.1 Selected examples of different catalysts used for the Kabachnik-Fields reaction.189, 192-204

Entry Catalyst Mol% Solvent Time

(min.)

Temp.

(°C)

Yield

(%)a

1 Yb(OTf)3 10 CH2Cl2 150 r.t. 96b

2 HfCl4 2 EtOH 30 60 98

3 MoO2Cl2 5 Neat 20 80 80c

4 [Ce(L-Pro)]2Oxalate 1 PhMe 10 r.t. 96d

5 GaI3 10 CH2Cl2 168 r.t. 88

6 Cellulose-SO3H -e Neat 15 r.t. 98

7 MWCNT-

[mpIm]HSO4f

7 Neat 40 r.t. 96

a Isolated yield. b 1,1,1,3,3,3-hexamethyldisilazane used in place of aniline, later deprotected to reveal the primary amine. c Yield from isolated imine. d Diphenyl phosphite used in place of diethyl phosphite. e 0.04 g per mmol. f 1-Methyl-3-(ethoxysilylpropyl)imidazolium hydrogen sulfate anchored on multiwalled carbon nanotube (MWCNT-[mpIm]HSO4).

The highly varied nature of catalysts used to facilitate the Kabachnik-

Fields reaction shown in Table 4.1 reveal the diversity of conditions able

to effect this transformation. The use of ytterbium triflate at 10 mol%

requires 150 minutes to furnish the desired product in 96% yield (Entry 1,

Table 4.1).192 It must be noted here that the amine used in this case was

not aniline, but 1,1,1,3,3,3-hexamethyldisilazane, which was later

deprotected to reveal the primary amine.

The use of 2 mol% hafnium(IV) chloride achieved a yield of 98% in 30

minutes when diethyl phosphite was combined with benzaldehyde and

aniline, though did require heating to 60 °C (Entry 2, Table 4.1).193

Molybdenium(VI) dichloride dioxide catalysed the reaction of the isolated

imine with diethyl phosphite, resulting in an 80% yield in 20 minutes, neat

at 80 °C (Entry 3, Table 4.1).199

74

Implication of the proline-chelated cerium at 1 mol% in toluene required

10 minutes at room temperature to access the product of benzaldehyde,

aniline and diphenyl phosphite in 96% (Entry 4, Table 4.1).189 Gallium

triiodide (10 mol%) needed 168 minutes at room temperature to achieve

an 88% yield of 4.28 (Entry 5, Table 4.1).201

Solid-supported catalyst cellulose-SO3H employed at 0.04 g per mmol

required only 15 minutes in neat conditions at room temperature to form

4.28 in 98% yield (Entry 6, Table 4.1).203 Finally, 1-methyl-3-

(ethoxysilylpropyl)imidazolium sulfate anchored on multiwalled carbon

nanotubes (MWCNT-[mpIm]HSO4) was able to catalyse the reaction at 7

mol%, synthesising 4.28 in 96% in 40 minutes, neat at room temperature

(Entry 7, Table 4.1).204

The synthesis of α-aminophosphonates may also be achieved using

Quinine as an organocatalyst (Scheme 4.4).205

Scheme 4.4 Synthesis of N-Boc protected α-aminophosphonate catalysed by Quinine.205

Although reaction times are significantly extended (multiple days), the

hydrophosphorylation of N-Boc imines (4.29) is achieved in good yields

and enantiomeric excess over a range of aryl groups. This demonstrates

good potential as the other catalysts discussed earlier are often

expensive, toxic, and require special disposal, or all three. The use of

quinine exemplifies the need for catalysts that are relatively cheap and

non-toxic as quinine is present in tonic water and is a treatment for

malaria.206

75

This wide variance in conditions and catalysts in such a select few

examples must also be contextualised with the type of phosphite used.

With the exception of the cerium-based catalyst, all other examples

employed the use of diethyl phosphite, which is less sterically hindered

than diphenyl phosphite, and so may favour the reaction slightly.

The use of ionic liquids to promote the Kabachnik-Fields reaction have

also been demonstrated (Scheme 4.5).207 This is serves as another point

of comparison with the solvate ionic liquids, which should exhibit a greater

Lewis acidity than traditional, imidazolium based ionic liquids (as seen in

Chapter 3), thus improve reaction outcomes.

O

PhOP

OPh

OPh 60 min, r.t.,68%

NH

P

OPhOPh

O+ +[Emim]Br

NH2

N+N

Br-

4.11 4.31 4.32 4.33

Scheme 4.5 Synthesis of α-aminophosphonate 4.33 in the ionic liquid 1-ethyl-3-methylimidazolium bromide ([Emim]Br).207

The combination of benzaldehyde (4.11), benzylamine (4.31) and

triphenyl phosphite (4.32) in [Emim]Br gave the desired α-

aminophosphonate 4.33 in 68% after column chromatography.207 This

reaction was attempted in a suite of ionic liquids, though this example

proved the best. The study continues with a variation of substrates,

though yields are lower than stated above, and in the same time frame

(60 minutes). Two exceptions are when cyclohexylamine was used in

place of benzylamine (75%) or trimethyl phosphite in place of triphenyl

phosphite (75%).

Indeed, α-aminophosphonates have exhibited many therapeutic effects in

antitumour,208-210 antifungal,211 antioxidant and antimicrobial

applications212-213 (Figure 4.7), making them keen compounds of interest

for medicinal and agricultural chemistry. Compound 4.34 demonstrated

good antioxidant and anticancer properties, and was accessed via

Cu(I)/Cu(II) inorganic coordination polymers in 6 hours a room

76

temperature in 87% yield when recrystallized from ethanol.210 Anti-

inflammatory compound 4.35 was synthesised by pre-forming the imine in

toluene for 1 hour at room temperature, before the dropwise addition of

phosphite over 30 minutes, and subsequent ‘gentle heating’ of the

reaction mixture for ‘5-6 hours’ whilst monitoring by TLC, gave the product

in excellent isolated yield (90%).213

Figure 4.7 Examples of therapeutic α-aminophosphonate compounds. Structure 4.37 is an example of a cerium(IV) extractant. α-Aminophosphonate moiety shown in blue. 209-210, 213-214

The anti-tumour compound 4.36 was also synthesised from the preformed

imine, reacting with diisopropyl phosphite under nitrogen at 120 °C,

accessing the desired product in 67% yield, though no detail was given

about the solvent, thus it is assumed this was done neat.209

α-Aminophosphonates have also been demonstrated to act as potential

drug delivery vehicles through transport of small, hydrophilic molecules

through the phospholipid bilayer,215 and used as extractants of cerium(IV)

and thorium(IV) from complex mixtures (4.37).214, 216 The final molecule in

Figure 4.7, compound 4.37, was accessed in 80% yield via refluxing the

phosphite, amine and paraformaldehyde in toluene in a Dean-Stark

apparatus until no more water was formed, before aqueous work up and

evaporation of organic solvent.214 It should be noted that p-toluenesulfonic

acid was used as a catalyst in this last instance.

77

This brief description of the synthesis of these α-aminophosphonates

demonstrates the variety of methods required to produce them, most

notably requiring extended reactions times, elevated temperatures, and

expensive catalysts.

Synthesis of α-Aminophosphonates in SILs

Given the abundant uses of α-aminophosphonates, and the enhanced

reaction outcomes effected using both SILs as previously demonstrated in

other systems, investigations into the production of these small molecules

were initiated. Diphenyl phosphite was chosen above other dialkyl

variants with the aim of testing the efficacy of the system, as the aromatic

phosphonate is more sterically hindered. This contrasts with much of the

literature generally preferring dialkyl substituents, though in examples of

studies that employ both aromatic and alkyl variations, the alkyl groups

generally outperform the aromatics.193, 217

Table 4.2 Initial screening of Kabachnik-Fields reaction in solvate ionic liquids.

Entry Solvent MWa Time Temp (°C) Yield (%)b

1 [Li(G3)]TFSI N 4 h r.t 86

2 [Li(G3)]TFSI N 18 h r.t 83

3 [Li(G3)]TFSI Y 30 min 110 46

4 [Li(G3)]TFSI Y 5 min 60 69

5 [Li(G3)]TFSI Y 5 min 100 72

6 Neat Y 5 min 100 76

7 CHCl3 Y 5 min 100 76

8 [Li(G3)]TFSI N 30 min r.t 97

9 CHCl3 N 30 min r.t 67 a Microwave irradiation. b Isolated yield.

The initial attempt saw the use of benzaldehyde (4.11), benzylamine

(4.31) and diphenyl phosphite (4.38), combined in [Li(G3)]TFSI for 4 hours

78

at room temperature, giving a good yield of 86% (Entry 1, Table 4.2). The

product was isolated through dissolution of the reaction mixture in Et2O

and transferring to a separatory funnel and washing with water, revealing

a precipitate at the organic-aqueous interphase. This precipitate was

filtered, analysed and found to be the desire product (Figure 4.8).

Figure 4.8 1H NMR spectrum of product 4.39 in CDCl3.

The 1H NMR spectrum of product 4.39 (Figure 4.8) shows the proton at

the carbon between the phosphorus and the nitrogen just below δ4.5, a

peak not present in any of the starting materials. Below this peak are the

benzylic protons, which have split due to diastereotopicity. The purity of

the product after such a simple work up proves a distinct advantage over

much of the literature, which commonly reports extended liquid/liquid

extractions and column chromatography.

Endeavouring to improve the yield of the first attempt, the reaction time

was extended to 18 hours at room temperature, though this saw a slight

reduction of yield to 83% (Entry 2, Table 4.2).

Previous success incorporating the use of microwave irradiation had been

seen when using these SILs, improving outcomes and reducing reaction

times. This was attempted, heating to 110 °C for 30 minutes using

microwave irradiation, resulting in a yield of only 46% (Entry 3, Table 4.2).

It should be noted here, as in previous chapters, the power required to

79

heat these SILs is much less than that required for traditional solvents

(~6 W compared to 200 W). Despite that the power was kept in check,

some degradation of the reactants may have been experienced at this

time and temperature, translating to the decreased yield.

Reducing both the temperature and time to 60 °C and 5 minutes, gave an

improved yield (relative to the other MW reaction, though still depressed

from the original) of 69% (Entry 4, Table 4.2), with greater success

observed when the temperature was increased to 100 °C during the same

time (72%, Entry 5, Table 4.2).

Repeating these parameters in neat conditions resulted in a slightly

increased yield to 76%, a result echoed when using chloroform as the

solvent (Entries 6 and 7, Table 4.2). These marginally better yields may

be the result of isolation troubles, but are nonetheless comparable to the

result of the SIL, though the latter benefits from a reduced toxicity relative

to chloroform. The isolation issues when using the SILs stem from the

need to precipitate, sometimes multiple times, to obtain the pure product

as residual glyme can become trapped in the precipitate and observed in

the 1H NMR spectrum. Past reactions using SILs have also seen trouble

when trying to isolate compounds, as the glyme tend to be dragged

through multiple aqueous washes into the organic phase, with removal

effective only through column chromatography. Due to their miscibility in

both organic and aqueous phases, this can reduce the isolated yield

through solvation of the product. In this current study, however,

precipitation is enough to purify products, avoiding column

chromatography.

Given that the best results so far were achieved without the use of

microwave irradiation, another reaction at room temperature was

attempted for 30 minutes, which lead to a yield of 97% (Entry 10, Table

4.2). These conditions were then repeated in chloroform at the same

concentration, giving a comparably diminished yield of only 67%,

potentially due to the absence of Lewis acidity possessed by [Li(G3)]TFSI.

80

Having determined the feasibility of the Kabachnik-Field reaction to

proceed in SILs, the scope of the reaction was yet to be identified. The

simplest method of which would be to replace benzylamine with aniline as

the amine component of the reaction, and examine the aromatic

substitution effects of both aniline and benzaldehyde components. This

also provides context in regard to the literature, allowing more accurate

comparison. It should be noted that this preliminary investigation was

performed solely in [Li(G3)]TFSI as this has generally been found to have

the most success in previous reactions, but [Li(G4)]TFSI will also be

examined from here.

Aniline Derivatives in the Kabachnik-Fields Reaction using SILs

With the initial conditions of 30 minutes at room temperature in

[Li(G3)]TFSI provided by the benzylamine experiments, the initial test with

aniline was replicated giving a good yield of 82% (Entry 1, Table 4.3).

Table 4.3 Optimisation of aniline-based Kabachnik-Fields reacition in solvate ionic liquids.

Entry Solvent Time (min) Yield (%)a

1 [Li(G3)]TFSI 30 82

2 [Li(G3)]TFSI 5 87

3 [Li(G3)]TFSI 1 78

4 [Li(G4)]TFSI 5 91 a Isolated yield.

It was noted that when using aniline (4.14), benzaldehyde (4.11) and

diphenyl phosphite (4.38), a precipitate rapidly formed. This was used as

a general indicator of reaction progress as the precipitate was identified

as the desired product. Reducing the reaction time to only 5 minutes saw

the isolation of pure product in 87% yield (Entry 2, Table 4.3), slightly

higher than the extend reaction time. Further reduction of time to only 1

81

minute provide the desired product in good yield of 78% (Entry 3, Table

4.3). Although this was considered highly efficient, the rapid reaction time

was deemed too short to be practically viable and given the greater yield

when reacting for only 4 minutes longer, the 5-minute reaction time was

preferred.

In light of this, the reaction was repeated for 5 minutes, using [Li(G4)]TFSI

as the solvent, giving a slightly increased yield of 91% (Entry 4, Table 4.3)

compared to the same reaction in [Li(G3)]TFSI.

The isolation of these compounds was developed to be extremely

proficient and robust. The dissolution of the entire reaction mixture in

diethyl ether and addition of water gave rise to a biphasic system, with the

SILs mostly contained in the ethereal organic layer. The ether layer was

then removed under reduced pressure, causing the α-aminophosphonate

to precipitate into the aqueous phase. This precipitate may then be filtered

and collected to give rise to analytically pure products (Figure 4.9) with the

SIL remaining in the aqueous phase. This method showed very consistent

repeatability, and allowed the production of and access to analytically

pure, novel compounds in under an hour from the time one enters the

laboratory.

Figure 4.9 1H NMR spectrum of the crude precipitate of 3-Cl derivative 4.41 in CDCl3.

Above is an example 1H NMR spectrum of a crude precipitate (3-

chloroaniline derivative 4.41). As can be seen, the spectra is clean and

the pure product is observed (with only trace amounts of diethyl ether).

82

The diagnostic peak is that of the chiral proton at ~δ5.1, which shows

strong splitting of 27 Hz due to phosphorus-proton coupling.

With the determination of preferred reaction conditions, and the isolation

procedure in hand, attention was turned to the investigation of reactants.

First explored was the electronic effects of the substitution on the aromatic

ring of the aniline component of the reaction.

Table 4.4 Investigation of aniline derivatives to produce α-aminophosphonates in SILs.

Entry Compound R Solvent Yield (%)a

1 4.43a 4-NO2

[Li(G3)]TFSI 64

2 [Li(G4)]TFSI 25

3 4.43b 4-OH

[Li(G3)]TFSI 82

4 [Li(G4)]TFSI 92

5 4.43c 4-F

[Li(G3)]TFSI 84

6 [Li(G4)]TFSI 68

7 4.43d 4-Cl

[Li(G3)]TFSI 96

8 [Li(G4)]TFSI 96

9 4.41 3-Cl

[Li(G3)]TFSI 83

10 [Li(G4)]TFSI 59

11 4.43f 3-CF3

[Li(G3)]TFSI 86

12 [Li(G4)]TFSI 81

13 4.43g 3,5-CF3

[Li(G3)]TFSI 54

14 [Li(G4)]TFSI 60 a Isolated yield.

Reactant investigation began with 4-nitroaniline, maintaining

benzaldehyde and diphenyl phosphite throughout this scoping process.

Performing the reaction in [Li(G3)]TFSI resulted in a 64% yield which is

attributed to the electron-withdrawing group on the aromatic ring, reducing

the nucleophilicity of the amine and potentially minimising the formation of

the imine. When repeated in [Li(G4)]TFSI, the yield was greatly reduced

83

to only 25% (Entry 1 and 2, Table 4.4). This large discrepancy in yield is

unclear, though it is worth noting that the isolation of 4-nitroaniline derived

α-aminophosphonate required multiple precipitations to adequately

remove the residual glyme from the product. There may be some effect of

the extra ethereal linker of the tetraglyme solubilising the compounds in

water more readily, as this was a repeated outcome and isolation of

product from [Li(G4)]TFSI was typically more intensive than from

[Li(G3)]TFSI.

Greatly improved results may be seen the case of the electron-donating 4-

aminophenol, exhibiting excellent yields of 82% in [Li(G3)]TFSI and 92%

in [Li(G4)]TFSI (Entry 3 and 4, respectively, Table 4.4). Incorporating 4-

fluoroaniline into the given reaction conditions resulted in a high yield of

84% in [Li(G3)]TFSI (Entry 5, Table 4.4). This result was not replicated in

[Li(G4)]TFSI, providing a diminished yield of 68% (Entry 6, Table 4.4).

Substituting the halogen from fluorine to chlorine in 4-chloroaniline proved

a much better outcome, with identical yields of 96% for both [Li(G3)]TFSI

and [Li(G4)]TFSI (Entry 7 and 8, Table 4.4). Though altering the

substitution position from 4- to 3-chloroaniline gave a only a slightly lower

yield in [Li(G3)]TFSI (84%, Entry 9, Table 4.4), repeating in [Li(G4)]TFSI

gave a drastically reduced yield of 59% (Entry 10, Table 4.4).

Replacing 3-chloroaniline with 3-(trifluoromethyl)aniline demonstrated very

good, similar yields in both [Li(G3)]TFSI and [Li(G4)]TFSI (86% and 81%,

respectively, Entry 11 and 12, Table 4.4). Introducing 3,5-

bis(trifluoromethyl)aniline demonstrated the robust nature of the reaction

conditions with good yields of 54% and 60% for [Li(G3)]TFSI and

[Li(G4)]TFSI (Entry 13 and 14, Table 4.4).

This procedure shows high tolerance for functional groups and electronic

effects, though there is no discernible trend for the preference of

[Li(G3)]TFSI versus [Li(G4)]TFSI. Regardless, this work preceded the

investigation of varying the aldehyde portion of this system.

84

Benzaldehyde Derivatives in the Kabachnik-Fields Reaction using

SILs

Table 4.5 Investigation of benzaldehyde derivatives to produce α-aminophosphonates in SILs.

Entry Product R Solvent Yield (%)a

1 4.45a 4-Br

[Li(G3)]TFSI 90

2 [Li(G4)]TFSI 91

3 4.45b 4-Me

[Li(G3)]TFSI 90

4 [Li(G4)]TFSI 86

5 4.45c 4-NO2

[Li(G3)]TFSI 69

6 [Li(G4)]TFSI 59b

7 4.45d 4-F

[Li(G3)]TFSI 77

8 [Li(G4)]TFSI 78

9 4.45e 2-OH

[Li(G3)]TFSI 84

10 [Li(G4)]TFSI 76

11 4.45f 3,4-Cl

[Li(G3)]TFSI 74

12 [Li(G4)]TFSI 79

a Isolated yield. b This material contained α-hydroxyphosphonate (17% by 1H NMR spectroscopy) resulting from direct attack of the phosphite on 4-nitrobenzaldehyde.

With an adequate array of anilinic-derived nucleophiles examined,

attention turned to the examining the aldehyde portion of the reaction.

Investigation began with 4-bromobenzaldehyde (4.44a), giving exemplary

yields in both SILs of 90% and 91% (Entry 1 and 2, Table 4.5). This result

was followed with the introduction of 4-tolualdehyde (4.44b), also giving

an excellent yield of 90% in [Li(G3)]TFSI (Entry 3, Table 4.5). Replicating

this reaction in [Li(G4)]TFSI also gave a very good yield of 86% (Entry 4,

Table 4.5).

The use of 4-nitrobenzaldehyde (4.44c) showed good yields of 69% and

59% in [Li(G3)]TFSI and [Li(G4)]TFSI, respectively (Entry 5 and 6, Table

4.5). The presence of the nitro group in the 4 position of benzaldehyde

greatly influences the δ+ carbon at the base of the carbonyl group,

resulting in some formation (17% by 1H NMR spectroscopy) of the α-

85

hydroxyphosphonate 4.46 through the direct attack of the phosphite on 4-

nitrobenzaldehyde (Figure 4.10). This has been observed before and the

1H NMR data is consistent with literature values.218 This undesired

outcome was not seen with other aldehyde derivatives, and most likely

due to the electron deficient aldehyde, reacting with the phosphite before

or in competition with the imine formation.

Figure 4.10 Formation of α-hydroxyphosphonate 4.46 from 4-nitrobenzaldehyde and diphenyl phosphite 4.38. α-Aminophosphonate product 4.44c also shown for reference. 1H NMR spectrum (CDCl3) shows the presence of α-hydroxyphosphonate relative to the α-aminophosphonate 4.45c.

Good, consistent yields of 77% and 78% were observed for 4-

fluorobenzaldehyde (4.44d) in [Li(G3)]TFSI and [Li(G4)]TFSI, respectively

(Entry 7 and 8, Table 4.5). Utilizing salicylaldehyde (4.44e) in the reaction

provided very satisfactory yields of 84% in [Li(G3)]TFSI and 76% in

[Li(G4)]TFSI (Entry 9 and 10, Table 4.5).

Finally, introduction of a bis-substituted aldehyde in 3,4-

dichlorobenzaldehyde (4.44f) further demonstrated the resilience of these

reaction conditions, giving very good yields of 74% and 79% in

[Li(G3)]TFSI and [Li(G4)]TFSI, respectively (Entry 11 and 12, Table 4.5).

It was observed that, in general, [Li(G3)]TFSI proved to be the better

performing solvent of the two SILs in most cases. This is consistent with

previous findings when using these SILs as reaction solvents.

1.00

0.20

86

With the ability of the SILs to facilitate this reaction with a range of

aldehydes and mono- amines, the focus of this study shifted to multiple

reactions of bis-amines (Table 4.6).

Synthesis of Bis-α-Aminophosphonates from Arylenediamines

Table 4.6 Investigation of bis-α-aminophosphonates.

Entry Product R Solvent Yield (%)a

1 4.49a Ph

[Li(G3)]TFSI 64

2 [Li(G4)]TFSI 52

3 4.49b 4-BrPh

[Li(G3)]TFSI 36

4 [Li(G4)]TFSI 65

5 4.49c 4-NO2Ph

[Li(G3)]TFSI 18

6 [Li(G4)]TFSI 33 a Isolated yield

Treating 1,4-phenylenediamine with 2 equivalents of benzaldehyde

(4.47a) and 2.4 equivalents of diphenyl phosphite gave the desired

product 4.49a in good yields of 64% in [Li(G3)]TFSI and 52% in

[Li(G4)]TFSI (Entry 1 and 2, Table 4.6) in only 5 minutes. It should be

noted that the time has been maintained to be consistent with the earlier

investigation.

Changing the aldehyde to 4-bromobenzaldehyde (4.47b) gave the desired

product in 36% and 65% in [Li(G3)]TFSI and [Li(G4)]TFSI, respectively

(Entry 3 and 4, Table 4.6). Finally, incorporating 4-nitrobenzaldehyde

(4.47c) into the bis-α-aminophosphonate structure, giving 4.49c, resulted

in the lowest yield of 18% in [Li(G3)]TFSI, though in [Li(G4)]TFSI a slightly

higher yield of 33% was obtained (Entry 5 and 6, Table 4.6).

87

Unlike the earlier trend of [Li(G3)]TFSI outperforming [Li(G4)]TFSI in the

production of mono-α-aminophosphonates, there seems a reversal in this

trend when introducing substituted aldehydes into the bis-versions of

these α-aminophosphonates 4.49b-c. The reason for this is unclear, but it

was noted that with increasing complexity of structures, so too did the

difficulty in isolation from both SILs increase, mainly the removal of glyme

from the desired products during precipitation.

With these successful examples of para substituted diamino anilines,

analysis of both ortho and meta analogues was conducted (Scheme 4.1).

When coupling 1,3-phenylenediamine (4.50) with benzaldehyde and

diphenyl phosphite, again in 5 minutes, satisfactory, if somewhat reduced

(compared to the 1,4-substitution of phenylenediamine), yields were

obtained. These manifested as 25% in [Li(G3)]TFSI and 33% in

[Li(G4)]TFSI (Scheme 3.1). Presumably the depression of this yield,

relative to the para-substituted version is due to the increase in steric

hindrance.

Scheme 4.6 Synthesis of bis-α-aminophosphonates from ortho- or meta- phenylenediamine in SILs.

Repeating this process with 1,2-phenylenediamine (4.52) gave only 9% in

[Li(G3)]TFSI and [Li(G4)]TFSI failed to provide any product (Scheme 4.1).

This is to be expected as the closer the substituted amines are, the

greater the effect of steric hindrance. Comparing the para, ortho and meta

bis-α-aminophosphonates is an elegant example of this as the respective

yields decrease with the decreasing proximity of the two amino groups.

88

In light of the successful synthesis of bis-variants of α-

aminophosphonates was possible in the determined reaction conditions,

the efficacy of producing a non-C2-symmetric bis-α-aminophosphonate

using different aldehydes was investigated (Scheme 4.2).

Scheme 4.7 Synthesis of a non-C2-symmetric bis-α-aminophosphonate 4.54 from p-phenylenediamine and incorporating different aldehydes in the SILs.

Utilising benzaldehyde initially, the reaction was carried out as described

above, and after 5 minutes 4-tolualdehyde and a second equivalent of

diphenyl phosphite was added and allowed to stir for another 5 minutes

(Scheme 4.2). The product was isolated in good yields from both SILs

(43% in [Li(G3)]TFSI and 26% in [Li(G4)]TFSI) using the same method of

dissolution in diethyl ether and evaporation of the organic into an aqueous

phase, leaving the precipitated product in analytical purity.

The combination of benzaldehyde and p-tolualdehyde was especially

selected for this asymmetric compound as the methyl group of p-

tolualdehyde serves as an easy 1H NMR spectroscopic handle that can

prove the non-C2-symmetric nature of the product via integration ratios

(Figure 4.11).

89

Figure 4.11 1H NMR spectrum of the asymmetric bis-α-aminophosphonate 4.54 in DMSO-d6. The methyl peak at δ2.24 integrates for 3 when the chiral protons (δ5.35) are set to 2, confirming asymmetry.

It can be seen in Figure 4.11 that the methyl peak of compound 4.54 at

δ2.24, integrates for 3 protons. When this is compared with the proton at

each of the chiral centers (δ5.35), which integrate for 2 total, it is clear that

the product contains one equivalent of benzaldehyde and one of p-

tolualdehyde. This is further confirmed by the integration of the amine

resonances (~δ6.1) that both integrate for one proton each.

Given the prominent therapeutic impact of α-aminophosphonates in the

literature, each of the analogues synthesized were sent to collaborators at

Bond University to be assessed for their application as prostate cancer

inhibitors. Interestingly, the simple aniline and benzaldehyde derivative

showed very good anti-proliferative specificity for leukemia cell line (1-

5 μM level) when it was investigated amid other medicinal compounds

from our research group. This data was considered too preliminary to

include in full for this chapter, but was worth mentioning

This work was collated and published in RSC Advances:

Eyckens, D. J. and L. C. Henderson (2017). "Synthesis of α-

aminophosphonates using solvate ionic liquids." RSC Advances 7(45):

27900-27904. IF: 3.11, citations: 2

90

Application of an α-Aminophosphonate as a Flame Retardant

Introduction

The above work lead to the investigation of the α-aminophosphonate

moiety in a materials application as a potential flame retardant. Given the

multi-disciplinary nature (carbon fibre composites, medicinal, inorganic

complexes and engineering) of the author’s research group, many

broader concepts are brought to attention. It was apparent from the

literature that the introduction of phosphorus to resin systems improves

the system’s fire resistance.219-224 This is not a new area of research,

though with the increasing use of epoxy-dependant composites in many

industrial sectors, it is fast becoming a priority for numerous areas of

academia and industry.

Most commonly resin systems consist of two main compounds; a bis-

epoxide bearing compound and a bis-amine (Figure 4.12), that when

combined, produce a dense polymer matrix that at a basic level serves as

an adhesive, and at a complex level, as the basis of automotive and

aerospace parts.

Figure 4.12 General structures bis-epoxy and bis-amine compounds.

Given the synthetic potential of epoxides and amines as versatile

functional groups, it is possible to take advantage of this and install new

material properties, including flame retardance. Commonly, this occurs

91

through introduction of flame retardants containing halogen species,225-226

phosphorus227-229 especially in conjunction with nanoclay additives.230-232

Generally, the installation of flame retardant characteristics occurs via the

covalent incorporation of the flame retardant compound into the polymer

network (Figure 4.13, phosphorus-derived retardants in green),233-238 or

through an inorganic additive (Figure 4.13, encapsulates in brown). The

latter option often leads to changes in mechanical properties and may

form aggregates in a resin system, reducing the homogeneity and

ultimately, the efficacy of the flame retardant’s application.239-240

Figure 4.13 Comparison of the use of flame retardant additives (brown particles, left) to covalently incorporating inherently flame-retardant compounds (green sections, right).

The introduction of phosphorus units into the structure of curing agents

(Figure 4.14) is a common method219-224 of reducing the flammability of

polymer matrices, but these structures often require specific target design,

and multiple synthetic steps to reach this target.

92

O

PN

PN

P

N

HN

NH

NHHN

NH

Ph

Ph

Ph

Ph

Ph

PN

PN

P

N

NH

HN

HN NH

HN

Ph

Ph

Ph

Ph

Ph

O

P

O

NH2H2N

NH

NOH

O

NH

NHO

O

N N

OP

O

MeOOMe

OP

O

OMeOMe

4.55(3 steps*)

4.56(3 steps, overall yield: 16%)

4.57(4 steps, overall yield 35%)

Figure 4.14 Literature examples of phosphorus-containing flame retardants. *Overall yield unable to be calculated based on information in the corresponding publication. Compound references: 4.55,229 4.56,241 4.57.242

Each of the examples displayed in Figure 4.14 require multiple synthetic

steps before the desire product can be realised and introduced for testing.

4.55 is accessed in three steps but the overall yield was unable to be

calculated from the published information.229 Similarly, compound 4.56

was synthesised in three steps, with an overall yield of 16%.241 This

reduces the viability of this compound to be used in large scale

applications, given the initial steps would require large quantities to

achieve practical amounts of product.

Finally, the deceptively simple looking compound 4.57 was produced in 4

synthetic steps, in an overall yield of 35%.242 This compound suffers from

the same scale up restrictions as the former.

The benefit of the approach presented herein is that it is rapid, simple,

and potentially applicable to many different curing agents. These

compounds could be rapidly accessed in good yields, ready for

application into the resin system.

The bis-amine, herein referred to as the ‘curing agent’ or ‘hardener’, was

the subject of manipulation for the introduction of an α-aminophosphonate

moiety.

93

Flame retardance

The mechanism of flame retardance occurs through two main avenues,

the first is the release of radical scavenging and non-combustible gases,

mainly exhibited by halogen-based flame retardants (Figure 4.15, left).243

In the case of phosphorus derivatives, the process is characterised by the

formation of a char layer on the outside of the material, preventing further

incineration (Figure 4.15, right).

Figure 4.15 Mechanism of degradation when a sample is degraded by fire.243

A typical means of testing flame retardant capability is by using

thermogravimetric analysis (TGA).244 The model TGA trace (Figure 4.16)

compares the expected TGA traces for a neat resin and the same resin

which has an “active” flame retardant with in the backbone. The

decreased flammability is characterised by a decrease in the onset

temperature of degradation (Point 1, Figure 4.16), while the formation of a

char layer occurs at a higher weight percent (Point 2, Figure 4.16). This

results in a higher residual weight in the flame retardant sample compared

to the original sample, at the same temperature (Point 3, Figure 4.16).

Typically, a temperature between 400 – 600 °C is used to compare the

char yield as this is where a plateau occurs in the TGA trace. The

formation of char serves to lessen flame proliferation, though in the case

of the TGA, if the external temperature continues to rise, the end result is

the same and total degradation of the sample is observed.

94

Figure 4.16 Example TGA trace showing the effect of increasing flame resistance from an original sample.

Compound Design

Figure 4.17 demonstrates the general design of the α-aminophosphonate

derived flame retardant, with the aim to promote covalent integration into

the polymeric backbone of the resin system. The amine was converted to

the mono-α-aminophosphonate to allow the aromatic primary amine to

crosslink with the epoxy resin, similar to the parent diamine.

Figure 4.17 General design of the α-aminophosphonate based flame retardant used in this study.

This type of mono-substitution had already been achieved in earlier work

in this chapter with diamines, and deeper incorporation into the matrix has

95

shown to have an enhanced benefit in flame retardance as well as

maintaining mechanical properties.239-240

In this work, the commercial hardener 4,4’-diaminodiphenylmethane (4.58,

Scheme 4.3) was selected as the starting scaffold, due to its similarity to

previous aromatic aniline derivative explored earlier in this chapter.

Scheme 4.8 Mono-α-aminophosphonation of 4,4'-diaminodiphenylmethane (DDM, 4.58).

The synthesis of 4.59 was carried out on a gram scale in [Li(G3)]TFSI in

30 minutes at room temperature in good yield of 71% using benzaldehyde

and diphenyl phosphite as the other components of the reaction. Although

there are many examples of halogen-containing flame retardants in the

literature,225-226 the use of a halogen-substituted aldehyde was not

considered as the expulsion of potentially toxic gases is often a result of

halogen-derived flame retardants.245

With the desired compound in hand, attention was turned to the

incorporation of this compound into an epoxy resin system. It should be

noted at this point, that although all synthesis, physical burning tests and

project design was conducted by the author, the production of resin

samples and subsequent investigation by thermogravimetric analysis

(TGA) was carried out by a research student (Melissa Stanfield) under co-

supervision of the author. All collation, interpretation and refining of results

into a journal article (under review) remained the task of the author. For

these reasons, the following is presented briefly, with a focus on

outcomes.

Evaluation

The epoxy system chosen (RIMR937/RIMH935 - Hexion) was one that

was familiar to our research group, and is common in automotive

applications. The flame retardant compound 4.59 was introduced to the

96

system as a weight percentage (wt%), in place of the given percentage of

hardener. Unfortunately, being proprietary mixtures, there is great

difficulty in determining a mol% loading of the α-aminophosphonate,

which would have been preferable.

To determine a pseudo-dose-response relationship, 10 wt%, 20 wt% and

30 wt% were investigated. These values correspond to phosphorus

percentage contents of 0.16P%, 0.33P% and 0.49P% respectively, and

are quite low loadings in regard to literature examples (up to 6.39%).228,

239, 246

Table 4.7 Calculation of phosphorus in a molecular compound.

Compound Molecular Formula

Mw Molecule

P% C H N O P 12.0107 1.0079 14.0067 15.9994 30.9738

4.59 32 29 2 3 1 520.56 0.060 Literature Example228

0 4 1 3 1 97.01 0.32

To calculate the P% loading of the final resin samples, first the percentage

of phosphorus in the molecule was calculated. This was done by dividing

the standard atomic weight of phosphorus by the total molecular weight of

the compound, as seen in Table 4.7. Also shown is an example from the

literature.

From here the loading in each sample is calculated by multiplying the

molecule percentage of phosphorus by the mass of the flame retardant

used in the sample, then dividing this number by the total weight of the

resin mixture before multiplying by 100.

97

Table 4.8 - Calculation of P% in given resin samples.

Compound Mass ratios (g)

P% RIMR935 RIMH937 4.59

Baseline 4.34 1.64 0 0.00 10 wt% 4.34 1.49 0.1652 0.16 20 wt% 4.34 1.32 0.33 0.33 30 wt% 4.34 1.15 0.496 0.49

RTVa APPb P% Literature 100 25 6.39

a Room temperature vulcanised silicone rubber. b Ammonium polyphosphate.

The curing of these resin samples was done by adhering to the

manufacturer’s specifications; precuring at room temperature for 2 days,

followed by 12 hours at 100 °C. These are typically the conditions for

systems using aliphatic or alkyl amines as curing agents (which is the

case for RIMH935). It was reasoned that the 2° aromatic amine,

possessed by 4.59, may require a more rigorous curing procedure, so a

second set of samples were produced. These used the specified 12 hours

at 100 °C initial curing, followed by a post cure of 5 hours at 150 °C. This

first set of samples (12 hours at 100 °C) are referred to as standard cure

(SC) and the latter are referred to as post cured (PC).

Figure 4.18 TGA trace of standard cure (SC) samples in an oxidative environment (air), dotted line indicates the temperature (520 °C) at which char yield was determined.

0

10

20

30

40

50

60

70

80

90

100

100 200 300 400 500 600 700

Wei

ght %

Temperature °C

Control SC

0.16 P% SC

0.33 P% SC

0.49 P% SC

98

Thermogravimetric analysis of the SC samples in an oxidative

environment showed a good trend of flame retardance with introduction of

4.59 at all P% investigations, typified by lower onset temperatures

compared to the control (blue line, no added flame retardant, Figure 4.18).

In the region of 480 – 550 °C, the plateau section (representing the char

yield) is noticeably increased with increasing phosphorus content.

Analysing the post cure samples using the same method revealed similar

trends of decreased onset temperatures and the elevation of char yields

with introduction of 4.59 (Figure 4.19). This is to be expected, given the

previous results, however when comparing the PC samples to the SC,

there is a noticeable increase in flame retardance (Table 4.9).

Figure 4.19 TGA trace of post cured (PC) samples in an oxidative environment.

0

10

20

30

40

50

60

70

80

90

100

100 200 300 400 500 600 700

Wei

ght %

Temperature °C

Control PC

0.16 P% PC

0.33 P% PC

0.49 P% PC

99

Table 4.9 Thermogravimetric analysis results.

Entry Sample T10%a

T10%

(°C)b

Char yield at

530 °C (%)

Char yield

(%)b

1 Control 345.9

(348.1) - 14.4 (14.0) -

2 0.16 P% 317.1

(328.4)

-28.8

(-19.7) 17.1 (21.2) 2.7 (7.2)

3 0.33 P% 313.8

(323.4)

-32.1

(-24.7) 18.8 (21.0) 4.4 (6.6)

4 0.49 P% 316.6

(323.9)

-29.3

(-24.2) 23.0 (25.5) 8.6 (11.1)

Values in parenthesis refer to samples post-cured (PC) at 150 °C for 5 hours. a The temperature at which 10% weight loss occurred. b The difference between the flame retardant sample and the control.

Initial analysis of the 0.16 P% standard cure sample showed a change in

the temperature at which 10% weight loss occurred (T10%) of -28.8 °C

from the control SC and an increase in char yield of 2.7% (Entry 2, Table

4.9). Examining the post-cured samples of the same P% demonstrated a

similar decrease in T10% of -19.7 °C and an increase of char yield from

14.0% to 21.2% (Entry 2, Table 4.9). These relative decreases and

increases, respectively, demonstrate the strong ability of 4.59 to impart

flame retardance at very low loadings.

Increasing the amount of 4.59 to give 0.33 P% resulted in further

decreases in T10% (-32.1 °C SC and -24.7 °C PC) compared to the

controls, as well as increases in char yields of 4.4% and 6.6% for

standard cured and post cured samples, respectively (Entry 3, Table 4.9).

T10% values of 316.6 °C and 323.9 °C (SC and PC) were achieved at the

highest P% of 0.49 (Entry 4, Table 4.9), coinciding with the greatest

increases in char yields with the SC increasing by 23.0% and the PC

samples increasing by 25.5% relative to the controls (Entry 4, Table 4.9).

The significant decrease in T10% at 0.16 P% incorporated does not see a

linear response when doubling the P%, rather hits a plateau maintaining

at similar values with increasing P%. This shows the significant impact

100

only a small loading may incur. Interestingly, it seems that the post curing

procedure has an impact on the efficacy of the flame retardant 4.59. The

increases in char yields are higher than those observed for the standard

cured samples, suggesting that the post cured samples may have had

better incorporation of the α-aminophosphonate into the polymer

backbone.

With the successful results of the flame retardant 4.59 in hand,

performance in a physical burn test was undertaken. Small samples of

resin, both SC and PC at the same P% already discussed where

subjected to ignition in a butane torch for 10 seconds, then allowed to self-

extinguish and the time taken (Table 4.10).

Table 4.10 Results of physical flame test.

Entry P% Burn Time(s)a Mass Loss (%)b

1 0.00 60 (48) 83.6 (87.6)

2 0.16 33 (23) 69.2 (70.2)

3 0.33 27 (20) 61.5 (58.5)

4 0.49 24 (24) 55.7 (58.7)

Values in brackets refer to post cured samples. a Time take to self-extinguish after 10 seconds of ignition. b Mass lost after flame test.

The control SC sample, when subjected to the burn test took 60 seconds

to self-extinguish and lost 83.6% of its original mass after self-

extinguishing (Entry 1, Table 4.10). This was slightly improved upon from

post curing alone, which showed a 48 second burn time, although the

mass loss was slightly higher (87.6%, Entry 1, Table 4.10).

Even small amounts of 4.59 (eg. 0.16 P%) was enough to elicit an almost

halved burn time (33 seconds) compared to the control for the SC

samples, and a slightly more than halved burn time (23 seconds) for the

PC sample (Entry 2, Table 4.10). The mass lost from burning these

samples was also reduced compared to the controls for both SC (69.2%)

101

and PC (70.2%) samples (Entry 2, Table 3.8), suggesting successful

formation of a char layer.

Increasing to 0.33 P% saw reductions in burn time to 27 seconds (SC)

and 20 seconds (PC), and in mass loss percentage (61.5% SC and 58.5%

PC) across all samples (Entry 3, Table 4.10). Interestingly, the highest

loading of 0.49 P% gave the same burn time of 24 seconds for both the

SC and PC samples (Entry 4, Table 4.10). This represented a reduction in

burn time with increasing P% in the SC samples, but was the longest

value for the PC samples. Despite this, the results obtained demonstrate

a good deal of flame retardancy with only minimal loading of 4.59, and the

differences in burn time are most significant compared to the control. 0.49

P% also resulted in the lowest mass loss of 55.7% in the SC samples,

and 58.7% in the PC samples.

Figure 4.20 is a visual demonstration of the reduction in flammability of

resin samples when increasing the loading of 4.59.

Figure 4.20 Images of given resin samples, after physical burn test. Larger particles correspond to higher phosphorus content in both standard cure (SC) and post cure (PC) samples, demonstrating a reduction flammability.

Increasing the P% loading in the resin samples clearly shows the larger

particle size after the burn test. This represents a real-world advantage, in

that a given composite may not fail completely, if there is substantial

residual mass and the fire is self-extinguished soon enough.

The reduction in burn times of these samples and their increase remaining

mass after burning, coupled with the findings of TGA, demonstrate the

0.16 P% SC

0.33 P% SC

0.49 P% SC

Control PC

0.16 P% PC

0.33 P% PC

0.49 P% PC

102

strong ability of 4.59 to decrease flammability in an epoxy resin system at

low loadings. The acquisition of the desired compound is rapid and

effective, in high yield and may, in future, be applicable to a range of

different curing agents. This study has highlighted the application and

success of an α-aminophosphonate moiety for better flame resistance.

This is work was collated and is submitted to Polymer Degradation and

Stability:

Stanfield, M. K., Stojcevski, F., Hendlmeier, A. J., Varley, R. J., Eyckens,

D. J., Henderson, L. C. (2018). “Phosphorus based α-amino acid mimetic

for enhanced flame retardance in an epoxy resin.” Aust. J. Chem.,

available online.

Chapter Summary

This chapter discussed the application of solvate ionic liquids [Li(G3)]TFSI

and [Li(G4)]TFSI in the production of α-aminophosphonates. This was

achieved rapidly (5 minutes), at room temperature, and demonstrated

excellent yields (up to 97%) across a range of substrates.

This was greatly improved from other literature examples that required the

use of expensive or toxic catalysts, extended reaction times and high

temperature to access these compounds.

Also synthesized were bis-α-aminophosphonates, including a non-C2-

symmetric example. These bis-compounds are less frequent in the

literature, and the methodology of mono-functionalising a bis-amine was

extend to the production of an epoxy resin curing agent, with a primary

amine on one side, and an α-aminophosphonate moiety on the other.

This mono-substituted compound was then employed in epoxy resin

samples at incremental loadings to determine the reduction in flammability

with introduction of phosphorus compounds. This was confirmed by

thermogravimetric analysis and physical burning tests, proving a clear

103

reduction in flammability with higher concentrations of the α-

aminophosphonate derivative.

The work described in this chapter was collated into two publications.

104

105

– Synthesis and Evaluation of an Ion-Tagged

Organocatalyst

Introduction

Chirality

Chirality describes the specific arrangement of a molecule and its

substituents in three-dimensional space. A molecule is chiral if it does not

contain a plane of symmetry, or if it has a nonsuperimposable mirror

image. This usually relates to a carbon atom, though can extend to other

atoms,247-249 albeit with greater complication of rules and conventions

surrounding its description (i.e. R or S). In the context of this thesis, the

chirality of compounds is due to the presence of an asymmetric carbon

atom (in which all four substituents differ) referred to as a chiral or

stereogenic centre.

COOHC

H OH

ClHOOCC

HHO

Cl

5.1a 5.1b

Figure 5.1 A pair of stereoisomers (enantiomers) with a chiral carbon centre.

Stereoisomers are molecules with the same molecular formula, but with a

different spatial arrangement of atoms. Due to this fact, compounds can

exist as a range of stereoisomers, even as a product of the same reaction.

Stereoisomers is a broad term that encompasses diastereomers,

enantiomers and atropisomers possessing helical or rotational chirality.

Diastereomers are non-mirror images of the same molecule that have at

least one, but not all of their chiral centres inverted. Enantiomers are

stereoisomers that have all stereocentres inverted, and are assigned

either (R)- or (S)- depending on arrangement of priority substituents in

three-dimensional space. They are mirror images of each other, but

neither can be superimposed on the other, regardless of how they are

orientated. A diagram depicting these terms is shown below (Figure 5.2).

106

Figure 5.2 Diastereomers and enantiomers of a chiral molecule.

The need for producing compounds of high enantio-purity is derived from

the fact that different enantiomers of the same compound can have

devastingly contrasting effects when introduced to a biological system.

The example of the anti-tuberculosis medication Ethambutol is an

excellent example of this, as the compound can exist as two enantiomers

(either S,S- or R,R-). One of these enantiomers treating tuberculosis, and

the other causing blindness via destruction of retinal ganglion cells (Figure

5.3).250-251

Figure 5.3 Enantiomers of Ethambutol, (S,S)-Ethambutol treats tuberculosis, whilst (R,R)-Ethambutol causes blindness.

Methods of inducing chirality

In the endeavour to synthesise highly enantiopure compounds, an

invaluable tool in the synthetic chemist’s arsenal is the asymmetric

catalyst. A catalyst works by lowering the activation energy of a reaction,

allowing a greater reaction rate. An extension of this in terms of

asymmetric catalysis, is that a chiral catalyst lowers the activation energy

for only one enantiomeric product.

107

Figure 5.4 Reaction profile. Left: General; Right: Asymmetric showing preference for the S-isomer via lower activation energy.

There are three main categories of asymmetric catalysis, often referred to

as the three pillars of catalysis. The first are enzymes that are isolated

from a biological source. The second are that of transition-metal catalysts,

a catalogue of catalysts known for their efficiency and broad utility in

organic synthesis.

The third, organocatalysts, are small molecules that are positively

regarded for their high tolerance to air and moisture. Though they do

suffer for the relatively high catalytic loading required (≥ 10 mol%) to

obtain synthetically useful yields.

There have been many examples in the literature of organocatalysts,252-255

though the most pertinent to this study is the use of the amino acid

proline. First applied to the aldol reaction between acetone and 4-

nitrobenzaldehyde by List et al.,256 (S)-proline (5.4) was demonstrated as

one of the best performing organocatalysts from a range of amino acid

derivatives (Scheme 5.1).

Scheme 5.1 (S)-proline catalysed asymmetric aldol reaction between acetone (5.2, 20 vol% of DMSO) and 4-nitrobenzaldehyde (5.3).256

108

This example was only succeeded by the use of trans-4-hydroxy-(S)-

proline (5.6), with an excellent yield of 85% and ee of 78% (Scheme

5.2).256

Scheme 5.2 trans-4-Hydroxy-(S)-proline catalysed asymmetric aldol reaction between acetone (5.2) and 4-nitrobenzaldehyde (5.3).256

These examples demonstrate the success found when using

organocatalysts, though also exemplify the high catalytic loading required

when using these types of catalysts. The use of proline-based

organocatalysts (including those that are substituted in the 4-position) still

is still being reported in contemporary literature, and reaction conditions

surrounding its catalytic efficiency are improving.257-260

These secondary amine catalysts typically operate through an enamine

mechanism, shown below with the example of (S)-proline (Figure 5.5).256

109

Figure 5.5 Catalytic cycle of the asymmetric aldol reaction with (S)-proline (5.6) as the catalyst.256

The catalytic cycle shown above is characterised by the condensation of a

ketone with proline, forming an iminium ion (5.9). This may rearrange to

give the enamine resonance structure (5.10), which can then react with an

aldehyde, reforming an iminium ion (5.13). Finally, the addition of water

serves to expel the aldol product (5.15) and regenerate the proline

catalyst (5.6).256

Ion-Tagged Organocatalysts

Organocatalysis is an ever-growing area of research, though suffers from

some disadvantages, such as the aforementioned high catalytic loading

as well as an inability to reuse the catalyst after reaction. Efforts in

improving the recyclability of these compounds involved conjugation to a

solid support, to remove the tethered catalysts by filtration.261-265 Recently,

the introduction of imidazolium salts into the catalyst structure has been

used to control the solubility properties of the catalyst to employ selective

solubilisation techniques as a means of separating products and

catalysts.67, 264, 266-274

110

Figure 5.6 trans-4-Hydroxy-(S)-proline 5.6.

Many of the published imidazolium-supported catalysts utilise the 4-

hydroxy-(S)-proline scaffold 5.6 via attachment at the 4-hydroxyl moiety.

This method leaves the amine and carboxylic acid moieties of the proline

unmodified, and has been shown to be a successful strategy in producing

efficient catalysts of broad scope. Zlotin et al.67 recently reported an

exception to this method, in which a C2-symmetric bis-prolinamide

organocatalyst (5.16) was produced, and retained good catalytic activity

despite the absence of the α-carboxylic acid of the proline motif.

Figure 5.7 C2-symmetric catalyst linked at C-terminus of proline motif and example asymmetric aldol reaction.67

Catalyst 5.16 was accessed in a good yield of 51% over 5 steps and was

subsequently evaluated in the asymmetric aldol reaction. The

replacement of the terminal carboxylic acid with an amide showed no

deleterious effects to the catalytic activity of 5.16, nor did the incorporation

of the ionic moiety from the oxygen in the 4-position. The catalyst showed

excellent catalytic activity across a range of substrates when employed in

an asymmetric aldol reaction, on water. The best of these results was the

reaction between cyclohexanone 5.17 and benzaldehyde 5.18 to form

diastereomers 5.19a and 5.19b. The transformation was achieved with

99% conversion and excellent dr (95:5, anti:syn) and exceptional ee

(96%, Figure 5.7).

111

In another example published by the Zlotin group,266 a catalyst was

produced with an ionic moiety attached via the oxygen in the 4-position,

and the absence of a carboxylic acid group, though this time installing a

(S)-diphenylvalinol fragment (5.20, Figure 5.8). (S)-Diphenylvalinol

originates from the amino acid valine, where it derives its chirality. The

combination of two-chiral, amino acid units (proline and valine) conveys a

strong preference for the formation of a particular stereoisomer in

asymmetric reactions. Catalyst 5.20 was realised in in an overall yield of

54% over 5 steps and was also employed in the asymmetric aldol

reaction.

Figure 5.8 4-hydroxyproline based organocatalyst with (S)-diphenylvalinol moiety (5.20) and example asymmetric aldol reaction.266

The best reaction outcome was achieved when catalyst 5.20 was use with

cyclohexanone 5.17 and aldehyde 5.21 at a catalytic loading of 1 mol%,

giving excellent conversion (99%), dr (99:1, anti:syn) and ee (99%) in 15

hours, but perhaps most notably the reaction was performed at 3 °C

(Figure 5.8). the authors do not elaborate on this choice of temperature,

but it is likely linked to the enantiopurity.

The recyclability of catalyst 5.20 was also examined, utilising the reaction

between cyclohexanone 5.17 and 4-nitrobenzaldehyde 5.3 (Table 5.1).

112

Table 5.1 Recycling study by Zlotin et al. 266

Run Conversion (%) dr (anti:syn) ee (anti %)

1 98 99:1 99

2 97 99:1 99

3 95 >99:1 99

4 72 >99:1 >99

The catalyst demonstrated excellent recycling capabilities, with minimal

depression in conversion in the first 3 runs and a drop to 72% only in the

final run (Table 5.1). Contrary to this, the dr and ee were maintained

throughout the recoverability study (Table 5.1).

Interestingly, the group also tested a compound formed in the penultimate

step in the synthesis of 5.20, varying only in the anion (Br instead of PF6,

5.23).

Figure 5.9 4-Hydroxyproline based organocatalyst with (S)-diphenylvalinol moiety and example asymmetric aldol reaction.266

Despite this change in anion, 5.23 still exhibited good catalytic activity,

catalysing the asymmetric aldol reaction between cyclohexanone (5.17)

and 4-nitrobenzaldehyde (5.3) in water at 5 mol% in 20 hours (Figure 5.9).

The reaction maintained excellent conversion (99%), though a slight

depression in dr of 85:15 (anti:syn) as well as reduction in ee (89%),

113

compared to the PF6- anion. This demonstrated the subtle effect on

catalytic activity that different anions may cause. Nonetheless, both

anionic varieties (5.20 and 5.23) are an example of the success found

when the carboxylic acid moiety is replaced with an amide group.

For this project, attachment of an organocatalyst to an ionic support was

proposed. This would be achieved through an amide bond in place of the

carboxylic acid of trans-4-hydroxy-(S)-proline 5.6, rather than the oxygen

at the 4-position as previously demonstrated in the literature.

An imidazolium salt was installed from the C-terminus of trans-4-

hydroxyproline scaffold. In addition to the potential improvement in

catalyst recycling, it was proposed that the hydrogen bonding abilities of

the imidazolium group in close proximity to the amine of the proline unit

may assist the catalytic activity of the compound.275-276 The incorporation

of the imidazolium cation, is consistent with the previously mentioned

organocatalysts, as is the anionic component, PF6-, though anionic

variation will be tested. In keeping with published 4-hydroxyproline based

organocatalysts, the final product should also include a tert-

butyldiphenylsilyl group at the 4-position, to allow broad comparison and

reduce unwanted interactions.277-279

114

Synthesis of an Ion-Tagged Organocatalyst

The design of the ion-tagged organocatalyst and retrosynthetic analysis is

shown in Figure 5.10. The introduction of an ion tag is achieved through

the quarternisation of an imidazole moiety (5.25), which may be attached

via amide formation between 5.26 and the commercially available 1-(3-

aminopropyl)imidazole.

Figure 5.10 Retrosynthetic analysis of the ion-tagged organocatalyst target compound 5.24.

Prior to the amide formation, both the amine and 4-hydroxy atoms of

trans-4-hydroxy-(S)-proline (5.6) must be protected to give 5.26. This is to

limit side reactions, and the protection of the 4-hydroxy group is desired in

the final product 5.24. The anion may be altered through anion metathesis

when the final structure is obtained and the amine of the proline unit

should be deprotected at this final stage.

There is also the option for further derivatisation from the 4-OH position,

though this is beyond the scope of this study.

The organocatalyst component is derived from trans-4-hydroxy-(S)-proline

(5.6) and the ionic component is an imidazolium-based cation with a

hexafluorophosphate (PF6-) anion. This ionic moiety will be attached via

amide bond formation at the carboxylic acid portion of proline. It is also

necessary to protect the hydroxy group in the 4-position to minimise

unwanted interactions at this site.

115

Scheme 5.3 TBDPS protection of the hydroxyl group at the 4-OH position, followed by Boc-protection of the secondary amine to 5.26.

The protection of the hydroxyl group in the 4-position of the proline

backbone required the addition of tert-butyldiphenylsilyl chloride (TBDPS-

Cl) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) to achieve the desired

product 5.27 in a yield of 61% in 24 hours (Scheme 5.3). The next step

involved the protection of the amine with Boc anhydride, requiring sodium

hydroxide (NaOH) to facilitate this reaction, giving the protected-amine

5.26 in good yield (74%) in 16 hours (Scheme 5.3).

Scheme 5.4 Amide formation and alkylation synthesis steps.

With 5.26 in hand, attention was then turned to amide formation with 3-

aminopropylimidazole (5.28) to give 5.25 in excellent yield (99%, Scheme

5.3). Treatment of 5.25 with methyl iodide under microwave irradiation to

quarternise the imidazolium nitrogen gave 5.29 in good yield, 79%

(Scheme 5.3).

116

Scheme 5.5 Production of ion-tagged organocatalyst 5.30 and 5.31.

From 5.29, the removal of Boc using 10% trifluoracetic acid (TFA) in DCM

gives product 5.30 in good yield (73%, Scheme 5.3). This is accompanied

by the concomitant exchange of anion from iodide to trifluoroacetate,

indicated by the shift of the H2 proton observed by 1H NMR spectroscopy

(Figure 5.11). The two peaks for the PF6- salt is likely due to facial

preference for the anion. This is consistent with other procedures and

isolate imidazolium tags in the literature. This may also be seen to a

lesser extent with the broad peak of the TFA- salt and the slight shoulder

of the iodide version (Figure 5.11). Isolation of 5.30 was achieved by

careful organic extraction and washing with sodium bicarbonate.

117

Figure 5.11 Overlayed 1H NMR spectra showing variation of the H2 proton on the imidazolium group, relative to each anion. Iodide = green, PF6 = red, TFA = blue.

This gave the first ion-tagged organocatalyst for testing, though it was of

interest to investigate how varying the anion may manipulate the physical

behaviour of the catalyst. Therefore, 5.30 was treated with potassium

hexafluorophosphate (KPF6) to initiate an anion metathesis, giving

product 5.31 in good yield in only 90 minutes (82%, Scheme 5.3).

Organocatalysts 5.30 and 5.31 were both investigated for the physical

properties, and only 5.31 identified as an ionic liquid, with a melting point

of 66.3 °C, well below the generally accepted 100 °C cut-off. The melting

point of 5.30 was 118 °C, thus not technically an ionic liquid, therefore

isothermal thermogravimetric analysis was only conducted with 5.31 at

100 °C to determine evaporation phenomena, if any (Figure 5.12). After

80 minutes at 100 °C, no major loss in weight was observed for this

compound, consistent with the behaviour of ionic liquids and the fact of

their negligible vapour pressure. Initial loss in sample weight is

presumably due to the evaporation of water from the solid sample and the

variation seen is typically <10% than the sample weight. Additionally,

Iodide

PF6

118

differential scanning calorimetry (DSC) was conducted on 5.31, giving a

glass transition temperature (Tg) of 14.5 °C (Figure 5.12).

Figure 5.12 Isothermal TGA showing no evaporation of 5.31 when in the liquid state (left) and DSC showing Tg (right) with key curve (inset).

Evaluation of 5.30 and 5.31 as Organocatalysts

With the successful production of organocatalysts 5.30 and 5.31, attention

was then turned to their evaluation as organocatalysts. The direct

asymmetric aldol reaction was chosen for this evaluation, as it is a

benchmark for asymmetric catalysis in the literature.261, 277-279

119

Table 5.2 Optimisation of organocatalyst 5.30 and 5.31.

Entry Catalyst Solvent Time

(h)

Conversion[a]

(%)

dr[a]

(anti:syn) er[b]

1 - Neat 24 0 0 0

2 5.30 Neat 72 97 1:1 -

3 5.30 H2O 24 93 71:29 60:40

4 5.30 Neat 24 88 68:32 53:47

5 5.30 CHCl3 24 15 72:28 -

6 5.31 Neat 24 99 80:20 77:23

7 5.31 H2O 24 71 85:15 76:24

8 5.31 Neat[c] 24 96 96:4 92:8

9 5.31 CHCl3 24 18 82:18 -

[a] Determined by 1H NMR spectroscopy. [b] Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95). [c]

Reaction carried out in 0.25 mL (12.5 eqivalents) of 5.17. Reaction conditions: Aldehyde (0.1 mmol), ketone (0.5 mmol), and catalyst (20 µmol), in water (250 µL) were stirred for 24 hours at room temperature, followed by aqueous work-up Note: no HPLC was conducted when conversion was < 20%.

Optimisation began with catalyst 5.30, and showed full conversion by 1H

NMR spectroscopy in 72 hours, however no diastereomeric enrichment

was achieved, which may have been due to the extended reaction time

(Entry 2, Table 5.2).

The conversion of the initial aldehyde into the target compound was

determined by the integration of key peaks within the 1H NMR

spectrum (Figure 5.13). The diastereomeric ratio was determined by

integration of the chiral proton peaks for both the syn- and the anti-

diastereomers (Figure 5.13). All compounds show 1H NMR spectra

consistent with previously published compounds.

120

Figure 5.13 Example 1H NMR spectrum for determining reaction outcomes of crude product 5.32.

The key 1H NMR signals that are integrated are determined from reported

examples and lie in uncluttered regions of the NMR spectra (Figure 5.14).

Figure 5.14 Chemical shifts for the diagnostic peaks of the asymmetric aldol reaction.

Repeating the reaction on-water at a reduced reaction time resulted in a

similar conversion (93%), but an improved dr of 71:29 (anti:syn, Entry 3,

Table 5.2). Unfortunately the product possessed minimal enantio-

enrichment (5%). Maintaining the reaction duration under neat reaction

conditions resulted in a reduced conversion (88%) and dr 68:32 (anti:syn,

Entry 4, Table 5.2). This is consitent with the literature, as neat conditions

result in a homogenous mixture, while the addition of water creates and

emulsion giving an ‘on-water’ effect that enhances reaction outcomes.277-

290 This phenomena is supported when reacting 5.30 in an organic solvent

syn

anti

121

which gave very poor conversion to the desired product (15%, Entry 5,

Table 5.2).

To determine the effect that the counter ion has on catalytic activity,

catalyst 5.31 was employed in the optimisation proceedure. This resulted

in quantitative conversion under neat reaction conditions in 24 hours, with

a good dr of 80:20 and er of 77:23 (Entry 6, Table 5.2). Conducting the

reaction in water reduced conversion (71%) and er (76:24), but did offer

slightly better dr with 85:15 (anti:syn, Entry 7, Table 5.2). To ensure

complete solvation in the neat reactions a vast excess of 5.17 was

employed, giving excellent conversion (96%), dr (96:4, anti:syn) and er

(92:8) (Entry 8, Table 5.2). Finally, assessing 5.31 in an organic solvent

demonstrated poor conversion (18%), though a good dr of 82:18 (anti:syn)

was maintained (Entry 9, Table 5.2).

The preliminary evaluation of the organocatalysts 5.30 and 5.31

demonstrate the ease of manipulation of the catalyst by simply changing

the anionic component. The influence of the anion has been observed in

other works, 291-293 though the effect on catalytic performance is extremely

pronounced in this instance.

The optimal conditions were determined to be the on-water process using

catalyst 5.31 (Entry 7, Table 5.2), despite the best stereochemical

outcome resulting from the large excess of cyclohexanone 5.17 (Entry 8,

Table 5.2). The latter conditions were deemed impractical and thus were

not considered. The scope of catalyst 5.31 was then investigated with a

range of ketones and aldehydes, the latter of which comprised of a cross-

section of substituents on the aromatic portion, representing a variety of

electronic effects on the aldehyde.

122

Table 5.3 Substrate investigation for catalyst 5.31.

Entry R X Product Conversion[a]

(%) dr[a]

(anti:syn) er[b]

1 4-NO2 - 5.40a 99 27:73 54:46

2 H - 5.40b 99 30:70 66:34

3 4-Me - 5.40c 83 34:66 76:24

4 4-Br - 5.40d 99 35:65 74:26

5 4-NO2 O 5.41a 99 69:31 85:15

6 H O 5.41b 55 84:16 96:4

7 4-Me O 5.41c 65 89:11 80:20

8 4-Br O 5.41d 84 71:29 81:19

9 4-NO2 S 5.42a 99 97:3 85:15

10 H (CH2) 5.43b 54 89:11 77:23

11 4-Me (CH2) 5.43c 29 86:14 90:10

12 4-Br (CH2) 5.32 87 88:12 92:8

13 3-NO2 (CH2) 5.43e 91 96:4 85:15

14 2-NO2 (CH2) 5.43f 83 98:2 85:15

[a] Determined by 1H NMR spectroscopy. [b] Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95), er is reported for major diastereoisomer only. Reaction conditions: Aldehyde (0.1 mmol), ketone (0.5 mmol), and catalyst (20 µmol), in water (250 µL) were stirred for 24 hours at room temperature, followed by aqueous work-up.

The use of cyclopentanone 5.36 with the chosen aldehydes showed

excellent conversions in all cases (Entries 1–4, Table 5.3), as well as

preferential formation of the syn-diastereomer over the anti-diastereomer.

123

The dr and er values of observed for these reactions varied from poor to

moderate (Entries 1 & 3, respectively, Table 5.3).

The low er values obtained employing cyclopentanone 5.36 are presumed

to be a result of the epimerisation of the products. This may be due to the

presence of the catalyst reforming the substituted enamine, thus

scrambling the enantiomeric centre. This is supported by Vilarrasa et al.294

in finding the Keq value for the formation of enamine with cyclopentanone

to be almost three times high than for the case of cyclohexanone

(Scheme 5.6).

Scheme 5.6 Work by Vilarrasa et al.294 regarding enamine formation with cyclic ketones.

Employing tetrahydropyranone 5.37 gave much better reaction outcomes

across all parameters (Entries 5–8, Table 5.3). Despite the variability of

conversion (55–99%), good to high dr and er values were observed,

especially when using 4-nitrobenzaldehyde (Entry 5, Table 5.3), giving an

er value of 85:15, and benzaldehyde (Entry 7, Table 5.3), with an er of

96:4. Replacing the oxygen atom of 5.37 with sulfur (5.38) (Entry 9, Table

5.3) gave excellent conversion (99%) and diastereoselectivity (97:3) and

an excellent er of 85:15. Similarly, employing cyclohexanone 5.17 for

remaining aldehydes gave excellent stereochemical outcomes (Entries

10–12, Table 5.3).

Also examined, was the effect of the position of the substituted nitro group

had on the reaction outcome. Using both 3- and 2-nitrobenzaldehyde

delivered products 5.43e and 5.43f respectively, both with excellent

conversion, dr and er of 85:15 (Entries 13 & 14, Table 5.3).

124

Having shown good catalytic activity across arrange of different

compounds, it was logical to determine the recyclability of catalyst 5.31.

This was undertaken by repeating the on-water reaction of cyclohexanone

5.17 with 4-bromobenzaldehyde 65, giving product 64d. The full aqueous

workup was replaced by the simple addition of a diethyl ether:hexane

(1:1) solution to extract the aldol product only, which was previously

determined to not solubilise catalyst 57.

Table 5.4 Recycling of catalyst 57.

Entry Conversion (%) dr (anti:syn)

1 87 88:12

2 23 90:10

3 20 92:8

Each recycling effort resulted in severely depressed reaction conversion,

suggesting that the organocatalyst was leaching into the ethereal phase.

Despite this, the dr remained high, even improving across each attempt

(Entries 1–3,

Table 5.4). It is interesting to note that catalyst 5.31 was observed by 1H

NMR spectroscopy to have leeched into the diethyl ether:hexane solution,

effectively lowering the catalytic loading over subsequent attempts, albeit

in small quantity.

Having successfully evaluated the organocatalysts 5.30 and 5.31 in the

aldol reaction, it was pertinent to determine their application to another

reaction system. Therefore, the conjugate addition of cyclohexanone

(5.17) with trans-β-nitrostyrene (5.47) was chosen, as it is another

commonly used reaction for the evaluation of organocatalysts.295-297

125

Nitro-Michael Reaction

Table 5.5 Application of catalysts 5.30 and 5.31 to the conjugate addition of cyclohexanone 5.17 with trans-β-nitrostyrene 5.47.

Entry Catalyst Solvent Time (h)

Conversion[a]

(%) dr[a]

(anti:syn) er[b]

1 - Neat 24 0 0 0

2 5.30 Neat 72 99 53:47 -

3 5.31 PhMe 24 87 83:17 52:48

4 5.31 THF 24 88 88:12 67:33

5 5.31 Water 24 83 75:25 63:37

6 5.31 Neat 24 95 81:19 63:37

7 5.31 Neat 96 90 91:9 66:34

8 5.31 Water[c] 24 90 93:7 67:33

9 5.31 Neat[c] 24 95 91:9 65:35

[a] Determined by 1H NMR spectroscopy. [b] Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95) for major diastereoisomer only. [c] 5 mol% catalyst loading. Reaction conditions: trans-β-nitrostyrene (0.1 mmol), ketone (0.5 mmol), and catalyst (20 µmol), in water (250 µL) were stirred for 24 hours at room temperature, followed by aqueous work-up.

Catalyst 5.30 was able to effectively catalyse the formation of 5.48,

despite the excellent conversion (99%), the dr was very low (53:47,

anti:syn, Entry 2, Table 5.5) and as such, the er was not investigated. The

similarity of this result to that of the aldol reactions when catalysed by

catalyst 5.30 led to its abandonment for this reaction type, with the

attention focused on catalyst 5.31. The reaction conducted with catalyst

5.31 in organic solvents toluene and tetrahydrofuran (THF), gave

promising results as conversions and dr were both high (Entry 3 & 4,

Table 5.5). Of the two, THF gave a superior enantiomeric ratio (er) to

toluene 67:33 compared to 52:48, respectively. In contrast to results

previously obtained in the aldol reaction, conducting the reaction neat or

126

on-water resulted in poorer stereochemical outcomes (Entry 6 & 7, Table

5.5) when compared to THF. This same preference for THF in nitro-

conjugate addition was also observed by Lin et al.295 Nevertheless, dr

could be improved under neat reaction conditions through extended

reaction times at the expense of er (Entry 7, Table 5.5). Decreasing the

catalytic loading to 5 mol% showed little reduction in conversion, dr or er

when compared to that of 20 mol% loading (Entry 8 & 9, Table 5.5).

Table 5.6 Effect of additives in the nitro-Michael reaction of cyclohexanone 5.17 and trans-β-nitrostyrene 5.47.

Entry Additive Conversion[a]

(%) dr[a]

(anti:syn) er[b]

1 Benzoic Acid 75 95:5 57:43

2 p-nitrobenzoic

acid 83 97:3 56:44

3 Trifluoroacetic

acid 76 84:16 60:40

[a] Determined by 1H NMR spectroscopy. [b] Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95) for major diastereoisomer only. Reaction conditions: trans-β-nitrostyrene (0.1 mmol), ketone (0.5 mmol), and catalyst (20 µmol), in water (250 µL) were stirred for 24 hours at room temperature, followed by aqueous work-up.

In an effort to improve the reaction outcomes in THF, the reactions were

repeated with a series of additives as is common with this type of

reaction.298 Unfortunately, in each case the conversions were depressed

and no gain of er was observed in any case (Entries 1-3, Table 5.6).

Despite this, improvements in dr were observed in the reactions using

benzoic-derived additives.

This work demonstrates a concise, high-yield synthesis of two ion-tagged

organocatalysts 5.30 and 5.31 and their subsequent evaluation as

catalysts. Variation of the anionic component of the catalysts proved to be

of high catalytic significance as well as demonstrating the difference in

physical parameters exhibited by such manipulation. The latter catalyst

(5.31) being technically classified as a chiral ionic liquid, possessed a

127

melting point below 100 °C and experienced no evaporation phenomena

by isothermal TGA and a Tg of 14.5 °C.

This work was published in Catalysis Letters:

Eyckens, D.J.; Brozinski, H.L.; Delaney, J.P.; Servinis, L.; Naghashian,

S.; Henderson, L.C., (2016). “Ion-Tagged Prolinamide Organocatalysts for

Direct Aldol Reaction On-Water.” Catal. Lett., 146(1): 212-219. IF: 2.80,

citations: 3

128

129

– Future Work (Solvate ILs)

The results shown in this project provide a solid foundation of research,

however there is still much that can be done in the synthetic and physical

chemistry of solvate ionic liquids.

Physical Chemical Parameters

To accurately recreate the conditions of an organic reaction, the Kamlet-

Taft parameters should be examined at a range of temperatures. These

include both elevated and depressed temperatures to maintain

consistency with the synthetic application of SILs. This also extends to the

Gutmann Acceptor Numbers, in that an increase in Lewis acidity may

occur with an increase in temperature. It is theorised that the more energy

that is introduced to the system, the more available the lithium cation will

become to interact with reactants. In addition to building on previous

physical characterisation methods, the chelation effect of the lithium

cation at a range of temperatures may also be investigated via both 7Li

and 17O NMR. This work has been preliminarily undertaken by a

collaborator at Deakin University.

Synthetic Methods in SILs

As outlined previously, the impact 5.0 M LPDE has had on the literature is

broad and penetrative, so future work in determining synthetic

applications of the solvate ILs can be largely based off this work. A more

in-depth investigation into the stereoselective effects of the solvents in the

Diels-Alder reaction could be undertaken, though different reaction types

should be explored as well. These include, but are not limited to, the

Baylis-Hillman reaction, nucleophilic addition reactions such as the

Michael addition, the addition of allylstannanes to aldehydes and

transition metal catalysis. Also of interest may be performing reactions at

low temperature, which is not easily accessible in traditional ionic liquids.

With this foundation of research of comparative reactions, it would be

pertinent to trial reactions that are previously unable to be performed in

130

either traditional ILs or 5.0 M LPDE. This has been explored to some

extent in terms of the latter with the introduction of elevated temperature,

though of great interest would be the ability to perform cryogenic

reactions, or those requiring strongly basic conditions.

Ion-Tagged Organocatalysis

The successful production and evaluation of the ion-tagged

organocatalyst discussed in Chapter 5 proved the dramatically different

effects on reaction outcome that are possible with changing anion. This

work could lead to the screening of various anions for their effect on

catalytic activity. It is also possible to functionalise the organocatalyst from

the 4-hydroxyl position of trans-4-hydroxy-(S)-proline. Further to this, the

ionic moiety may be substituted from imidazolium to an alkaloid-based

structure, or the length of alkyl chain between catalytic and ionic units to

be lengthened or shortened. This would determine the role of proximity of

ion tag to reaction outcomes.

131

Experimental

General Chemical Experimental

Thin Layer Chromatography (TLC) was performed using aluminium-

backed Merck TLC Silica gel 60 F254 plates, and samples were visualised

using 254 nm ultraviolet (UV) light, and potassium

permanganate/potassium carbonate oxidising dip (1:1:100

KMnO4:K2CO3:H2O w/w). Column Chromatography was performed using

silica gel 60 (70-230 mesh). All solvents used were AR grade, and those

denoted as anhydrous were dried using a pressurised dry solvent

dispenser. Petroleum spirits refers to the fraction boiling between 40-

60 °C.

All 1H, 13C, 19F and 31P NMR spectra were recorded on a Jeol JNM-EX

270 MHz, Jeol JNM-EX 400 MHz or Bruker AVANCE III 500 MHz

standard bore (solution) as indicated. Samples were dissolved in

deuterated chloroform (CDCl3) with the residual solvent peak used as an

internal reference (CDCl3 – δ H 7.26) unless otherwise stated. Proton

spectra are reported as follows: chemical shift δ (ppm), (integral,

multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = doublet of

doublets, t = triplet, q = quartet, m = multiplet), coupling constant J (Hz),

assignment).

Attenuated Total Reflectance – Fourier Transform Infrared Spectroscopy

(ATR-FTIR) measurements were conducted using an Alpha FTIR

spectrometer (Bruker Optik GmbH, Ettlingen, Germany) equipped with a

deuterated triglycine sulfate (DTGS) detector and a single-reflection

diamond ATR sampling module (Platinum ATR QuickSnap™). The

samples were analysed in a thin film (from a chloroform solution) from 400

to 3900 wavenumbers and all absorption bands are reported in

wavenumbers (cm-1). Background spectra of a clean ATR surface were

acquired prior to each sample measurement using the same acquisition

parameters.

132

Reactions performed under microwave irradiation were conducted using a

CEM Discover S-Class Explorer 48 Microwave Reactor. Instrument was

operated at a frequency of 50/60 Hz under continuous irradiation from 0 -

300 W power. Reactions were performed in a 10 mL quartz vessel

equipped with an airtight cap.

Chiral HPLC was performed with a 1200 series Agilent. Separation of

stereoisomers was carried out with a Diacel Chiralpak AD-H chiral

column (0.46 cm × 25 cm). Retention times were reported at ambient

temp (24 °C) with an injection volume of 20 μL at a flow rate of 1

mL/min. A mobile phase of 10% isopropanol/ 90% hexane was used.

HRMS was found viaa 6210 MSD TOF mass spectrometer under the

conditions: gas temperature (350 °C), vaporizer (28 °C), capillary voltage

(3.0 kV), cone voltage (40 V), nitrogen flow rate (7.0 L/min), nebuliser (15

psi). Samples were dissolved in MeOH.

Melting points were found on a Stuart Scientific Melting Point Apparatus

SMP3, v. 5 and are uncorrected. DSC measurements were taken on a TA

instrument DSC-Q200.

Ultraviolet spectroscopy was performed using quartz cuvettes in on an

Agilent Cary 300 UV-vis spectrophotometer at 23 °C.

Preparation of Solvate Ionic Liquids

A round bottom flask was charged with lithium

bis(trifluoromethanesulfonyl)imide (10 g, 0.035 mol) under N2, before the

addition of either triethylene glycol dimethyl ether (6.30 mL, 0.035 mol) or

tetraethylene glycol dimethyl ether (7.67 mL, 0.035 mol)and stirring at

room temperature. Stirring was continued to complete dissolution of the

salt and a homogenous mixture formed, which may be accelerated by

heating to 60 °C, though typically takes between 2 and 6 hours. At the

conclusion of this, the clear mixture is subjected to heating (c.f. 120 °C)

under high vacuum for 2 hours to remove any adventitious water and any

spectating glyme molecules, though these only appear as trace amounts

133

when analysed by 1H NMR spectroscopy. Finally, the solvate ionic liquid

appears as a viscous, yellow-honey coloured liquid.

Chapter 3 Experimental

Addition of dyes and preparation.

All dyes were loaded to high boiling point solvents according to the

same general procedure: The appropriate dye was dissolved in

DCM to a concentration of 0.9 mM, then 3 mL of dye solution and 3

mL solvent were combined and DCM was removed under reduced

pressure.

Dyes loaded to low-boiling point solvents were made up in

concentration of 0.9 mM in the solvent being tested.

The UV-vis spectrum of the sample was then measured at 23 °C.

Equations used:

1 ( ) = 1000 (1)

∗ =( ) ( )

=( ) .

. (2)

(30) =( )

(3)

=( )( ) ( )( )

( )( ) ( )( )=

( )( ) .

. (4)

Worked example for α and polarity measurements

First, a series of non-hydrogen bond donating solvents must be

selected, and each UV-vis spectroscopically analysed in relation to

two dyes; one hydrogen bond accepting (Reichardt’s Dye) and one

non-hydrogen bond accepting (p-nitroanisole). The vmax for these

134

solvents are converted to kiloKaisers (kK) and the results of the two

dyes plotted against each other, from which a line of best fit and be

generated, and an equation for that line elucidated.

For example, if the Average vmax for THF was 762.80 nm in

Reichardt’s Dye:

1762.80 × 10

= 1310959.622

1310959.622 100

= 13109.60

13109.60 1000

= 13.11

Repeat this process for a strongly hydrogen bond donating solvent

(MeOH) to compare unknowns against and plot. Then calculate the

distance of MeOH using the equation of the line.

= −1.8225 + 73.208; = 32.72( )

= −1.8225(32.72) + 73.208 = 13.58

135

− = 19.28 − 13.58 = 5.7

From here, the measurements of the unknown solvents can be

taken and added to the graph. Using the same methodology, the

distance between the data point of the solvent and the line can be

calculated and the differences compared to that of MeOH.

[ ( )] − = 7.5221

=∆ [ ( )]

∆=

7.52215.7

= 1.32

Therefore, [Li(G3)]TFSI is 1.32 times more ‘hydrogen bond donating’

than MeOH.

136

General procedure for the determination of Gutmann Acceptor

Number

A 0.2 M solution of triethylphosphine oxide in benzene-d6 was produced

for the 31P NMR experiments. Samples were prepared by dissolving 3

mole equivalents of the compound (0.3 mmol) of interest in 0.5 mL of the

Et3PO in benzene-d6 solution previously mentioned (0.2 M). Complete

dissolution was assisted by sonication, if required.

The Acceptor Number was determined by the monitoring the change in

31P chemical shift (ppm) of Et3PO in n-heptane (non-Lewis Acid) and the

shift in the solvent/salt of interest, and this value then substituted into the

below equation:

Acceptor Number (kcal/mol) = 2.348 × (δ31PSolvent – δ31PHeptane)

31P NMR experiments were completed at 22.0 °C, 0.0485 M

triphenylphosphate used as external reference in acetone-d6.

137

31P NMR overlayed spectra of [Li(G3)]TFSI and n-heptane.

Chemical Synthesis

Note: All compounds in this section are present in the associated peer

reviewed publication with electronic supplementary information

available. Therefore, no NMR spectra are shown in this document.

The ESI is available at the DOI: 10.1002/ejoc.201501614.

General Procedure for Diels-Alder reactions

Dimethyl Fumarate/Maleate

To a 10 mL microwave vial containing 1 mL of solvent was added

Isoprene (1.0 mmol), Dimethyl maleate/fumarate (0.2 mmol). The reaction

was stirred in the microwave for the specified time at 100 °C, the crude

mixture was extracted into CH2Cl2 (5 mL). The organic layer washed was

washed with water (3 × 5 mL), and the combined organic layers dried with

MgSO4 and solvent removed in vacuo to give a clear oil. Analysis of the

crude oil by 1H NMR spectroscopy indicated the presence of the desired

material. Purification by column chromatography (EtOAC:PET, 1:4, Rf:

0.27) gave the desired product as a clear oil. 1H NMR (270 MHz, CDCl3):

n-heptane [Li(G3)]TFSI

138

δ 5.33 (1H, m, H-C=C), 3.66 (6H, d, J = 2.7 Hz, C-H), 3.0 (2H, m, C-H),

2.46; 2.28 (4H, m, C-H), 1.64 (3H, s, C-H).

Dimethyl Acetylenedicarboxylate

A 10 mL microwave vial was charged with 1 mL of solvent and isoprene

(10.56 mmol) was added. To this mixture, dimethyl acetylenedicarboxylate

(2.11 mmol) was combined and the reaction was subjected to microwave

irradiation at 100 °C for the specified amount of time. The crude mixture

was extracted into DCM (5 mL) and washed with H2O (3 × 5 mL) before

subsequent washing with brine (3 × 5 mL). The organic layer was dried

over MgSO4 and excess solvent was removed under reduced pressure to

yield a clear, viscous oil. Analysis of the crude oil by 1H NMR

spectroscopy indicated the presence of the desired material. Purification

by column chromatography (EtOAc:PET spirits, 1:1, Rf: 0.28) gave the

desired product as a clear oil. 1H NMR (270 MHz, CDCl3): δ 5.35 (1H, m,

H-C=C), 3.72 (6H, comp, C-H), 2.91 (2H, m, C-H), 2.83 (2H, m, C-H),

1.65 (3H, s, C-H).

General procedure for [2+2] reactions

To a foil covered round bottom flask containing 2 mL of solvent was

added aldehyde (1.0 mmol), acid chloride (4.0 mmol), Et3N (4.4 mmol).

The solution was stirred for 6 hours at room temperature, then quenched

with sodium carbonate and extracted into CH2Cl2 (3 × 10 mL). The

combined organic layer was washed with water (3 × 20 mL), then dried

with MgSO4 and solvent removed in vacuo to give a yellow oil. Analysis of

the crude oil by 1H NMR spectroscopy indicated the presence of the

desired material. Purification by column chromatography (diethyl

ether:PET sprits, 1:9, Rf: 0.26) gave the desired product. NOTE: where

indicated the reaction was moved to a pre-heated oil bath (80 °C) for the

final hour of the reaction. 1H NMR (270 MHz, CDCl3): δ 7.41 (2H, m, Ar-

H), 7.33 (2H, m, Ar-H), 7.20 (1H, m, Ar-H), 7.00 (1H, dd, J = 13.5 Hz, 15.6

Hz C-H), 6.42 (1H, d, J = 8.1 Hz, C-H), 6.02 (1H, d, J = 10.8 Hz, C-H),

1.86 (6H, d, J = 2.7 Hz, CH3).

139

Chapter 4 Experimental

Note: All compounds in this section are present in the associated peer

reviewed publication with electronic supplementary information

available. Therefore, no NMR spectra are shown in this document.

The ESI is available at the DOI: 10.1039/C7RA04407K.

General preparation of α-aminophosphonates

Monomers

A round bottom flask was charged with aldehyde (1.00 mmol), which was

dissolved in either [Li(G3)]TFSI or [Li(G4)]TFSI (0.5 mL). Aniline (1.00

mmol) was then added, before the addition of diphenyl phosphite (0.230

mL, 1.20 mmol) and stirred at room temperature for the given time period.

Diethyl ether (10 mL) was added at the conclusion of the reaction, before

the addition of deionised water (10 mL) causing a fine precipitate to form.

The removal of diethyl ether under reduced pressure afforded a

suspension of precipitate in the aqueous phase, which was then filtered

washing with excess water and petroleum spirits (40-60 °C). The solid

compound was collected and analysed by 1H NMR spectroscopy.

Dimers

A round bottom flask was charged with aldehyde (1.00 mmol), which was

dissolved in either [Li(G3)]TFSI or [Li(G4)]TFSI (0.5 mL).

Phenylenediamine (0.5 mmol) was then added, before the addition of

diphenyl phosphite (0.299 mL, 1.56 mmol) and stirred at room

temperature for 10 minutes. Diethyl ether (10 mL) was added at the

140

conclusion of the reaction, before the addition of deionised water (10 mL).

Precipitate formed from the organic phase at reduced temperature (0 °C –

r.t.), which was then filtered washing with excess water and petroleum

spirits (40-60 °C). This process may have been repeated to obtain any

product that may have remained in the organic phase after filtration. Any

purification was achieved through redissolving crude material in Et2O and

repeating the above process. The solid compound was collected and

analysed by 1H NMR spectroscopy.

Compound reports

Diphenyl ((benzylamino)(phenyl)methyl)phosphonate 4.39

White solid (0.364 g, 81%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): 7.53 (2H, m, Ar-H), 7.23 (15H, m,

Ar-H), 6.85 (3H, m, Ar-H), 4.38 (1H, d, J= 21.6 Hz, CH), 3.95 (1H, d, JH-P =

13.5 Hz, CH2), 3.65 (1H, d, JH-P = 13.5 Hz, CH2) 3.21 (1H, bs, NH).

Diphenyl (phenyl(phenylamino)methyl)phosphonate 4.40

White solid (0.377 g, 91%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): δ 7.55 (2H, m, Ar-H), 7.22 (14H, m,

Ar-H), 6.85 (2H, m, Ar-H), 6.74 (1H, m, Ar-H), 6.65 (2H, m, Ar-H), 5.14

(1H, d, JH-P = 27 Hz, CH), NH not seen.

Diphenyl (((4-nitrophenyl)amino)(phenyl)methyl)phosphonate 4.43a

Sandy-brown solid (0.297 g, 64%). Analytically pure by 1H

NMR spectroscopy and consistent with literature

reports.189 1H NMR (270 MHz, CDCl3): δ 7.97 (2H, d, J =

8.1 Hz, Ar-H), 7.52 (2H, m, Ar-H), 7.22 (12H, m, Ar-H), 6.72 (2H, d, J =

8.1 Hz Ar-H), 6.57 (2H, d, J = 8.1 Hz, Ar-H), 6.14 (1H, bs, NH) 5.18 (1H,

dd, JH-P = 8.1, 24.3 Hz, CH).

Diphenyl (((4-hydroxyphenyl)amino)(phenyl)methyl)phosphonate 4.43b

White solid (0.395 g, 92%); m.p. = = 118.2 °C; 1H NMR

(270 MHz, CDCl3): δ 7.53 (2H, m, Ar-H), 7.36-7.07 (11H,

141

m, Ar-H), 6.84 (2H, m, Ar-H), 6.63 (2H, d, J = 8 Hz, Ar-H), 6.54 (2H, d, J =

8 Hz, Ar-H), 5.04 (1H, d, JH-P = 24 Hz, CH), NH and OH not seen; 13C

NMR (100 MHz, CDCl3): δ 150.39, 150.32, 150.23, 148.81, 129.82,

129.72, 128.91, 128.89, 128.44, 128.34, 128.28, 125.48/ 125.30/ 120.80/

120.76/ 120.45/ 120.40/ 116.23/ 115.82/ 71.89/ 70.45/ 59.13; 31P NMR

(202 MHz, CDCl3): δ 16.10; HRMS (ESI) calculated for [C25H22NO4P +

H]+: 432.1359, found 432.1361.

Diphenyl (((4-fluorophenyl)amino)(phenyl)methyl)phosphonate 4.43c

White solid (0.364 g, 84%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): δ 7.52 (2H, m, Ar-H), 7.23 (13H,

m, Ar-H), 6.83 (4H, m, Ar-H), 6.58 (2H, m, Ar-H), 5.06 (1H, d, JH-P = 24.3

Hz, CH), NH not seen.

Diphenyl (((4-chlorophenyl)amino)(phenyl)methyl)phosphonate 4.43d

White solid (0.430 g, 96%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): δ 7.52 (2H, m, Ar-H), 7.17 (12H, m, Ar-H), 6.82

(2H, m, Ar-H), 6.56 (2H, m, Ar-H), 5.07 (1H, d, JH-P = 27 Hz, CH), NH not

seen.

Diphenyl (((3-chlorophenyl)amino)(phenyl)methyl)phosphonate 4.41

White solid (0.393 g, 81%); m.p. = = 135.5 °C; 1H NMR (270

MHz, CDCl3): δ 7.54 (2H, m, Ar-H), 7.34 (8H, m, Ar-H),

7.20 (2H, m, Ar-H), 7.07 (3H, m, Ar-H), 6.82 (2H, m, Ar-H),

6.70 (1H, m, Ar-H), 6.63 (1H, m, Ar-H), 6.50 (1H, m, Ar-H) 5.09 (1H, d, JH-

P = 16.2 Hz, CH), NH not seen; 13C NMR (100 MHz, CDCl3): δ 130.38,

129.90, 129.76, 129.05, 128.23, 125.61, 123.97, 120.70, 120.66, 120.35,

120.31, 113.92, 112.28; 31P NMR (160 MHz, CDCl3): δ 15.33; HRMS

(ESI) calculated for [C25H21ClNO3P + H]+: 450.1020, found 450.1014.

142

Diphenyl (phenyl((3-(trifluoromethyl)phenyl)amino)methyl) phosphonate

4.43f

Off-white solid (0.414 g, 86%); m.p. = = 122.1 °C; 1H NMR

(270 MHz, CDCl3): δ 7.54 (2H, m, Ar-H), 7.40-7.06 (12H,

m, Ar-H), 6.98 (1H, m, Ar-H), 6.80 (4H, m, Ar-H), 5.14 (1H,

d, JH-P = 24.3 Hz, CH), NH not seen; 13C NMR (100 MHz, CDCl3): δ

150.35, 146.09, 134.21, 129.91, 129.86, 129.76, 129.10, 129.07, 128.77,

128.74, 128.24, 128.18, 125.64, 125.44, 120.67, 120.63, 120.33, 120.29,

116.84, 110.54, 56.70, 55.16; 31P NMR (160 MHz, CDCl3): δ 15.23;

HRMS (ESI) calculated for [C26H21F3NO3P + H]+: 484.1284, found

484.1331.

Diphenyl (phenyl((3,5-bis(trifluoromethyl)phenyl)amino)methyl)

phosphonate 4.43g

White solid (0.331 g, 60%); m.p. = = 138.4 °C; 1H NMR

(400 MHz, CDCl3): δ 7.54 (2H, m, Ar-H), 7.41-7.34 (3H, m,

Ar-H), 7.31-7.27 (3H, m, Ar-H), 7.22-7.16 (4H, m, Ar-H),

7.13-7.08 (3H, m, Ar-H), 6.98 (2H, s, Ar-H), 6.78 (2H, m, Ar-H), 5.41 (1H,

bs, NH), 5.15 (1H, d, JH-P = 24 Hz, CH); 13C NMR (100 MHz, CDCl3): δ

129.98, 129.78, 129.28, 129.26, 129.05, 128.20, 128.14, 125.78, 125.53,

120.56, 120.52, 120.21, 120.17, 97.26; 31P NMR (160 MHz, CDCl3): δ

14.54; HRMS (ESI) calculated for [C27H20F6NO3P + H]+: 552.1158, found

552.1225.

Diphenyl ((4-bromophenyl)(phenylamino)methyl)phosphonate 4.45a

White solid (0.451 g, 91%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): δ 7.46 (4H, m, Ar-H), 7.32-7.06

(10H, m, Ar-H), 6.92 (2H, m, Ar-H), 6.77 (1H, m, Ar-H), 6.60 (2H, m, Ar-

H), 5.09 (1H, d, JH-P = 24.3 Hz, CH), NH not seen.

Diphenyl ((phenylamino)(p-tolyl)methyl)phosphonate 4.45b

White solid (0.384 g, 90%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): δ 7.44 (2H, m, Ar-H), 7.31-7.07

143

(12H, m, Ar-H), 6.88 (2H, m, Ar-H), 6.74 (1H, m, Ar-H), 6.65 (2H, m, Ar-

H), 5.12 (1H, d, JH-P = 24.3 Hz, CH), 2.33 (3H, s, CH3), NH not seen.

Diphenyl ((4-nitrophenyl)(phenylamino)methyl)phosphonate 4.45c

Sandy-yellow solid (0.320 g, 69%). Analytically pure by 1H

NMR spectroscopy and consistent with literature

reports.189 1H NMR (270 MHz, CDCl3): δ 8.21 (2H, m, Ar-

H), 7.75 (2H, m, Ar-H), 7.32-7.06 (10H, m, Ar-H), 6.95 (2H, m, Ar-H), 6.79

(1H, m, Ar-H), 6.58 (2H, m, Ar-H), 5.23 (1H, d, JH-P = 24.3 Hz, CH), NH

not seen.

Diphenyl ((4-fluorophenyl)(phenylamino)methyl)phosphonate 4.45d

White solid (0.337 g, 78%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.189 1H

NMR (270 MHz, CDCl3): δ 7.52 (2H, m, Ar-H), 7.32-7.00

(12H, m, Ar-H), 6.90 (2H, m, Ar-H), 6.76 (1H, m, Ar-H), 6.63 (2H, m, Ar-

H), 5.12 (1H, d, JH-P = 24.3 Hz, CH), NH not seen.

Diphenyl ((2-hydroxyphenyl)(phenylamino)methyl)phosphonate 4.45e

White solid (0.360 g, 84%). Analytically pure by 1H NMR

spectroscopy and consistent with literature reports.299 1H

NMR (270 MHz, CDCl3): δ 7.32-7.23 (5H, m, Ar-H), 7.19-7.13

(5H, m, Ar-H), 7.04 (2H, d, J = 8 Hz, Ar-H), 6.98 (2H, d, J = 8 Hz, Ar-H),

6.90-6.79 (3H, m, Ar-H), 6.75 (2H, d, J = 8 Hz, Ar-H), 5.35 (1H, d, JH-P =

24 Hz, CH), NH not seen

Diphenyl ((3,4-dichlorophenyl)(phenylamino)methyl)phosphonate 4.45f

White solid (0.382 g, 79%); m.p. = = 162.7 °C; 1H NMR

(500 MHz, DMSO-d6): δ 8.00 (1H, s, Ar-H), 7.71 (1H, m, Ar-

H), 7.66 (1H, d, J = 8.4 Hz, Ar-H), 7.35 (4H, m, Ar-H), 7.19

(2H, m, Ar-H), 7.09 (4H, m, Ar-H), 6.98 (2H, d, J = 8.7 Hz, Ar-H), 6.92

(2H, d, J = 7.7 Hz, Ar-H), 6.86 (1H, dd, J = 5.3, 10.9 Hz, NH), 6.62 (1H,

app. t, Ar-H), 5.77 (1H, dd, J = 10.9 Hz, JH-P = 26.4 Hz, CH); 13C NMR

(126 MHz, DMSO-d6): δ 150.55, 150.47, 150.30, 150.22, 147.05, 146.93,

137.69, 131.48, 131.45, 131.11, 131.08, 131.01, 130.96, 130.93, 130.37,

130.28, 129.47, 129.42, 129.35, 125.81, 121.01, 120.98, 120.71, 120.68,

144

118.17, 114.25, 54.27, 53.02; 31P NMR (202 MHz, DMSO-d6): δ 15.42;

HRMS (ESI) calculated for [C25H20Cl2NO3P + H]+: 484.0631, found

484.0687.

Tetraphenyl ((1,4-phenylenebis(azanediyl))bis(phenylmethylene))

bis(phosphonate) 4.49a

Chalky, white solid (0.242 g, 64%); m.p. = = 184.0 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.67 (4H, m, Ar-H),

7.38-7.30 (14H, m, Ar-H), 7.19 (4H, m, Ar-H), 7.10

(4H, m, Ar-H), 6.86 (4H, m, Ar-H), 6.72 (4H, d, Ar-H), 6.13 (2H, m, NH),

5.43 (2H, dd, JH-P = 10, 25 Hz, CH); 13C NMR (126 MHz, DMSO-d6): δ

150.71, 150.63, 150.45, 150.37, 139.38, 139.30, 139.25, 139.17, 136.46,

130.19, 130.17, 129.83, 129.19, 129.14, 128.64, 128.24, 125.59, 125.54,

121.14, 121.11, 120.79, 120.76, 115.67, 115.57, 115.55, 56.46, 56.41,

55.21, 55.16; 31P NMR (202 MHz, DMSO-d6): δ 17.11 (d, JP-P = 24.24);

HRMS (ESI) calculated for [C44H38N2O6P2 + H]+: 753.2278, found

753.2360.

Tetraphenyl ((1,4-phenylenebis(azanediyl))bis((4-

bromophenyl)methylene)) bis(phosphonate) 4.49b

Chalky, white solid (0.295 g, 65%); m.p. = =

206.5 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.59

(4H, m, Ar-H), 7.53 (4H, m, Ar-H), 7.31 (8H, m,

Ar-H), 7.16 (4H, m, Ar-H), 7.06 (4H, m, Ar-H),

6.93 (4H, m, Ar-H), 6.67 (4H, m, Ar-H), 6.15 (2H, m, 2NH), 5.44 (2H, dd,

JH-P = 10.9, 26.15 Hz, 2CH); 13C NMR (126 MHz, DMSO-d6): δ 150.65,

150.57, 150.37, 150.29, 139.15, 139.02, 136.13, 131.57, 131.31, 131.26,

130.27, 130.20, 125.65, 121.58, 121.54, 121.09, 121.06, 120.77, 120.74,

115.59, 55.77, 54.52.; 31P NMR (202 MHz, DMSO-d6): δ 16.32; HRMS

(ESI) calculated for [C44H36Br2N2O6P2 + H]+: 911.0468, found 911.0689,

fragment [C32H25Br2N2O6P2 + H]+: 677.0022, found 677.0105.

145

Tetraphenyl ((1,4-phenylenebis(azanediyl))bis((4-nitrophenyl)methylene))

bis(phosphonate) 4.49c

Mustard-yellow solid (0.141 g, 33%); m.p. = =

141.8 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.27

(4H, d, J = 8.1 Hz, Ar-H), 7.86 (4H, m, Ar-H), 7.36 (8H, m, Ar-H), 7.19

(7H, m, Ar-H), 7.09 (8H, m, Ar-H), 6.75 (1H, m, Ar-H), 5.71 (2H, m, 2CH),

2NH not seen; 13C NMR (126 MHz, DMSO-d6): δ 157.76, 150.55, 150.47,

150.43, 150.35, 147.63, 147.60, 145.51, 130.34, 130.29, 129.82, 129.16,

129.11, 125.72, 125.67, 123.69, 123.66, 120.91, 120.88, 120.85, 119.24,

115.66, 69.80, 68.50; 31P NMR (202 MHz, DMSO-d6): δ 14.29; HRMS

(ESI) calculated for [C44H37N4O10P2 + H]+: 843.1979, found 843.1978,

Tetraphenyl ((1,3-phenylenebis(azanediyl))bis(phenylmethylene))

bis(phosphonate) 4.51

Chalky, white solid (0.128 g, 34%); m.p. = = 95.5 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.64 (4H, m, Ar-H),

7.30 (15H, m, Ar-H), 7.15 (4H, m, Ar-H), 7.08 (4H, m,

Ar-H), 6.84 (4H, m, Ar-H), 6.74 (1H, m, Ar-H), 6.48 (2H, bs, 2NH), 6.23

(2H, m, Ar-H), 5.56 (2H, m, 2CH); 13C NMR (126 MHz, DMSO-d6): δ

157.76, 150.68, 150.60, 150.41, 150.33, 148.25, 148.12, 136.40, 136.33,

130.22, 130.19, 130.16, 129.83, 129.54, 129.21, 129.16, 128.63, 128.26,

128.24, 125.66, 125.61, 121.18, 121.16, 121.13, 121.10, 120.81, 120.78,

119.25, 115.67, 105.20, 98.11, 55.24, 53.99.; 31P NMR (202 MHz, DMSO-

d6): δ 17.00; HRMS (ESI) calculated for [C44H38N2O6P2 + H]+: 753.2278,

found 753.2281.

Tetraphenyl ((1,2-phenylenebis(azanediyl))bis(phenylmethylene))

bis(phosphonate) 4.53

Yellow/brown solid (0.040 g, 9% by 1H NMR); m.p. = =

145.8 °C; 1H NMR (500 MHz, DMSO-d6): δ 8.53 (2H, s,

Ar-H), 7.65 (4H, d, J = 7.35 Hz, Ar-H), 7.35 (4H, m, Ar-

H), 7.29 (4H, m, Ar-H), 7.18 (4H, m, Ar-H), 7.08 (4H, d, J = 7.75 Hz, Ar-

H), 6.84 (4H, d, J = 7.75 Hz, Ar-H), 6.74 (4H, d, J = 8.05 Hz, Ar-H), 6.50

(4H, m, Ar-H), 6.15 (2H, m, 2NH), 5.41 (2H, dd, JH-P = 10.95, 25.8 Hz,

2CH); 13C NMR (126 MHz, DMSO-d6): δ 150.29, 150.21, 150.01, 149.93,

146

149.42, 139.39, 139.25, 135.96, 129.76, 129.75, 128.78, 128.74, 128.20,

128.19, 127.83, 125.18, 125.12, 120.71, 120.68, 120.36, 120.32, 115.45,

115.35, 64.95, 56.12, 54.87, 15.20. ; 31P NMR (202 MHz, DMSO-d6): δ

17.07; HRMS (ESI) calculated for [C44H38N2O6P2 + Na]+: 775.2097, found

775.2436

Diphenyl (((4-(((diphenoxyphosphoryl)(p-tolyl)methyl)amino)phenyl)amino)

(phenyl)methyl)phosphonate 4.54

A round bottom flask was charged with

benzaldehyde (0.051 mL, 0.5 mmol), which was

dissolved in either [Li(G3)]TFSI or [Li(G4)]TFSI (0.5 mL). 1,4-

Phenylenediamine (0.054 g, 0.5 mmol) was then added, before the

addition of diphenyl phosphite (0.299 mL, 1.56 mmol) and stirred at room

temperature for 5 minutes. Following this, p-tolualdehyde (0.059 mL, 0.5

mmol) was added to the reactionmixture, and allowed to stir for a further 5

mins. Diethyl ether (10 mL) was added at the conclusion of the reaction,

before the addition of deionised water (10 mL). Precipitate formed from

the organic phase at reduced temperature (0 °C – r.t.), which was then

filtered washing with excess water and petroleum spirits (40—60 °C). The

solid compound was collected and analysed by 1H NMR spectroscopy,

proving to be the desired compound as a chalky, white solid (0.164 g,

43%); m.p. = 192.2 °C; 1H NMR (500 MHz, DMSO-d6): δ 7.63 (2H, m, Ar-

H), 7.49 (2H, m, Ar-H), 7.30 (11H, m, Ar-H), 7.13 (6H, m, Ar-H), 7.05 (4H,

m, Ar-H), 6.83 (4H, m, Ar-H), 6.66 (4H, q, J = 6.2 Hz, Ar-H), 6.07 (1H, m,

NH), 6.01 (1H, m, NH), 5.35 (2H, m, 2CH), 2.25 (3H, s, CH3); 13C NMR

(126 MHz, DMSO-d6): δ 136.47, 133.34, 130.19, 130.16, 129.23, 129.06,

128.64, 125.55, 121.14, 121.11, 120.83, 120.79, 120.76, 115.58, 21.19;

31P NMR (202 MHz, DMSO-d6): δ 17.24; HRMS (ESI) calculated for

[C45H40N2O6P2 + H]+: 767.2434, found 767.2605.

Synthesis of diphenyl (((4-(4-aminobenzyl)phenyl)amino)(phenyl)methyl)

phosphonate 4.59

A round bottom flask was charged with 4,4’-

diaminodiphenylmethane (DDM, 0.05 g, 0.252

147

mmol), which was then dissolved in [Li(G3)]TFSI (0.5 mL) with gentle

heating. To the resulting mixture, benzaldehyde (0.026 mL, 0.252 mmol)

was added, before diphenyl phosphite (0.058 g, 0.303 mmol) and allowing

to stir at 23 °C for 30 minutes. At the conclusion of this time, the mixture

was dissolved in diethyl ether (≈20 mL) and added to water. The organic

phase was removed under reduced pressure, leaving the aqueous phase

and a yellow precipitate that was then filtered and collected, proving the

crude desired product. The method of dissolution in diethyl ether, addition

to water and removal of organic was repeated to analytical purity,

providing the pure product as a yellow precipitate (71%). m.p. = = 124.0

°C; 1H NMR (400 MHz, MeCN-d3): δ 7.57 (2H, m, Ar-H), 7.32 (7H, m, Ar-

H), 7.19 (2H, m, Ar-H), 7.09 (2H, m, Ar-H), 6.91 (6H, m, Ar-H), 6.68 (2H, t,

Ar-H), 6.58 (2H, t, Ar-H), 5.33 (1H, br s, CH), 5.27 (1H, br s, NH2), 3.65

(2H, t, CH2), CHNH and one NH2 not seen; 13C NMR (101 MHz, MeCN-

d3): δ 130.73, 130.20, 130.18, 130.13, 130.08, 129.51, 129.49, 129.42,

129.38, 126.32, 126.30, 126.28, 126.27, 121.58, 121.53, 121.40, 121.35,

118.26, 116.09, 116.05, 115.20, 40.61, 1.47.; 31P NMR (161.8 MHz,

MeCN-d3): δ 16.74; IR max (cm-1) : 1587.54, 1514.91, 1485.07, 1251.44,

1183.07, 1158.83, 1024.31, 934.92, 798.69, 760.59, 684.71, 589.53,

495.46.

Preparation of resin samples

Control samples were prepared according to manufacture specifications

using RIMR935 and RIMH937 and curing at 100 °C for 12 hours

(Standard Cure, SC). Samples containing the flame retardant 4.59 where

prepared in the same manner, at the following P% 0.16, 0.32, and 0.49%

phosphorus (P%). These samples were also cured for 12 hours at 100 °C.

Due to the different nature of the amine of 4.59 to that of RIMH937

(aromatic versus alkyl), a second post-curing procedure was employed on

a replicate set of samples, whereby following the first curing process (12

hours at 100 °C) there was a second curing step of 5 hours at 150 °C

(Post Cure, PC). This was completed in order to promote the reactivity of

the aromatic amine of 4.59, encouraging crosslinking with the epoxy

148

matrix, and increase incorporation into the polymer network. Amounts of

epoxy, hardener, and aminophosphonate are given here:

0P% (control): RIMR935 (4.34 g, 13.6 mmol), RIMH935 (1.64 g,13.8 mmol), 4.59 (0 mg, 0 mmol)

0.16P%: RIMR935 (4.34 g, 13.56 mmol), RIMH935 (1.49, 12.6 mmol), 4.59 (165 mg, 0.6 mmol)

0.32P%: RIMR935 (4.34 g, 13.56 mmol), RIMH935 (1.32, 11.1 mmol), 4.59 (330 mg, 1.3 mmol)

0.49P%: RIMR935 (4.34 g, 13.56 mmol), RIMH935 (1.15, 9.7 mmol), 4.59 (496 mg, 1.9 mmol)

Thermogravimetric Analysis

Thermogravimetric analysis was carried out in both oxidative and non-

oxidative environments using the TA Instruments TGA Q50. For air

atmospheres a flow rate 60.00 mL/min was used, and those performed in

nitrogen a flow rate of 40.0 mL/min was employed. Resin samples of

approximately 5 – 10 mg were heated from 20 °C to 700 °C in air and to

600 °C in nitrogen at a constant heating rate of 20 °C/min.

Flame Test

A piece of resin (12 mm × 5 mm × 3 mm, approx. 0.2 g) containing the

given percentage of modified hardener was subjected to a butane torch at

a 45° angle for 10 seconds, and allowed to burn until self-extinguished.

Each sample was timed and weighed before and after burning.

149

Figure 6.1 13C NMR spectrum of compound 4.59.

Figure 6.2 31P NMR spectrum of compound 4.59.

150

Figure 6.3 1H NMR spectrum of compound 4.59.

Figure 6.4 IR spectrum of compound 4.59.

151

Pre and Post Burn Samples:

Image 1 - Resin samples prior to the burn test.

The above image shows resin samples, prior to the burn test. In order

from left to right are the control, 0.16 P%, 0.33 P% and the 0.49 P%

samples. The top row shows the standard cured (100 °C for 12 hours)

samples, and the bottom row are those sample subjected to post curing

(additional 5 hours at 150 °C), all in the same order.

The image below are the samples in the same order as above, after the

burn test.

Image 2 - Resin samples after the burn test.

152

Chapter 5 Experimental

Note: All compounds in this section are present in the associated peer

reviewed publication with electronic supplementary information

available. Therefore, no NMR spectra are shown in this document.

The ESI is available at the DOI: 10.1007/s10562-015-1630-4.

(2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic acid 5.27

trans-4-Hydroxy-(S)-proline (2.00 g, 7.63 mmol) was dissolved

in MeCN (30 mL) and TBDPS-Cl (13.88 mL, 0.053 mol) was

added, then cooled to 0 °C. DBU (8.43 mL, 0.056 mol) was

added and the reaction allowed to stir for 16 hours, reaching room

temperature. At completion, the reaction was quenched with PET (20 mL)

and the reaction washed with further PET (3 × 20 mL) before removal of

excess solvent under reduced pressure. The resulting solid was dissolved

in a solution of MeOH:THF:H2O:2M NaOH (32:18:16:24, 20 mL) and

stirred at 23 °C for 90 minutes. The solution was then acidified to pH 6 via

the addition of 2M HCl, before the removal of solvents under reduced

pressure. The solid was then dissolved in a solution of Et2O:H2O (1:1,

20 mL) and allowed to sit for 16 hours, causing crystals to form in

between the aqueous and organic phases. The crystals were then filtered

and washed with cold Et2O, resulting in the acquisition of pure product as

determined by 1H NMR spectroscopy in a white, fine crystalline form (6.85

g, 61%). 1H NMR was consistent with literature values.300 1H NMR (270

MHz, CDCl3): 7.62-7.60 (4H, m, Ar-H), 7.46-7.38 (6H, m, Ar-H), 4.55 (1H,

app. t, CH), 4.40 (3H, m, CH), 3.45 (1H, m, CH2), 3.18 (1H, m, CH2), 2.23

(2H, m, CH2), 1.04 (9H, s, Si-t-butyl), (NH not observed).

(2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-

2-carboxylic acid 5.26

(2S,4R)-4-((tert-Butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic

acid (1.64 g, 4.45 mmol) was dissolved in THF:H2O (1:1, 40

mL), prior to the addition of NaOH (0.445 g, 0.011 mmol).

Boc2O (1.26 g, 5.78 mmol) was then added and the reaction allowed to

stir for 16 hours at 23 °C. At the conclusion of this time, the solution was

153

acidified using 2M HCl (5 mL) and organic matter extracted into Et2O (3 ×

20 mL), dried with MgSO4 and excess solvent removed under reduced

pressure. The resultant oil was then purified with column chromatography

(EtOAc:PET, 1:4) and identified by 1H NMR spectroscopy as pure

product, present as a clear viscous oil (1.64 g, 74%).1H NMR was

consistent with literature values.300 1H NMR (270 MHz, CDCl3): 7.62-7.60

(4H, m, Ar-H), 7.46-7.38 (6H, m, Ar-H), 4.55 (1H, app. t, CH), 4.40 (3H, m,

CH), 3.45 (1H, m, CH2), 3.18 (1H, m, CH2), 2.23 (2H, m, CH2), 1.04 (9H,

s, Si-t-butyl), 1.48 (9H, s, Boc-t-butyl), (NH not observed).

tert-butyl (2S,4R)-2-((3-(1H-imidazol-1-yl)propyl)carbamoyl)-4-((tert-

butyldiphenylsilyl)oxy) pyrrolidine-1-carboxylate 5.25

(2S,4R)-1-(tert-Butoxycarbonyl)-4-((tert-

butyldiphenylsilyl)oxy)pyrrolidine-2-carboxylic

acid (0.174 g, 0.3497 mmol) was dissolved in

DCM (10 mL) and cooled to 0 °C. EDCI (0.081 g, 0.4196 mmol) was

added, followed by HOBt (0.024 g, 0.175 mmol) whilst stirring. 1-(3-

Aminopropyl)imidazole (0.067 mL, 0.5595 mmol) was then incorporated

into the solution and the reaction allowed to stir 16 hours, reaching 23 °C.

The solution was then washed with brine (10 mL) and extracted into DCM

(3 × 10 mL) prior to drying with MgSO4 and the subsequent evaporation of

excess solvent under reduced pressure. The pure product (determined by

1H NMR spectroscopy) was collected as a white solid with no further

purification (0.199 g, 99%). 1H NMR (270 MHz, CDCl3): δ 7.64-7.60 (m,

6H, Ar-H), 7.46-7.34 (m, 7H, Ar-H), 7.07 (br s, 1H, Ar-H, 6.95 (br s, 1H,

Ar-H), 4.45-4.40 (app. T, 2H, CH), 4.01-3.97 (m, 3H, CH2), 3.50-3.41 (m,

1H, CH2), 3.21-3.12 (m, 4H, CH2), 2.00-1.90 (m, 3H, CH2), 1.45 (s, 9H,

Boc-t-butyl), 1.04 9s, 9H, Si-t-butyl), (NH not observed); 13C NMR (400

MHz, CDCl3): δ 137.25, 135.72, 135.66, 133.49, 130.00, 129.73, 127.89,

127.88, 118.90, 80.89,f 77.42, 77.11, 76.79, 71.52, 59.08, 44.16, 37.10,

36.32, 28.46, 26.92, 26.90, 19.17; IR ʋ max = 2243, 2178, 1988, 1948,

1060, 1022, 741, 705, 551, 483, 469, 415, 404; HRMS for C32H45N4O4Si

[M+H]+ (predicted) 577.3205, found 577.3192.

154

1-(3-((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-

butyldiphenylsilyl)oxy)pyrrolidine-2-carboxamido)propyl)-3-methyl-1H-

imidazol-3-ium iodide 5.29

(2S,4R)-2-((3-(1H-Imidazol-1-

yl)propyl)carbamoyl)-4-((tert-

butyldiphenylsilyl)oxy)pyrrolidine-1-carboxylate

(0.936 g, 1.62 mmol) was dissolved in PhMe (10 mL) and MeI (0.202 mL,

3.25 mmol) was added. The reaction was then heated to 100 °C and

exposed to microwave irradiation for 1 hour. Excess solvent was then

removed under reduced pressure and the resulting orange, viscoue oil

purified by column chromatography (MeOH:CHCl3, 1:4, Rf = 0.17)

affording the pure product as a pale yellow solid (0.925 g, 79%). 1H NMR

(270 MHz, CDCl3): δ 9.51 (s, 1H, Ar-H), 7.74 (s, 1H, Ar-H), 7.61-7.57 (m,

4H, Ar-H), 7.40-7.34 (m, 7H, Ar-H), 4.45 (t, 1H, J= 8.1 Hz, CH), 4.37-4.33

(m, 3H, CH2), 3.98 (s, 3H, CH3), 3.50-3.35 (m, 3H, CH2), 3.21-3.16 (m,

2H, CH2), 2.27-2.14 (m, 3H, CH2), 1.98-1.89 (m, 1H, CH2), 1.41 (s, 9H,

Boc-t-butyl), 1.01 (s, 9H, Si-t-butyl), (NH not observed); 13C NMR (500

MHz, CDCl3): δ 173.79, 156.00, 137.76, 135.93, 133.84, 133.69, 130.18,

128.13, 128.10, 123.50, 123.41, 80.57, 71.82, 60.25, 56.07, 46.80, 41.66,

39.30, 37.25, 34.83, 30.26, 29.38, 28.80, 27.99, 27.17, 27.14, 22.95,

20.76, 19.76, 19.41, 19.09, 14.65, 11.77; IR ʋ max = 2177, 1662, 1533,

1388, 1027, 735, 710, 507, 446; HRMS for C33H47N4O4Si

(predicted):591.3361, found 591.3393.

1-(3-((2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-

carboxamido)propyl)-3-methyl-1H-imidazol-3-ium 2,2,2-trifluoroacetate

5.30

1-(3-((2S,4R)-1-(tert-Butoxycarbonyl)-4-((tert-

butyldiphenylsilyl)oxy)pyrrolidine-2-

carboxamido)propyl)-3-methyl-1H-imidazol-3-

ium iodide (0.709 g, 0.988 mmol) was dissolved

in DCM (9 mL) then trifluoroacetic acid (1 mL) was added and the reaction

was allowed to stir for 16 hours at 23 °C. The reaction was then washed

with NaHCO3 (10 mL) and extracted in DCM (3 × 10 mL). Excess solvent

N

NH

O

O

Boc

TBDPSN

N

MeI

155

was then removed under reduced pressure to afford the pure product as a

pale yellow solid (0.4369 g, 73%) as determined by 1H NMR

spectroscopy. m.p. = 118 °C; 1H NMR (500 MHz, CDCl3): δ 10.15 (br s,

1H, Ar-H), 8.10 (br s, 1H, Ar-H), 7.66 (s, 1H, Ar-H), 7.63-7.59 (m, 5H, Ar),

7.42-7.39 (m, 2H, Ar-H), 7.37-7.34 (m, 4H, Ar-H), 4.36 (s, 1H, CH), 4.27

(app. t, 2H, CH2), 4.04 (app. t, 1H, CH2), 3.96 (s, 3H, CH3), 3.28-3.23 (m,

2H, CH2), 3.17-3.14 (m, 1H, CH2), 2.93 (d, 1H, J = 11.9 Hz, CH2), 2.69

(dd, 1H, J= 11.9,3.5 Hz, CH2), 2.25-2.20 (m, 1H, CH2), 2.06 (app. s, 2H,

CH2), 1.70-1.65 (m, 1H, CH2), 1.04 (s, 9H, Si-t-butyl), (NH not observed);

13C NMR (500 MHz, CDCl3): δ 176.41, 138.65, 135.93, 135.88, 134.15,

134.02, 130.06, 128.02, 123.23, 123.16, 123.09, 74.90, 60.07, 55.85,

53.76, 47.44, 40.22, 36.77, 35.20, 31.07, 27.19, 27.11, 19.37; IR ʋ max =

2177, 2049, 2025, 1989, 1948, 1693, 1081, 1059, 1044, 1025, 769, 705,

524, 493, 483, 469, 448, 415, 404; C28H39N4O2Si (predicted):491.2837,

found 491.2864.

1-(3-((2S,4R)-4-((tert-butyldiphenylsilyl)oxy)pyrrolidine-2-

carboxamido)propyl)-3-methyl-1H-imidazol-3-ium 5.31

1-(3-((2S,4R)-1-(tert-butoxycarbonyl)-4-((tert-

butyldiphenylsilyl)oxy)pyrrolidine-2-carboxamido)propyl)-3-methyl-1H-

imidazol-3-ium iodide (0.949 g, 1.32 mmol) was dissolved in DCM (9 mL),

prior to the addition of TFA (1 mL). The reaction was allowed to stir for 16

hours at 23 °C. Excess solvent was then removed under reduced

pressure and the resulting gel was redissolved in an EtOH/H2O mix (1:1,

4 mL), to which KPF6 (0.559 g, 3.04 mmol) was added and allowed to stir

for 2 hours at 23 °C. The solution was then washed with a saturated

NaHCO3 solution (10 mL) and organic matter extracted in DCM (3 ×

15 mL). Once again, excess solvent was removed under reduced

pressure to afford the crude compound as a pale yellow solid (0.692 g,

82%). m.p. = 66.3 °C; 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H, Ar-H),

156

7.88-7.86 (t, 1H, J= 5.0 Hz, Ar-H ), 7.63-7.60 (m, 4H, Ar-H ), 7.47 (s, 1H,

Ar-H) 7.43-7.35 (m, 7H, Ar-H) 7.22 (br s, 1H, Ar-H), 4.39 (s, 1H, CH),

4.13-4.11 (m, 2H, CH2), 3.84 (s, 3H, CH3), 3.24-3.11 (br m, 2H, CH2),

3.01-2.84 (m, 4H, CH2, NH), 2.79-2.76 (m, 1H, CH2), 2.27-2.23(m, 1H,

CH2), 2.01-1.96 (m, 1H, CH2), 1.71-1.66 (m, 1H, CH2), 1.43-1.25 (m, 1H,

CH2), 1.04 (s, 9H, t-butyl); 13C NMR (500 MHz, CDCl3): δ 175.21, 136.51,

135.66, 135.58, 133.69, 133.53, 129.85, 127.80, 123.31, 122.71, 74.35,

59.64, 55.31, 47.04, 39.76, 36.20, 35.03, 30.39, 26.90, 19.08; IR ʋ max =

2332, 2189, 2063, 2012, 1071, 1027, 820, 736, 613, 479, 445;

C28H39N4O2Si (predicted):491.2837, found 491.2851.

General Method for Catalyst Testing (Aldol)

Catalyst 5.30 or 5.31 was weighed out (≈ 20 mg) and aldehyde (≈ 25 mg)

was added prior to the dissolutoin of both in ketone (≈ 80 μL). This

mixture was then briefly sonicated to provide thorough mixing. For neat

reactions, the mixture was then allowed to stir for 24 hours at 23 °C. For

reactions in different solvents, the given solvent (0.25 mL) was added at

the conclusion of sonication, then allowed to stir at 23 °C for 24 hrs before

the removal of solvents under reduced pressure. The crude material was

then analysed by 1H NMR spectroscopy and the percentage conversion

and diastereomeric ratio calculated. The product was then purified by

flash chromatography (DCM, Rf ≈ 0.4). Excess solvent was then removed

under reduced pressure and the pure material determined by 1H NMR

spectroscopy.

Determination of reaction outcomes: conversion and diastereomeric

ratio

The conversion of the initial aldehyde into the target compound was

determined by the integration of key peaks within the 1H NMR

spectrum. The diasteremeric ratio was determined by integration of the

chiral proton peaks for both the syn and the anti diastereomers. All

157

compounds show 1H NMR spectru consistent with previously published

compounds.

The key 1H NMR signals that are integrated are determined from reported

examples and lie in uncluttered regions of the NMR spectra.

syn

anti

Aldehyde

158

Determination of Reaction Outcomes: Enantiomeric Ratio.

Enantiomeric ratio was determined by chiral HPLC, integrating the peak

area of each enantiomer from the major diastereomer. The elution

times were compared to racemic examples synthesised through one of

two methods. Example below.

2-((S)-hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

Table 1, Entry 8

Signal 1: DAD1 A, Sig=254,4 Ref=360,100

Peak RetTime

Width Area Height Area # [min] [min] [mAU*s] [mAU] %

1 24.341 BB 0.7049 1784.14551 37.64417 24.3479

2 32.290 BB 0.9537 5543.56299 85.80730 75.6521

Totals : 7327.70850 123.45147

5 1 2 3

159

DSC Results

-50 0 50 100 150 200

-2

-1

0

1

2

3

4

5

0 5 10 15 20 25

-0.2

-0.1

0.0

0.1

0.2

He

at

Flo

w (

W/g

)Temperature (degrees Celcius)

He

at F

low

(W

/g)

Temperature (degrees Celcius)

DSC output with the glass transition inset of organocatalyst 5.31.

160

161

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269. Siyutkin, D. E.; Kucherenko, A. S.; Frolova, L. L.; Kuchin, A. V.; Zlotin, S. G., N-Pyrrolidine-2-ylmethyl)-2-hydroxy-3-aminopinanes as novel organocatalysts for asymmetric conjugate additions of ketones to α-nitroalkenes. Tetrahedron: Asymmetry 2013, 24 (12), 776-779.

270. Siyutkin, D. E.; Kucherenko, A. S.; Frolova, L. L.; Kuchin, A. V.; Zlotin, S. G., 2-Hydroxy-3-[(S)-prolinamido]pinanes as novel bifunctional organocatalysts for asymmetric aldol reactions in aqueous media. Tetrahedron: Asymmetry 2011, 22 (12), 1320-1324.

271. Maltsev, O. V.; Kucherenko, A. S.; Zlotin, S. G., Ionic polymer-supported O-trimethylsilyl-α,α-diphenyl-(S)-prolinols as recoverable organocatalysts for the asymmetric Michael reactions of carbon acids with α,β-enals. Mendeleev Commun. 2011, 21 (3), 146-148.

272. Maltsev, O. V.; Chizhov, A. O.; Zlotin, S. G., Chiral ionic liquid/ESI-MS methodology as an efficient tool for the study of transformations of supported organocatalysts: deactivation pathways of Jorgensen-Hayashi-type catalysts in asymmetric Michael reactions. Chem. Eur. J. 2011, 17 (22), 6109-17.

273. Larionova, N. A.; Kucherenko, A. S.; Siyutkin, D. E.; Zlotin, S. G., (S)-Threonine/α,α-(S)-diphenylvalinol-derived chiral ionic liquid: an immobilized organocatalyst for asymmetric syn-aldol reactions. Tetrahedron 2011, 67 (10), 1948-1954.

274. Kucherenko, A. S.; Siyutkin, D. E.; Nigmatov, A. G.; Chizhov, A. O.; Zlotin, S. G., Chiral Primary Amine Tagged to Ionic Group as Reusable Organocatalyst for Asymmetric Michael Reactions of C-Nucleophiles with α,β-Unsaturated Ketones. Adv. Synth. Catal. 2012, 354 (16), 3078-3086.

275. Izgorodina, E. I.; MacFarlane, D. R., Nature of hydrogen bonding in charged hydrogen-bonded complexes and imidazolium-based ionic liquids. J. Phys. Chem. B 2011, 115 (49), 14659-67.

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283. Gruttadauria, M.; Giacalone, F.; Noto, R., Water in Stereoselective Organocatalytic Reactions. Adv. Synth. Catal. 2009, 351 (1-2), 33-57.

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Published Works

This journal is© the Owner Societies 2016 Phys. Chem. Chem. Phys., 2016, 18, 13153--13157 | 13153

Cite this:Phys.Chem.Chem.Phys.,

2016, 18, 13153

Determination of Kamlet–Taft parameters forselected solvate ionic liquids†

Daniel J. Eyckens,ab Baris Demir,a Tiffany R. Walsh,a Tom Weltonc andLuke C. Henderson*ab

The normalised polarity ENT and Kamlet–Taft parameters of recently

described solvate ionic liquids, composed of lithium bis(trifluoro-

methyl)sulfonimide (LiTFSI) in tri- (G3TFSI) or tetraglyme (G4TFSI)

have been determined and compared to the parent glyme (G3 and

G4). We show that these solvate ionic liquids have a high polarity

(G3TFSI, (ENT ) = 1.03; G4TFSI, (EN

T ) = 1.03) and display very high

electron pair accepting characteristics (G3TFSI, a = 1.32; G4TFSI,

a = 1.35). Molecular dynamics simulations suggest that the chelated

lithium cation is responsible for this observation. The relatively

small hydrogen bond acceptor (b) values for these systems (G3TFSI,

b = 0.41; G4TFSI, b = 0.37) are thought to be due primarily to the

TFSI anion, which is supplemented slightly by the glyme oxygen

atom. In addition, these solvate ionic liquids are found to have a

high polarisability (G3TFSI, p* = 0.94; G4TFSI, p* = 0.90).

Introduction

Room temperature ionic liquids (ILs) have become an essentialtool within many areas of science including synthetic chemistry,engineering, and nanoscience.1–8 Their high polarity, negligiblevapour pressure, and high thermal tolerance window have impartedintrinsic advantages of ILs over traditional organic solvents.9,10

Recently, Watanabe and co-workers reported the use of solvateionic liquids as electrolytes for lithium ion batteries.11–19 These ILsare prepared by simply dissolving lithium bis(trifluoromethyl)-sulfonimide 1 in either tri-glyme (G3) or tetra-glyme (G4), givingsolvate ionic liquids, G3TFSI or G4TFSI (Scheme 1).

One of the most attractive aspects of ILs is their ability to betuned for a specific task based on their fundamental properties,such as hydrogen bond donating/accepting ability, etc. Thesedescriptors can be measured spectrophotometrically using arange of dyes, as described by Kamlet and Taft.20–25 Thesedescriptors, combined with the solvent polarity as described byReichardt,26,27 have been determined for a huge number ofsolvents, including ionic liquids,28–33 and allow for judiciouschoice of a solvent for a given application, or to explainobserved phenomena.31,34 To this end, we believe that G3TFSIand G4TFSI present a significant opportunity for application toa wide array of potential areas. Therefore, we have characterisedG3TFSI and G4TFSI in terms of normalised polarity (EN

T),Kamlet–Taft parameters (a, b, and p*), and compared these totheir corresponding values for the parent glyme solvent (G3 andG4, respectively), and [Bmim][TFSI], to provide context andmethod validation.

The solvate ILs which are the focus of this work (Scheme 1)are reminiscent of concentrated solutions of lithium per-chlorate in diethyl ether (5M LPDE), as reported by Griecoet al., and were used as organic reaction media for a number ofyears.35–41 We recently reported the use of these solvate ILs asreaction media for electrocyclization reactions, and comparedthem to 5M LPDE.9

Scheme 1 Simplified representation of solvate ILs used in this study.

a Institute for Frontier Materials, Deakin University, Waurn Ponds Campus,

Geelong, Victoria, 3216, Australia. E-mail: luke.henderson@deakin.edu.aub Strategic Research Centre for Chemistry and Biotechnology, Deakin University,

Waurn Ponds Campus, Geelong, Victoria, 3216, Australiac Department of Chemistry, Imperial College London, South Kensington, London,

SW7 2AZ, UK

† Electronic supplementary information (ESI) available: Additional methodology,snapshot of dye complex in G3TFSI liquid, radial distribution functions, coordinationnumbers and distance histograms from G3TFSI and G4TFSI simulations, generalisedexamples of K–T parameter calculations are provided. See DOI: 10.1039/c6cp01216g

Received 23rd February 2016,Accepted 19th April 2016

DOI: 10.1039/c6cp01216g

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To the best of the authors’ knowledge, the Kamlet–Taftparameters for 5M LPDE have never been reported, presumablydue to the moisture sensitive nature of that solvent. Thereforethe work presented herein fills this knowledge gap and high-lights the easy-to-use nature of these solvate ILs.

Experimental section

Solvate ILs G3TFSI and G4TFSI were prepared according toreported procedures.3 All chemicals were from Sigma Aldrich orOakwood Chemicals and used as received.

Preparation of UV samples

All dyes were loaded to high boiling point solvents according tothe same general procedure; the appropriate dye was dissolvedin DCM to a concentration of 0.9 mM, then 3 mL of dye solutionand 3 mL solvent were combined and DCM was removed underreduced pressure.

Dyes loaded to low-boiling point solvents were made up inconcentration of 0.9 mM in the solvent being tested. The UV-visspectrum of the sample was then measured at 23 1C on aUV-Cary 300 Spectrometer.

Equations

For a fully worked example of determining a (and b), pleaserefer to the ESI.† ‡

1 kK (kiloKaiser) = 1000 cm�1 (1)

p� ¼ vmaxðkKÞ � v0ðkKÞ�s ¼ vmaxðkKÞ � 27:52 kK

�4:12 (2)

ETð30Þ ¼28 591

lmaxðnmÞ(3)

ENT ¼

ETð30ÞðsolventÞ � ETð30ÞðTMSÞETð30ÞðwaterÞ � ETð30ÞðTMSÞ ¼

ETð30ÞðsolventÞ � 30:7

32:4

(4)

Results and discussionDetermination of solvent polarity and Kamlet–Taft parameters

As described previously by others, we used a series of dyes todetermine the polarity and Kamlet–Taft parameters of thesesolvents. The dyes used in this study are summarised in Fig. 1.

By far the most common solvatochromic dye used to deter-mine the polarity of a solvent is Reichardt’s dye 2. A zwitterioniccompound, when placed in a solvent, this dye produces uniquecharge-transfer absorption bands which are used to indicateoverall solvent polarity. Note that polarity can be referred to asET(30) which is converted to EN

T (the normalised polarity)against water (EN

T = 1).In the interest of thoroughness, we also determined the

Kamlet–Taft parameters of glymes G3 and G4 to ensure ourresults were due to the IL and not an artefact of the parentether. We observed that G3TFSI and G4TFSI possessed similar

high polarity, marginally greater than that of water, and fargreater than that of both glymes (G3 and G4). This outcome isnot surprising, as the inclusion of a salt into a solvent will, byits nature, increase the overall solution polarity. Nevertheless,these values place G3TFSI and G4TFSI in the same polaritycategory as alkylammonium salts (e.g. Et2NHNO3), which arederived from extremely strong acid–base combinations. Deter-mination of the Kamlet–Taft parameters for [Bmim]TFSI servedto both ensure our methodology was sound and to providecontext to the values obtained for the solvate ionic liquids(Table 1).

Using the spectral data from Reichardt’s dye, we plotted thisagainst absorbance spectra employing p-nitroanisole and usedthese plots to determine the a value for each of these solvents.Considering that a is typically referred to in the literature as ameasure of hydrogen bond donating ability, it was surprising tosee that both G3TFSI and G4TFSI possessed very high a values,because there are no acidic hydrogens present within any partof the IL. Indeed, the negligible a values for G3 and G4 werebetter aligned with our expectations.

Since the stabilisation of the betaine in Reichardt’s dye 2is caused by stabilisation of the phenoxy group, we haveattributed the high a value to a similar stabilisation effectoccurring between the phenoxy-moiety and the lithium cationembedded within both G3TFSI and G4TFSI. This is consistentwith our previous work where we determined the Gutmannacceptor number for G3TFSI and G4TFSI to be 26.5 each.42

Additionally, the use of betaine dyes as chromoionophores forthe detection of group 1 metal cations (including Li+) has beenshown previously.43–45 Recent work by Atkin et al.46 examinedthe conformation of poly(ethylene oxide) in G4TFSI andproposed that the ether oxygens of the solute could displace

Fig. 1 Solvochromic dyes used in this study.

Table 1 Polarity (ENT ) and Kamlet–Taft Parameters for G3TFSI, G4TFSI, G3,

G4, and [bmim]TFSI

Solvent ENT aa bb p*

G3TFSI 1.03 1.32 0.41 0.94G4TFSI 1.03 1.35 0.37 0.90G3 0.30 0.01 0.96 0.65G4 0.28 0.05 0.96 0.67[Bmim][TFSI] 0.59 0.59 0.29 0.96[Bmim][TFSI]c 0.55 0.61 0.24 0.98

a Normalised against methanol. b Normalised against DMSO. c Previouslypublished polarity and Kamlet–Taft values for this IL, ref. 26 and 31.

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the TFSI anion within the solvate IL, leading to a furtherstabilisation of Li+. This is consistent with our hypothesis,though in this case the oxygen donor is from Reichardt’s dyerather than the poly(ethyleneoxide) polymer.

Molecular dynamics simulations of both the G3TFSI andG4TFSI liquid systems (see ‘Additional Methodology’ in theESI†), including 2 as an exemplar dye, confirm this hypothesis.Our simulations of these two liquid systems revealed that thedye could remain in close and persistent contact with Li+, withan average Li+–O(Dye) separation of 1.78 � 0.06 Å for G3TFSIand (1.750 � 0.049 Å for G4TFSI). These average separations arecloser than the corresponding Li+� � �O(TFSI) and Li+� � �O(Glyme)average distances (B1.9 Å and 2.0 Å, respectively). Moreover,the coordination of the sterically-bulky dye to Li+ appearedto effectively exclude coordination of glyme molecules; allof the remaining coordination to the dye–Li+ complex wasprovided by two or three TFSI molecules (in roughly equivalentproportions), providing 2–3 coordinating oxygen atoms (2.2 �0.7 oxygen atoms on average). Fig. 2 provides a typical structureof the dye/TFSI/Li+ complex taken from our simulations of theG4TFSI liquid (see Fig. S1 in the ESI† for a typical configurationtaken from our G3TFSI simulations).

This finding is remarkable given the dominance of G4 in thecoordination of Li when no dye is present. Simulations usingour force-field for the G4TFSI liquid in the absence of the dyeyielded Li� � �O(Glyme) and Li� � �O(TFSI) coordination numbersof 2.9 and 2.1 respectively (see ESI† for further details). Thesecoordination numbers are in very good agreement with veryrecently reported neutron scattering data10 for this system, andare a marked improvement on previously-reported simulationresults.11,15

The polarity of a solution is the sum of all possible inter-actions between the solvent and the solute; in this instance that

includes the ability of Li+ to act as a Lewis acid. It wouldbe inappropriate for this contribution to the overall solventpolarity to be ignored, but it should be noted that Reichardt’sdye is particularly sensitive to ionic interactions. It should alsobe noted that the measured solvent polarities are specific forequimolar mixtures of LiTFSI and G3 or G4, and thus may varysubstantially depending on the relative ratios of these speciesor for other lithium salts.

Next, to determine b we used p-nitroaniline 4 and N,N-diethyl-4-nitroaniline 5, both of which have been commonlyemployed previously.21,25,31 In this instance the values wereconsistent with what would be expected from simple inspectionof the ILs and G3 and G4. The former possesses excellenthydrogen bond accepting ability, while the suppressed capacityfor G3TFSI and G4TFSI to accept hydrogen bonds, via the ethergroups, is expected because the non-bonding electrons on theoxygen atom are already involved in stabilising the lithium cation.

Finally, we sought to elucidate p*, which is thought tocapture the polarity-polarizability effect of the solvent. Of allthe Kamlet–Taft parameters, p* is the most open to interpretationand hardest to definitively determine as a reproducible value. Thevariability in reported values for other systems seems to arise dueto the number of unique dyes being used to determine p*. As thesolvent–dye interaction is unique to each dye, this resulted in thecalculated value of p* being unique to each dye.

In this work N,N-diethylamino-4-nitroaniline 5 was used,because this dye has found the most widespread use inpreviously-reported determination of p* values. Furthermore,previous work by Welton et al.32 has determined an appropriate‘s value’ (eqn (2), above) for use with this dye. Therefore, takingall these factors into consideration, we argue that use of 5would give the most meaningful p* value here.

The values we observed for p* in each case are high; 0.94 and0.90 (for G3TFSI and G4TFSI, respectively). These valuesare comparable to those determined by Kamlet and Taft forformamide (0.97), 1,1,2,2-tetrachloroethane (0.95), and ethyleneglycol (0.92). The high polarizability of these ILs is consistentwith their structure; again, Li+ would be able to induce a largedegree of polarity in solutes and is also very polar. The slightdecrease in p* observed for G4TFSI compared to G3TFSI isattributed to the more diffuse positive charge in this chelate,being spread over five oxygens and the lithium, versus fouroxygens and the lithium in G3TFSI. Indeed, a large increase wasobserved compared to the parent glymes themselves with G3and G4 possessing p* values of 0.65 and 0.67, respectively.

Conclusions

In conclusion we have determined the Kamlet–Taft parametersfor a selection of solvate ionic liquids and compared them totheir parent solvent and commonly used imidazolium-derivedionic liquid. The solvate ILs G3TFSI and G4TFSI possessed veryhigh normalised polarity compared with water (EN

T = 1.03) andhydrogen bond donating properties (a = 1.32 and a = 1.35,respectively), despite the lack of acidic hydrogens present in

Fig. 2 Typical configuration predicted for the dye–Li+ complex, showingadditional coordination of three oxygen atoms provided by two TFSImolecules, taken from the G4TFSI liquid simulation. Remainder of theliquid not shown for clarity. Cyan = carbon, white = hydrogen, blue =nitrogen, red = oxygen, green = fluorine, yellow = sulphur and purple = Li+.

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these ILs. This observation was attributed to the stabilisationof the phenoxy-moiety within Reichardt’s dye, which wassupported by molecular dynamics simulations.

The hydrogen bond accepting ability of G3TFSI and G4TFSI(b = 0.41 and a = 0.37, respectively), is thought to be dominatedby the TFSI anion, with some contribution from the etheroxygens within the glyme. Finally, both ILs were found to possessa high p* value, indicating a high degree of polarizability. Weanticipate that these parameters will be useful when selectingpotential applications for these unique ionic liquids.

Acknowledgements

The authors acknowledge the Institute for Frontier Materials,the SRC for Chemistry and Biotechnology, the Faculty ofScience, Engineering, and Built Environment for their contin-ued support. We also gratefully acknowledge the Institute forFrontier Materials for their funding and scholarship to DE, andwe thank Deakin (AFFRIC) and the CSIRO for a scholarship toBD. We gratefully acknowledge the National Computing Infra-structure (NCI), Australia, for allocation of computingresources. TRW thanks veski for an Innovation Fellowship.

Notes and references‡ A spreadsheet to assist in the determination of Kamlet–Taft para-meters is available upon request to the corresponding author.

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DOI: 10.1002/ejoc.201501614 Communication

Ionic Liquids

Solvate Ionic Liquids as Reaction Media for ElectrocyclicTransformationsDaniel J. Eyckens,[a] Megan E. Champion,[a] Bronwyn L. Fox,[a]

Prusothman Yoganantharajah,[b] Yann Gibert,[b] Tom Welton,[c] and Luke C. Henderson*[a]

Abstract: Solvate ionic liquids (SILs) consisting of lithiumbis(trifluoromethylsulfonyl)imide dissolved in tri- or tetraglymehave recently emerged as a novel class of ionic liquids. Herein,the first use of solvate ionic liquids as a replacement for molec-ular solvents in electrocyclization reactions is reported. The SILspromoted both Diels–Alder and [2+2] cycloaddition reactions,

Introduction

Ionic liquids have permeated many areas of chemistry, biology,materials science, and are prevalent in industrial applications.They are commonly advocated for their negligible vapour pres-sure, solubilising ability, and their excellent application to or-ganic synthesis.[1] They have also found excellent utility in en-ergy applications as electrolytes for batteries and as corrosioninhibitors. Recently, Watanabe et al. have developed and elec-trochemically, physically, and thermally characterised a range ofnovel solvate ionic liquids (SILs) as potential electrolytes for lith-ium ion batteries.[2] While these SILs have excellent prospectsin energy storage applications, their potential use as an alterna-tive to both traditional organic solvents and commonly em-ployed ionic liquids for organic transformations remains com-pletely unknown.

The preparation of these solvate ILs attracts no syntheticchallenges, simple dissolution of Li[NTf2] in either tri- or tetra-glyme yields the ionic liquids, G3TFSI or G4TFSI, respectively,within a few hours (Figure 1). Additionally, they possess variousattractive attributes for organic chemists: (i) they are aprotic;(ii) they remain as liquids at low temperatures (e.g. 0 °C), whilemaintaining their highly polar nature. They also possess a hardcation, which has been “softened” due to complexation withthe polyether moieties and thus have great potential to stabilisepolar intermediates or, potentially, participate in Lewis acid acti-vation.

[a] Deakin University, Waurn Ponds Campus,Locked Bag 20000, Geelong, VIC 3220, AustraliaE-mail: luke.henderson@deakin.edu.auwww.deakin.edu.au/research/ifm

[b] Faculty of Natural Sciences, Imperial College LondonLondon SW7 2AZ, UKSupporting information for this article is available on the WWW underhttp://dx.doi.org/10.1002/ejoc.201501614.

Eur. J. Org. Chem. 2016, 913–917 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim913

compared to an appropriate molecular solvent, and 5 M lithiumperchlorate in diethyl ether. The Gutmann acceptor number(AN) of these solvate ionic liquids has also been determined by31P NMR spectroscopy to be 26.5, thus being modest Lewisacids.

Figure 1. Solvate ILs (G3TFSI and G4TFSI) used in this study and 5M LPDE(structure is simplified for comparison).

This latter point is reminiscent of the 5 M lithium perchloratein diethyl ether (5M LPDE) pseudo-ionic liquid, reported byGrieco et al.[3] which saw popularity in the late 1990s and early2000s.[4]

Despite its excellent potential, the use of 5M LPDE has fallenout of favour over the past decade. This has most likely arisendue to the potential explosive nature of perchlorates, in addi-tion to tedious drying procedures, and the high maintenancenature of this solvent.

Thus, the lithium-derived solvate ionic liquids examined hereare a potential alternative to 5M LPDE, which obviate theselimitations as both the G3TFSI and G4TFSI solvents can bestored over various drying agents (molecular sieves, MgSO4,etc.) or heated to remove water, without any detrimental ef-fects, nor the potential of explosion.

In this work, G3TFSI, G4TFSI and G4ClO4 are evaluated asorganic solvents and compared to 5M LPDE, and a suitablemolecular solvent as determined by the reaction. Also pre-sented is NMR spectroscopic data relating to the Lewis acidity

Communication

of these ILs, from which the Gutmann acceptor number (AN) isdetermined. It is the goal of this work to demonstrate prelimi-nary organic transformations, which can be carried out in thesesolvents, with more in-depth examination of each reaction tobe carried out in the future.

Results and Discussion

The suite of solvents employed in this work includes G3TFSI,G4TFSI, G4ClO4, 5M LPDE, and a suitable molecular solvent de-pending on the chosen reaction. This suite gives a cross-sectionof relevant solvents with consistency of ionic portions to give asolid foundation of solvent comparison. Note that G3ClO4 wasomitted as this combination gives a solid salt.

Examination of the literature surrounding the use of5M LPDE as a reaction solvent revealed a diverse collection oforganic reactions, which are enhanced in reaction rate, yield, orselectivity by being conducted in that solvent. To that a [2+2]reaction between dimethylketene (1) (generated in situ fromisobutyryl chloride) and (E)-cinnamaldehyde (2) was chosen,giving alkene 4, after carbon dioxide extrusion.[5] This reactionwas reported not to proceed in the absence of LiClO4 and hasbeen reported in 5M LPDE; therefore, it was an obvious choicefor this study. Carrying out this reaction in chloroform (Table 1,Entry 1) showed that the product was formed in trace amounts(<10 %), as expected. When repeating the literature condi-tions,[5] the high yield (95 %) reported originally in 5M LPDEwas unable to be reproduced.

Table 1. Comparison of solvents in the [2+2] cascade formation of dienes.

Entry Solvent t [h] T [°C] Yield [%][a]

1 CHCl3 6 r.t. <52 5M LPDE 6 r.t. ca. 203 G3TFSI 6 r.t. 564 G4TFSI 6 r.t. 415 G4ClO4 6 r.t. 15

6[b] G3TFSI 6 r.t. 607 G3TFSI 6[c] 80 °C 70

[a] Isolated yield post chromatography. [b] Activated molecular sieves(100 mg) were used throughout the reaction. [c] The reaction mixture washeated for the final hour of the specified time.

Attempts at optimising this reaction by freshly preparing the5M LPDE, extensive drying of both LiClO4 and diethyl ether,gave highly variable results at best. The yield of 4 in 5M LPDEvaried between 5–40 %, with <20 % being typical for repeatedattempts. Despite the complete consumption of the aldehyde2, a complex mixture of products was typically observed in the1H NMR spectra of the crude mixture.

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When the reaction was carried out in G3TFSI and G4TFSI(Table 1, Entries 3 and 4, respectively), the 1H NMR spectra ofthe crude mixtures showed complete consumption of aldehyde3, and the isolated yields were much higher at 56 % and 41 %,respectively. Note that the crude extract, when using eithersolvate ionic liquid, typically contains residual glyme. This mate-rial is easily removed by flash chromatography, and its presencein the crude extract can be minimized by using successive brinewashes during workup. Finally, the use of G4ClO4 in this reac-tion (Table 1, Entry 5) gave some conversion to the desiredproduct, though the isolated yield was quite low (15 %).

Examination of the crude reaction mixture for all examplessuggested a mixture of aldehyde 1, intermediate 3, and thedesired diene 4. To encourage higher yields we carried out thereaction in the presence of 4 Å molecular sieves (Table 1, En-try 6) to remove adventitious water. Finally, repeating the reac-tion in G3TFSI accompanied by heating of the solution (80 °C)for the final hour, gave 4 in a yield (Table 1, Entry 7, 70 %)similar to those of the previous entries.

It is worth noting that heating of perchlorates is extremelyill-advised due to their explosive potential. Thus, this highlightsa major advantage of G3TFSI and G4TFSI, which can be heatedto improve reaction yield or as part of any optimization process.These simple demonstrations show that both G3TFSI andG3TFSI can serve as viable solvents for organic transformations.

Highlighted in the original report by Cossio et al.[5] was thatthe aforementioned cycloaddition, when carried out with 4-nitrobenzaldehyde does not eliminate CO2 but stops at the 2-oxetanone 7, thus necessitating a comparative reaction to de-termine if this outcome was observed in the solvate ionic liq-uids.

Repeating this reaction under literature conditions in G3TFSIgave an excellent yield of 94 % (Table 2, Entry 1); indeed, halv-ing the reaction time had little effect on the isolated yield(90 %, Table 2, Entry 2). As such, applying these optimized reac-tion conditions to G4TFSI also gave a good yield of 75 %(Table 2, Entry 3). Once again, the solvate ionic liquids provedto be superior to both 5M LPDE and the examined molecularsolvent (chloroform), which gave modest and poor yields, re-spectively. Due to the limitations of the perchlorate anion andthe poor results seen previously, this investigation continuedwithout the use of G4ClO4.

Table 2. Formation of oxetanone 7.

Entry Solvent t [h] Yield [%][a]

1 G3TFSI 6 942 G3TFSI 3 903 G4TFSI 3 754 5M LPDE 3 45[b]

5 CHCl3 3 <5

[a] Isolated yield post chromatography. [b] Reported yield of 90 % in 6 h.[3]

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Keeping with the theme of electrocyclisation reactions, aDiels–Alder reaction between isoprene and dimethyl acetylene-dicarboxylate (6) was examined. It is well known that Diels–Alder chemistry is compatible with ionic liquids,[6] salt addi-tives,[7] and is another class of reaction, reported to proceedwell in 5M LPDE (94 % in 7 h, Table 3, Entry 1).[3b]

Table 3. Diels–Alder reactions in solvate ionic liquids.

Entry Reactant Solvent t [h] T [°C][a] Yield [%][b]

1 8 5M LPDE 7 h r.t. 94[c]

2 8 [bmim][PF6] 2 h 80[d] 96[e]

3 8 G3TFSI 10 min 100 484 8 G4TFSI 10 min 100 785 8 G3TFSI 30 min 100 736 8 G4TFSI 30 min 100 817 9 CHCl3 20 min 100 <58 9 G3TFSI 20 min 100 73[e]

9 9 G4TFSI 20 min 100 21[e]

10 9 G3TFSI 16 h r.t. 011 10 CHCl3 20 min 100 4512 10 G3TFSI 20 min 100 7413 10 G4TFSI 20 min 100 65

[a] Microwave irradiation. [b] Isolated yield. [c] Reported yield.[3b] [d] Reportedyield.[6]

Also, [bmim][PF6] at 80 °C gave a 98 % yield of the Diels–Alder product 11 in 2 h. It is interesting to note that, while thereported conditions for this Diels–Alder reaction in ionic liquidsuse 5 equiv. of the dienophile, this number of equivalents wasused in this study to remain consistent with the literature After10 min at 100 °C in G3TFSI, diene 11 was obtained in a moder-ate 48 % isolated yield (Table 3, Entry 3). Interestingly, this reac-tion proceeded better in G4TFSI giving 11 in a 79 % isolatedyield over 10 min (Table 3, Entry 4). Extension of the reactiontime to 30 min (Table 3, Entries 5 and 6) gave improved yieldsfor both G3TFSI and G4TFSI (73 % and 81 %, respectively).Again, this highlights the benefit of being able to heat theseionic liquids without limitation as part of an optimization proc-ess. We noted that isoprene is only sparingly soluble in bothG3TFSI and G4TFSI, forming two layers when added to the samereaction vessel. The high yields observed suggest that isopreneis miscible only at higher temperatures and that the reactionproceeds rapidly at a much lower effective concentration of thedienophile, compared to previous reports.

The Diels–Alder reaction between isoprene and dimethylmaleate (9) or dimethyl fumarate (10) was also investigated.Previous reports of a Diels–Alder reaction with dimethyl male-

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ate (9) and isoprene required the use of extremely high temper-atures to obtain good yields (cf. 195 °C and 66 %, respec-tively).[8] The difficult nature of this reaction was reinforced bythe poor result obtained when using chloroform as the solvent(Table 3, Entry 7) giving only traces of the desired product 12.The use of G3TFSI and G4TFSI (Table 3, Entries 8 and 9) gavemore promising, albeit low, isolated yields of 73 % and 21 %,respectively, although it was found that the isolated productwas 13 possessing the trans configuration of the esters andnot the expected cis configuration of 12. We presume that thisepimerization has occurred due to the high temperature em-ployed in this reaction. The reason for the drastic reduction inyield in G4TFSI is unknown but may be due to a slightly differ-ent solubility of isoprene in this IL compared to the G3TFSIvariation.

Therefore, we repeated this reaction with 9 at room tempera-ture in G3TFSI overnight (Table 3, Entry 10) to minimize possibleepimerization. Unfortunately, no reaction was observed in thecrude material, and only starting material 9 was isolated.

When employing dimethyl fumarate (10) as the dienophile,a much less pronounced improvement in yield was noted in thesolvate ionic liquids, when compared to the molecular solvent(Table 2, Entry 11 vs. Table 2, Entries 12 and 13). Nevertheless,this was still greatly improved from previous reports of thissame transformation requiring a substantially longer reactiontime (cf. 36 h, 70 °C).[9]

Another reaction for which 5M LPDE was commonly usedwas the rapid pseudo-pinacol rearrangement of epoxides, suchas that reported with styrene oxide (14).[4f ] When this samerearrangement was attempted, in both G3TFSI and G4TFSI(Scheme 1) none of the rearranged product 15 was observed,with only starting material being present in the 1H NMR spec-trum of the crude product. Extension of reaction time and tem-perature of this process gave the same result.

Scheme 1. Attempted rearrangement of styrene oxide (14) with solvate ionicliquids.

This outcome for G3TFSI and G4TFSI was attributed to thelithium ion having reduced “availability” to act as a Lewis acid.This was thought to be due to the chelation-coordination ofthe glymes being stronger than that of the diethyl ether coordi-nation to Li+ in solution for 5M LPDE. The structure of solvateionic liquids was recently investigated by Watanabe[2e] usingmolecular dynamics simulation and is consistent with thishypothesis.

To test the hypothesis that the lithium cation is less Lewis-acidic in these solvate ILs when compared to the naked salt orin 5M LPDE, their relative Lewis acidities were determined by

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NMR spectroscopy, as reported by Britovsek et al.[10] using amodified Gutmann methodology.[11] This technique monitorsthe shift of 31P atom of phosphine oxides in the presence ofLewis acids (Table 4).

Table 4. Determination of the Gutmann Acceptor Number (AN) for solvateionic liquids.

Lewis acid Et3P=O AN[a]

δ(31P) Δδ(31P)

None 46.88 0.22 –n-Heptane 46.66 0.00 0.00

G3TFSI 57.96 11.30 26.5G4TFSI 57.96 11.30 26.5

Triglyme 46.76 0.10 0.23Tetraglyme 46.75 0.09 0.21

LiTFSI 64.48 17.82 41.8[bmim][TFSI] 51.68, 47.94 5.07, 1.30 11.9, 3.10

[a] Acceptor number (AN) was calculated according to AN =2.348 × Δδ[31P(Et3P=O)].[11]

In this study, triethylphosphine oxide was used in a 1:3 ratioof phosphine oxide/Lewis acid in C6D6. The 31P resonances oftriethylphosphine oxide were standardised using the additionof n-heptane (AN = 0). Interestingly, the change in δ(31P) forboth G3TFSI and G4TFSI was the same, indicating a very similarlevel of Li+ accessibility within the ILs, giving AN values of 26.5.To confirm that the AN observed was due to the IL and not theether constituent, the AN of each glyme was also measured andfound to be negligible (AN < 0.3), as expected.

Evaluating non-glyme-solvated LiTFSI gave an acceptor num-ber of 41.8, markedly higher than that of both G3TFSI andG4TFSI. This is expected as the C6D6–Li+ interaction would berelatively weak, compared to the complexing glyme, and thusthe Li+ ion should be more accessible (i.e. a stronger Lewis acid)than the Li+ ion present in both G3TFSI and G4TFSI. Unfortu-nately, an AN was unable to be determined for 5M LPDE underthe same conditions. This was due to the instant precipitationof LiClO4 once added to the NMR solvent, through removal ofthe ether O–Li+ stabilization. Attempts to measure the 31P NMRsignals in neat 5M LPDE [with a trace of deuterium (CDCl3) forsignal lock] also failed to give a usable signal.

Finally, to put the above AN values into perspective, the ANof [bmim][TFSI] was also determined by comparing the Lewisacidity of the imidazolium and lithium cations. Two 31P NMRsignals were observed in this instance, giving AN values of 11.9and 3.10. Presumably, the observed Lewis acidity of[bmim][TFSI] is dominated by hydrogen-bonding effects be-tween the phosphine oxide and the acidic hydrogen atom atC2, and the pair at C4/C5 on the imidazolium ring. Consideringthat the Lewis acidity of the C2 hydrogen atom present in imid-azolium-derived ionic liquids has major ramifications for cataly-sis in ionic liquids,[12] this bodes very well for the use of thesolvate ionic liquids in similar reactions.

Conclusions

The use of solvate ionic liquids as solvents for organic transfor-mations has been demonstrated for the first time. These ionic

Eur. J. Org. Chem. 2016, 913–917 www.eurjoc.org © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim916

liquids are easy to prepare, store, and can be used without priorspecialist training. Their ability to be stored for extensive peri-ods of time, kept anhydrous, and their stability over a broadrange of temperatures enables them to be used where otherionic liquids (including 5M LPDE) may not be the optimalchoice. Additionally, they exhibit mild Lewis-acidic characteris-tics, both possessing Gutmann Acceptor Numbers of 26.5 asdetermined by 31P NMR spectroscopy. Thus, they can poten-tially be applied to any reaction in which Lewis acid catalysishas been successful.

AcknowledgmentsThe authors would like to thank the Institute for Frontier Materi-als (IFM), the Strategic Research Centre (SRC) for Chemistry andBiotechnology, and the Facuilty of Science, Engineering, andBuilt Environment for their continued funding. We additionallythank IFM for their postgraduate scholarship to D. E.

Keywords: Ionic liquids · Lithium · Solvates · Lewis acids ·Acceptor number

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Received: December 28, 2015Published Online: January 25, 2016

Synthesis of a-aminophosphonates using solvateionic liquids†

Daniel J. Eyckens and Luke C. Henderson *

A range of a-aminophosphonates were accessed in high yields and very rapidly, using solvate ionic liquids as

the reaction media. Reactions typically required less than 10 minutes to go to completion and precipitation

of these products into water excludes the use of traditional work up procedures, giving the products in very

high crude purity. Excellent functional group tolerance for both the aldehyde and amine reaction partners

was observed, and a range of bis-aminophosphonates derived from aromatic diamines were also accessed

in high yield and purity.

Introduction

a-Aminophosphonates are of great interest to organic chemistsas they have vast applications in elds such as medicine,1–10

agriculture, and in environmental decontamination.5,11,12 Theyare considered phosphorus analogues to a-amino acids and thephosphorus' geometry has served as a useful tool in medicinalchemistry.13–16

The synthesis of these compounds via the Kabachnik–Fieldsor Pudovik reaction (Scheme 1) is relatively straight forward,using nucleophilic attack of di-alkyl or -aryl phosphite with animine.12 The imine species can be generated in situ, as part ofa three-component reaction, or preformed and added to thephosphite, both methodologies have been presented in theliterature.12 Additionally, several reports employ excess of theamine or dialkyloxy-phosphite (in some cases both) whichlimits the broad appeal of this reaction.

A large amount of work has been focused on optimizing thesynthesis of these molecules using a variety of Lewis acidcatalysts,17,18 such as CeCl3–proline complex,19 GaI3,20 In(OTf)3,YbCl3, SmI2, MoO2Cl2,21 Sc(OTf)3, and Dy(OTf)3 (ref. 12) amongothers.19,22 These efforts have given a variety of means to accessthese compounds, though the use of these Lewis acids always

pose several problems: disposal of heavy metals and the reac-tion solvent, the high toxicity of these materials, their sensitivityto atmospheric conditions, and their expensive nature.

Ionic liquids (ILs), in their many forms, have been used inmany areas of chemistry from materials science through tosolvents to facilitate organic transformations.23–29 The use of ILsas solvents for this reaction have been reported with someexcellent results,30–34 particularly for the pseudo-ionic liquid5.0 M lithium perchlorate in dithethyl ether (5 M LPDE), or theuse of LiClO4 as an additive to the reaction mixture.18,35–40 Thesereactions were able to isolate a-aminophosphonates in veryhigh yield using reaction times under 1 hour.

Despite these benets, the use of 5.0 M LPDE as the reactionmedia experiences several limitations, which include: enhancedsensitivity to atmospheric conditions, problematic solventpreparation, inability to be heated (due to potential explosivenature of the ClO4

� anion), and reagent restriction as not allreagents will be soluble in the pseudo-ionic liquid. Also, whilethe use of ionic liquids is an improvement over the use of metal-based catalysts, these procedures still use large amounts oforganic solvent in the recovery and purication of the syn-thesised phosphonate. Accessing these compounds in highyield, short reaction time, and with minimal puricationremains a challenge in organic synthesis.

We recently reported the use of solvate ionic liquids (SILs),being equimolar mixtures of LiTFSI in tri- or tetra-glyme(referred to as [G3(Li)]TFSI or [G4(Li)]TFSI, respectively), assuitable reaction media for electrocyclisation reactions andcharacterised them using Kamlet–Ta parameters (Fig. 1).41,42

Indeed these solvate ionic liquids serve as a stable and easily-handled surrogate to 5.0 M LPDE, while oen giving superiorreaction outcomes. They are able to be heated without concern,present minimal toxicity,43 are simple and cheap to produce,and can be stored over molecular sieves to maintain theiranhydrous nature, if required. This work sought to determine ifthe synthesis of a-aminophosphonates could be successfully

Scheme 1 Common approaches to the synthesis of a-aminophosphonates.

Institute for Frontier Materials, Deakin University, 75 Pigdons Road, Geelong, Victoria,

3216, Australia. E-mail: luke.henderson@deakin.edu.au

† Electronic supplementary information (ESI) available. See DOI:10.1039/c7ra04407k

Cite this: RSC Adv., 2017, 7, 27900

Received 19th April 2017Accepted 18th May 2017

DOI: 10.1039/c7ra04407k

rsc.li/rsc-advances

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carried out in solvate ionic liquids and if so, how does thiscompare to other ionic liquid and molecular solvents.

Herein we report the application of solvate ionic liquids asa solvent for the rapid and high yielding synthesis of a-amino-phosphonates in a three-component reaction. This reactionproceeds at room temperature in 5minutes, with themajority ofcrude products being obtained by precipitation and areanalytically pure, with minimal workup.

This work began by examining the Kabachnik–Fields reac-tion (i.e. three-component reaction) to minimize reagenthandling and as it represents the more efficient reactionpathway compared to pre-synthesising the imine. As a modelsystem for optimisation, benzaldehyde 1, aniline 2, anddiphenyl phosphite were chosen (Table 1).

Initially, the three-component reaction was stirred at roomtemperature for 30 minutes in [G3(Li)]TFSI, accessing pure 3 ina very promising yield of 82% (Table 1, entry 1). In an effort toreduce reaction time, without sacricing the yield, the reactiontime was reduced to 5 minutes (Table 1, entry 2), givinga excellent yield of 87%. Further reduction to 1 minute (Table 1,entry 3) gave the desired product in a slightly depressed yield of78%. Using this, a 5 minute reaction was considered theoptimal due to excellent yield and the reaction occurring ona very practical timescale. Repeating this reaction in [G4(Li)]TFSI, gave the desired product in an excellent yield of 91%(Table 1, entry 4). Note that the isolation of these compoundswas achieved via precipitation of the crude products into water,and not via chromatographic methods.

Nevertheless, with these conditions in hand, our attentionturned to assessing the functional group tolerance of thisreaction in SILs (Table 2). During the reaction scoping process,many aniline derivatives were observed to react extremelyquickly, with some forming the solid product almost instantly,preventing further stirring.

The rst reaction using these conditions and 4-nitroanilineproceeded in good yield for [G3(Li)]TFSI (64%) and poor yield in[G4(Li)]TFSI (25%) (Table 2, entries 1 & 2, respectively). The pooryield for the latter SIL was attributed to both the poor nucleo-philicity of the aniline and the problematic isolation of theproduct, due to repeated recrystalisation. Interestingly, theintroduction of a halogen-substitution on the aniline gaveexcellent yields, with both [G3(Li)]TFSI and [G4(Li)]TFSI fetchingan exemplary yields of 96% each (Table 2, entries 3 & 4,respectively). A similar yield was obtained from the electron-donating 4-aminophenol in [G3(Li)]TFSI (82%) and [G4(Li)]TFSI (92%) (Table 2, entries 7 & 8, respectively). Incorporating 4-uoroaniline into the given reaction conditions gave an excel-lent yield in [G3(Li)]TFSI (84%, Table 2, entry 7). Though when

[G4(Li)]TFSI was used, a slightly diminished yield of 68% (Table2, entry 8) was obtained. Similarly, 3-chloroaniline proceededwell in [G3(Li)]TFSI (83%, Table 2, entry 9), a result notconsistent in [G4(Li)]TFSI (59%, Table 2, entry 10). Exploring theeffect of 3-(triuoromethyl)aniline in this reaction revealeda excellent yields of 86% and 81% in [G3(Li)]TFSI and [G4(Li)]TFSI, respectively (Table 2, entries 11 & 12, respectively). Intro-ducing a bis-triuoromethylaniline derivative demonstrated therobust nature of the reaction conditions, with both [G3(Li)]TFSIand [G4(Li)]TFSI proceeding in good yields of 54% and 60%,respectively (Table 2, entries 13 & 14, respectively). It is worthnoting as well that the isolation of some products from [G4(Li)]TFSI was slightly more difficult than the [G3(Li)]TFSI, wherebythe isolated material contained traces of the glyme from the IL.The repeated precipitation to remove these traces of glyme maybe responsible for the slightly reduced yield in certain

Fig. 1 Simplified structures of solvate ionic liquids used in this work.

Table 1 Optimisation of a-aminophosphonate synthesis

Entry Solvent Time (min) Yielda (%)

1 [G3(Li)]TFSI 30 822 [G3(Li)]TFSI 5 873 [G3(Li)]TFSI 1 784 [G4(Li)]TFSI 5 91

a Isolated yield.

Table 2 Reaction scoping using substituted anilinic amines

Entry Compound R Solvent Yielda (%)

1 5a 4-NO2 [G3(Li)]TFSI 642 [G4(Li)]TFSI 253 5b 4-Cl [G3(Li)]TFSI 964 [G4(Li)]TFSI 965 5c 4-OH [G3(Li)]TFSI 826 [G4(Li)]TFSI 927 5d 4-F [G3(Li)]TFSI 848 [G4(Li)]TFSI 689 5e 3-Cl [G3(Li)]TFSI 8310 [G4(Li)]TFSI 5911 5f 3-CF3 [G3(Li)]TFSI 8612 [G4(Li)]TFSI 8113 5g 3,5-CF3 [G3(Li)]TFSI 5414 [G4(Li)]TFSI 60

a Isolated yield.

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instances. With this nal example of the reaction's high func-tional group tolerance, attention was then turned to the effect ofaldehyde substitution (Table 3).

Varying the aldehyde component of the reaction, andmaintaining the aniline, scoping began with the use of 4-bro-mobenzaldehyde, which proceeded in excellent yield of 90%and 91% in both [G3(Li)]TFSI and [G4(Li)]TFSI (Table 3, entries 1& 2, respectively). Utilizing p-tolualdehyde also gave encour-aging yields of 90% in [G3(Li)]TFSI and 86% in [G4(Li)]TFSI(Table 3, entries 3 & 4, respectively). Good yields of 69% and59% were observed in [G3(Li)]TFSI and [G4(Li)]TFSI, respec-tively, when using 4-nitrobenzaldehyde as the aldehyde source(Table 3, entries 5 & 6, respectively). The reaction also proceedwell with the application of 4-uorobenzaldehyde, obtainingthe nal product in good yields of 77% and 78% in [G3(Li)]TFSIand [G4(Li)]TFSI (Table 3, entries 7 & 8, respectively). The use ofsalicylaldehyde also showed good promise, giving pure productin 84% and 76% in [G3(Li)]TFSI and [G4(Li)]TFSI, respectively(Table 3, entries 9 & 10, respectively) and inclusion of a bis-substituted aldehyde (3,4-dichlorobenzaldehyde) further exem-plied the ability of the SILs to assist this reaction, giving theproduct 7f in good yields of 74% in [G3(Li)]TFSI and 79% in[G4(Li)]TFSI (Table 3, entries 11 & 12, respectively). With thisdata in hand our attention turned to the examination ofcarrying out multiple reactions on bis-amines.

The reactions proceeded very smoothly within 5 minutes,giving the desired product for a range of functional groups. Theyields were variable depending on the SIL and the electronics ofthe aldehyde. No discernable trend or difference was notedbetween either the [G3(Li)]TFSI or [G4(Li)]TFSI, with similaryields given for each example presented (Table 4).

Repeating this process but using the ortho- and meta-substituted diamino anilines (Scheme 2), gave varied results. Asmay be expected, the formation of 11 proceeded in a good butreduced yield in both [G3(Li)]TFSI or [G4(Li)]TFSI of 25% and34%, respectively. This was attributed to the increased sterichinderance imposed by the meta-substitution of the parentdiamine 10. This was consistent with our observations for theformation of 13, possessing ortho-substitution where only 9%was isolated for [G3(Li)]TFSI and no product was able to beisolated when using [G4(Li)]TFSI.

A nal aspect of this work which was considered challengingand had not been investigated previously is the synthesis ofnon-symmetric bis-a-aminophosphonates, using two differentaldehydes (Scheme 3). There is a considerable challenge in thisprocedure considering the speed at which the reaction takesplace, thus controlling the regiochemistry will be difficult.Experimentally, the use of two aldehydes of similar electronicnature were chosen, reduce any bias in the reacting system, e.g.the use of a reactive aldehyde followed by an unreactive alde-hyde would favour the formation of the non-symmetric product.

Therefore, in this case the rst aldehyde was added to thesolution of phosphite and amine in [G3(Li)]TFSI, then aer 5

Table 3 Reaction scoping using substituted benzaldehydes

Entry Compound R Solvent Yielda (%)

1 7a 4-Br [G3(Li)]TFSI 902 [G4(Li)]TFSI 913 7b 4-Me [G3(Li)]TFSI 904 [G4(Li)]TFSI 865 7c 4-NO2 [G3(Li)]TFSI 696 [G4(Li)]TFSI 59b

7 7d 4-F [G3(Li)]TFSI 778 [G4(Li)]TFSI 789 7e 2-OH [G3(Li)]TFSI 8410 [G4(Li)]TFSI 7611 7f 3,4-Cl [G3(Li)]TFSI 7412 [G4(Li)]TFSI 79

a Isolated yield. b This material possessed some of the a-hydroxyphosphonate (17% by 1H NMR) resulting from direct attack ofthe phosphite on 4-nitrobenzaldehyde.

Table 4 Synthesis of bis-a-aminophosphonates

Entry Compound R Solvent Yielda (%)

1 9a Ph [G3(Li)]TFSI 642 [G4(Li)]TFSI 523 9b 4-BrPh [G3(Li)]TFSI 364 [G4(Li)]TFSI 655 9c 4-NO2Ph [G3(Li)]TFSI 186 [G4(Li)]TFSI 33

a Isolated yield.

Scheme 2 Common approaches to the synthesis of a-aminophosphonates.

27902 | RSC Adv., 2017, 7, 27900–27904 This journal is © The Royal Society of Chemistry 2017

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minutes the second aldehyde was added. Using p-tolualdehydeand benzaldehyde, the target non-symmetric-a-amino-phosphonate 14 was successfully synthesised in a moderateyield of 43% in [G3(Li)]TFSI, 26% in [G4(Li)]TFSI, and in only 10minutes (Scheme 3). In each case the standard precipitationdescribed was also successful, giving 14 in analytical purity.

Representative experimentalprocedure

A round bottom ask was charged with aldehyde (1.00 mmol),which was dissolved in either [G3(Li)]TFSI or [G4(Li)]TFSI (0.5mL). Aniline (1.00mmol) was then added, before the addition ofdiphenyl phosphite (0.230 mL, 1.20 mmol) and stirred at roomtemperature for the given time period. Diethyl ether (10mL) wasadded at the conclusion of the reaction, before the addition ofdeionised water (10 mL) causing a ne precipitate to form. Theremoval of diethyl ether under reduced pressure affordeda suspension of precipitate in the aqueous phase, which wasthen ltered washing with excess water and petroleum spirits(40–60 �C).

Conclusions

In conclusion, the use of solvate ionic liquids as excellentreaction media for the Kabachnik–Fields reaction has beenshown. A wide range of a-aminophosphonates were able to besynthesised in 5 minutes with simple precipitation giving thedesired compound in >95% purity. Extension of this method-ology to bis-a-aminophosphonates, using para-dia-minobenzene was also successful, in the same 5 minutereaction duration and in high yield. Using ortho- and meta-diaminobenzene gave the desired products but in lower yield(34% and 9%, respectively) presumably due to steric inuences.Finally, synthesis of a non-symmetric bis-a-aminophosphonatewas achieved, using sequential addition of the aldehydes inexcellent yield of 43%. No discernible trend with respect towhich SIL was optimal for a given reaction, though it was notedthat removal of G4 was more challenging compared to theshorter G3 analogue, this is presumably due to its slightly more‘organic’ nature.

Acknowledgements

The authors would like to thank the Institute of FrontierMaterials (IFM) for a postgraduate scholarship to DE.

Notes and references

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Scheme 3 Non-symmetric bis-a-aminophosphonate synthesis.

This journal is © The Royal Society of Chemistry 2017 RSC Adv., 2017, 7, 27900–27904 | 27903

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RSC Advances Paper

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Phosphorus-Based a-Amino Acid Mimetic for EnhancedFlame-Retardant Properties in an Epoxy Resin

Melissa K. Stanfield,A Filip Stojcevski,A Andreas Hendlmeier,A

Russell J. Varley,A Jeronimo Carrascal,B Andres F. Osorio,B

Daniel J. Eyckens,A,C and Luke C. HendersonA,C

ACarbon Nexus, Institute for Frontier Materials, Deakin University, Waurn Ponds,

Vic. 3216, Australia.BSchool of Civil Engineering, University of Queensland, St Lucia, Qld 4072, Australia.CCorrespondingauthors.Email:dan.eyckens@deakin.edu.au; luke.henderson@deakin.edu.au

This work demonstrates the introduction of a phosphonate moiety into a commonly used curing agent, 4,40-diaminodi-phenylmethane (DDM), via an a-aminophosphonate. This compound (DDMP) can be prepared and isolated in analyticalpurity in under 1 h and in good yield (71%). Thermoset polymer (epoxy-derived) samples were prepared using a room-temperature standard cure (SC) and a post-cured (PC) protocol to encourage incorporation of thea-aminophosphonate into

the polymer network, with improved flammability properties observed for the latter. Thermogravimetric analysis under anitrogen atmosphere showed increased char yield at 6008C, and similar observations were made when analysis wasconducted in air. Significant reductions in flammability are observed at very low phosphorus content (P%¼ 0.16–0.49%),

demonstrated by higher char yields (25.5 from 14.0% in air), decreased burn time from ignition (60 to 24 s), and decreasedmass loss after ignition (87.6 to 58.5%). Limiting Oxygen Index for the neat polymer (P%¼ 0%, 20.3� 0.8%) increasedwith increasing a-aminophosphonate additive (P%¼ 0.16%, 20.8� 0.6%; P%¼ 0.32%, 21.4� 0.4%; P%¼ 0.49%,

22.6� 0.8%).

Manuscript received: 25 October 2018.Manuscript accepted: 20 November 2018.

Published online:

Introduction

Epoxy resins find considerable use in a range of industriesthrough a substantial variety of applications including compo-sites, surface coatings, and adhesives. They have excellent

physical characteristics, including chemical and mechanicalresistance, making them an attractive option for the aerospaceand automotive industries, among others. Epoxy-derived poly-

mers are made by mixing small-molecular-weight bis-epoxideswith diamines, and the subsequent crosslinking generates athree-dimensional network, which causes the material to harden(or ‘cure’). Initial curing is typically done at room temperature

and at elevated temperatures, the latter referred to as a ‘post-cure’. One aspect that may reduce the efficacy of resins in thesesectors is their poor thermal and flame resistance. Reducing

the flammability of such materials is therefore key to enhancingthe viability and safety of epoxy resins with their variousapplications.

Two common methods for decreasing polymer flammabilityare the use of halogen or phosphorus-based[1–3] flame retardants,especially in conjunction with nanoclay additives.[4–6] Theintroduction of phosphorus-derived organic compounds in

epoxy resins is a well-known and effective method of impartingsome degree of flame-retardant properties into these sys-tems.[7–12] These may be either covalently incorporated into

the epoxy monomer or curing agent,[13–19] or included as

additives.[20,21] The former is incorporated into the epoxy

network, and the latter is simply dispersed throughout. Cova-lently integrating the phosphorusmoiety into thematrix is usefulto minimize deleterious effects on mechanical properties that

may be caused by additives. Additive-based options also tend torequire higher loadings, forming aggregates that reduce thehomogeneity of the final material and hence effectiveness as

fire retardants.[22,23]

The use of phosphorus-based compounds (Fig. 1) as flameretardants holds many benefits over halogen-based systems asthey are typically less toxic and reduce the expulsion of toxic

gas[26] during incineration.[27] The phosphorus moieties serve topromote a layer of char that prevents migration of combustiblemolecules to the gaseous phase and creates an insulation layer

that reduces the rate at which the solid produces combustiblemolecules, hence delaying the onset of and reducing the overallcombustion. This mechanism is in contrast to traditional fire

retardants that tend to exert their effect in the gaseous phasethrough free radical scavenging or the release of non-combusti-ble compounds.[28]

Incorporating phosphorus into the backbone of the polymer

network is thus an attractive option, although it often requiresthe specific design and synthesis of a desired target.[1,24] Thesynthesis of these compounds is often laborious, taking multiple

synthetic steps to reach the desired compound,[18,19,29,30]

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https://doi.org/10.1071/CH18527

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minimizing applicability on a large scale, as does the substantial

time required. Therefore, there is a continual need for effectiveflame retardants that are able to be accessed rapidly, in highyield, and with minimal purification.

Herein, we report the synthesis and analysis of a phosphorus-containing analogue in high yield, in a one-pot reaction, from thewidely used curing agent 4,40-diaminodiphenylmethane (DDM,Scheme 1). The a-aminophosphonate scaffold has a broad range

of application in agriculture,[31] medicinal, and therapeuticsectors,[32,33] but has not been thoroughly investigated previ-ously for application as a fire retardant for network polymers.[34]

This compound is an amino acid mimic and is rapidly accessedin high yield from the corresponding aldehyde, diamine, andphosphite in only 30 min, with simple precipitative isolation.

This compound, as exemplified by similar compounds in ourprevious work,[35] is able to be produced, isolated, and incorpo-rated into an epoxy resin-based system in under 1 h (excluding

cure time), proving it to be both time- and cost-effective. Thesolvent used is a solvate ionic liquid, shown to be non-toxic[36]

and to improve reaction outcomes.[37] This is owing to the highpolarizability of this solvent, and a degree of Lewis acidity

afforded by the chelated lithium ion in the glyme (Scheme 1).[38]

The monosubstitution of the DDM hardener was investigatedwith a view to allow the primary amine to react with the epoxy to

ensure incorporation into the network while the secondaryamine of the a-aminophosphonate would still be expected toreact with the epoxide groups, albeit more slowly.

The present work demonstrates a simple method of rapidlyeffecting flame retardance in a commercial epoxy resin system.The mechanism of inducing this outcome utilizes the primaryand secondary amines to react with the epoxy matrix, fully

incorporating diaminodiphenylphosphonate (DDMP) into thepolymer backbone (Scheme 1).

The incorporation of phosphorus-containing small mole-

cules into the backbone of a polymer to reduce flammability isa common approach, though typically requires higher loadingsof phosphorus than those examined here.[19,39] We demonstrate

a significant decrease in flammability in samples throughincreased char yields, greatly reduced burning times, andimproved Limiting Oxygen Index (LOI) results using thistechnique. Two methods of curing were employed in this work,

one according to manufacturer’s specifications for the givenresin system (12 h at 1008C), common for the crosslinking ofalkyl amine-based curing agents, and these samples are hence-

forth referred to as standard-cured (SC). The second method ofcuring required the initial standard cure, followed by a secondcuring of 1508C for 5 h to further encourage the crosslinking of

the aromatic secondary amine of the DDMP hardener, referredto as post-cured (PC).

Results and Discussion

Synthesis of DDMP and Examination of Cure Mechanism

The synthesis of DDMP began with the formation of the DDM-

benzaldehyde imine in situ, before the addition of diphenylphosphite. Subsequent attack of the phosphorus at the carbon ofthe imine gave the a-aminophosphonate product in high yield

(71%) in only 30 min at room temperature (Scheme 1).Monosubstitution of the parent diamine was selected with theaim of allowing the unreacted primary amine of DDM to react

with the epoxy matrix to facilitate greater incorporation into thepolymer network. Reacting only one side of the symmetricalDDM was achieved through careful regulation of aldehyde andphosphite stoichiometry. This method eliminates the need for

protecting and deprotecting steps, making the production ofDDMP synthetically concise. This modification has the

Crosslinkingamines

α-aminophosphonate

moiety

LinkerH2N

HN

O

O

OPh

PhP

PhP

O

O

OH

HO

O OP P

HN

HN

OPh

Ph

HN

NH

O

Ph

Ph

O OPN

PN P

N

NHHN

HN

NHNH

Ph

Ph

PhPhPh

P NP

NPN

HNHN

NH

HNHN

Ph

Ph

Ph

Ph Ph

Fig. 1. Left: Literature examples of phosphorus-containing flame retardants.[3,24,25] Right: The design of the flame retardant

used in the present work.

NH2H2NNH

H2N

Ph

P(OPh)2

O

aO

O O

OLi

CF3SNO

OS

F3CO

O

DDM DDMP

�

�

[Li(G3)]�TFSI�

Scheme 1. Left: introduction of a-aminophosphonate moiety into epoxy curing agent DDM to produce the phosphorus-

containing productDDMP. (a) Benzaldehyde (1 equiv.) and DDM (1 equiv.) dissolved in [Li(G3)]þTFSI–, room temperature (rt)

stirring for 5min, followed by addition of diphenyl phosphite (1.2 equiv.) and stirring for 25min, rt (71%). Right: the solvate ionic

liquid used in this reaction, [Li(G3)]þTFSI–, consisting of the charge-diffuse cation of the glyme-chelated lithium ion and the bis

(trifluoromethanesulfonyl)imide anion.

B M. K. Stanfield et al.

potential to be applied to other amine-based curing agents, thuspotentially inducing some level of flame retardance with a

minimal number of synthetic steps.With this compound in hand, our attention focussed on

examining the cure mechanism via near-infrared spectroscopy

(NIR) to see if the addition of this compound affects the degreeof curing using the manufacturer’s recommended conditions(Fig. 2). Using the peak corresponding to the epoxide functional

group (,4530 cm�1) as an indicator of degree of cure, thecontrol specimen (0P% [phosphorus percentage], teal) showedvery little residual peak, with concomitant increase in hydroxyl

absorbance (,7005 cm�1). This was also true for the 0.16P%(red) sample, though when the 0.33P% (black) and 0.49P%(blue) samples were analysed, a substantial amount of residualepoxy remained within the specimen (Fig. 2.). Thus, to encour-

age further curing and consumption of the unreacted material,these samples were then post-cured for 5 h at 1508C.

Reexamination of the NIR spectra for each of the samples

showed similar spectra for both the 0P% (teal) and 0.16P% (red)polymers, though no trace of epoxide was observed at4530 cm�1. For the 0.33P% (black) and 0.49P% (blue) samples,

the amount of residual epoxide present was substantiallyreduced, suggesting that the a-aminophosphonate DDMP hadsuccessfully been incorporated into the polymer network to a

higher degree after PC (Fig. 3).Despite the presence of unreacted epoxide in the SC samples,

in the interest of thoroughness, these specimens were stillevaluated for their potential flame-retardant properties.

Char Behaviour via Thermogravimetric Analysis

As is consistent with other works in this area,[14,28,40] thermo-gravimetric analysis (TGA) was used to explore the potential of

these compounds as flame retardants via the decomposition ofeachof the samples. Initially, TGAwas carried out in an oxidative(air) atmosphere and gave a three-step process of degradation

(Fig. 4). Itwas expected that the onset of degradation (initialmassloss) would be at a lower temperature than the neat resin, sug-gesting the promotion of a char layer, then a plateau would be

observed as the char layer stabilized (Fig. 4, 480–5608C).In comparison with the neat resin measurement (i.e. 0P%,

teal), all samples with increasing DDMP content exhibitdecreased onset temperatures, promoting the earlier formation

of a char layer. Similarly, the plateau in the trace (480–5608C)shows an incrementally increased weight percentage corre-

sponding to each increase inDDMP content. This demonstratesthe reduction in flammability imparted by the compoundDDMP.

TGA analysis of the SC control sample determined the

temperature at which 10% weight loss occurred (T10%) was345.98C, and 348.18C for the PC control in oxidative environ-ments (Entry 1, Table 1). The char yields at 5308C for each of

these samples was 14.4 and 14.0% respectively (Entry 1,Table 1). When examining the outcome of a 0.16P% loadingof DDMP, T10% decreased by 28.88C, consistent with the PC

0.16P% sample, which also saw a decrease in T10% though onlyby 19.78C when compared with the control (Entry 2, Table 1).Conversely, the char yield for SC samples increased by 2.7 andby 7.2% (PC samples) when compared with the controls for

each the SC and PC 0.16P% specimens respectively (Entry 2,Table 1). This demonstrates a large decrease in flammability isachieved through only very low P%.

Increasing the flame retardant to 0.32P% produced a similardecrease in T10% (SC: 313.88C; PC: 323.48C; Entry 3, Table 1),and an increased char yield to 18.8% for the SC sample (Entry 3,

Table 1). The PC 0.32P% sample also saw an increase in charyield of 6.6% when compared with the control sample (Entry 3,Table 1); this value was slightly reduced compared with the

0.16P% PC sample.At the highest loading of 0.49 P%, the SC sample showed a

decrease in T10% by 29.38C when compared with the control(Entry 4, Table 1). Similarly, the 0.49P% PC sample had a

decrease in T10% of 36.88C to 311.38C (Entry 4, Table 1). Thehighest increase in char yield at 5308C was also observed forthese samples, with the SC sample showing 23.0% (8.6%

higher than the control) and the 0.49P% PC giving 21.6%(7.6% higher than the control; Entry 4, Table 1).

These data demonstrate the reduction in T10% with introduc-

tion of the DDMP flame retardant into the polymer. Interest-ingly, the initial incorporation of phosphorus (0.16P%) shows asignificant decrease compared with the control, though the T10%for each subsequent increase in loading exhibits similar values(i.e. not a linear correlation). This is true for both standard- andpost-cured samples.

When considering the char yields at 5308C, a notable differ-

ence is observed between the SC and PC samples. Whereas thecontrol samples have similar char yields for both curing meth-ods, samples containing phosphorus consistently showed higher

char yields for the PC samples compared with the SC. Thissuggests the benefit of the PC method encouraging greater

7500 7000 6500 6000 5500 5000 4500

Wavenumber [cm�1]

Epoxide

Fig. 2. NIR for standard-cure samples. Teal: 0P%; blue: 0.16P%; black:

0.33P%; red; 0.49P%.

7000 6000 5000

Epoxide

Wavenumber [cm�1]

Fig. 3. NIR for post-cure samples. Teal: 0P%; blue: 0.16P%; black:

0.33P%; red: 0.49P%.

Decreasing Flammability in Polymers C

incorporation of the flame retardant, via either the aromaticamine or the secondary amine within the a-aminophosphonate

unit, into the polymer matrix, resulting in this increase in charyield. Repeating this analysis, the samples, both SC and PC,were evaluated by TGA in an inert (N2) atmosphere (Fig. 5).

Comparing the SC samples, the residual weight remaining at

5308C is 4.5%. This was improved slightly when DDMP isincluded into the polymer using standard curing conditions, withthe residual weight of the 0.16P%, 0.32P%, and 0.49P% samples

giving 6.6, 8.5, and 10.0% respectively (Table 2). This wasmarginally improved in the PC samples, which have a largerproportion ofDDMP crosslinked into the polymer backbone. In

this instance, at the same temperature, the 0.16P% sample gave aresidual mass of 3.8%, which is very similar to the neat resin at2.8%. This is unusual, but when 0.32P% and 0.49P% sampleswere exposed to these conditions, residual masses of 12.5 and

15.1% were obtained. To the authors, this suggests that there

may be a critical amount of DDMP that must be incorporatedinto the polymer network before a significant effect can be

observed.

Flammability Testing

To gain an understanding of the reduction in flammability with

the incorporation of DDMP, a flame test involving the ignitionof samples was undertaken, though initially determination of theLOI was conducted. Defined as the minimum concentration of

oxygen at which a material can sustain a flame, the LOI for theneat resin (0P%)was determined to be 20.3� 0.8%. Addition ofa small amount of a-aminophosphonate DDMP (0.16P%)

resulted in a correspondingly small increase to 20.8� 0.6%,though these two measurements are statistically indistinguish-able. Also, these two values are still less than the atmosphericconcentration of oxygen at 20.9% (though only marginally for

the latter). Higher loadings of DDMP to 0.33P% and 0.49P%

100 200 300 400 500 6000

25

50

75

100

Wei

ght [

%]

Temperature [°C]

0

25

50

75

100

Wei

ght [

%]

100 200 300 400 500 600

Temperature [°C]

Fig. 4. TGA in air for standard-cure (SC, left), and post-cured (PC, right) samples. Teal: 0P%; blue: 0.16P%; black:

0.33P%; red: 0.49P%.

Table 1. Summary of flammability parameters for standard and post-cured samples (air)

Values in parentheses refer to samples post-cured (PC) at 1508C for 5 h

Entry P% T10%A DT10% [8C]B Char yield at 5308C [%] D Char yield [%]B

1 0.00 345.9 (348.1) – 14.4 (14.0) –

2 0.16 317.1 (328.4) �28.8 (�19.7) 17.1 (21.2) 2.7 (7.2)

3 0.32 313.8 (323.4) �32.1 (�24.7) 18.8 (21.0) 4.4 (6.6)

4 0.49 316.6 (311.3) �29.3 (�36.8) 23.0 (21.6) 8.6 (7.6)

AThe temperature at which 10% weight loss occurred.BThe difference between the flame-retardant sample and the control (0P%).

100 200 300 400 500 600

0

25

50

75

100

Wei

ght [

%]

Temperature [�C]100 200 300 400 500 600

0

25

50

75

100

Wei

ght [

%]

Temperature [�C]

Fig. 5. TGAof samples under nitrogen that have been prepared by standard cure (SC, left), and post-cured (PC, right). Teal: 0P%;

blue: 0.16P%; black: 0.33P%; red: 0.49P%.

D M. K. Stanfield et al.

improved the LOI to 21.4� 0.4 and 22.6� 0.8% respectively.

To complement these values, a simple burn test was conducted(Table 3).

Conducting a full Underwriters Lab Test 94 (UL-94) verticalflame test could not be carried out, and in lieu of this, a

comparison of these samples was conducted by igniting eachsample for 10 s using a butane torch, then recording the timeuntil the samples self-extinguished. It can be seen in Table 3 that

there is the same trend of flame-retardant characteristics as seenin the TGA, supporting the reduction in flammability whenincorporating DDMP into the epoxy matrix, as the mass loss at

higher temperatures (TGA and ignited) is notably reduced(images of each sample provided in the SupplementaryMaterial).

Flammability testing began with the assessment of a control

SC resin sample, giving a burn time of 60 s, and an overall massloss of 83.6% (Entry 1, Table 3). The PC sample was alsoassessed, proving to have a shorter burn time compared with the

SC control (48 s), although the mass loss percentage slightlyincreased to 87.6%, leaving very little residual material (Entry1, Table 3). This reduction of burn time may be due to slight

oxidation of the sample surface with the extended cure time ofPC samples. IntroducingDDMP at 0.16P% resulted in an almosthalved burn time relative to the control, reducing it to 33 s and

reducing the mass loss by almost 15% (Entry 2, Table 3).Significant reduction in burn time was also observed for the

0.16P% PC samples, to less than half that of the control PCsample (23 s), with a reduction in mass loss of over 17% (Entry

2, Table 3). Increasing the loading of DDMP to 0.32P% gave afurther decreased burn time of 27 s, reducing the mass loss to69.2% (Entry 3, Table 3), which was further decreased after

post-cure to give a burn time of 20 s and mass loss of 58.5%(Entry 3, Table 3). Continuing this trend, the 0.49P%PC sampleshowed the greatest reduction in both burn time and mass loss

(24 s and 55.7% respectively) when compared with the control(Entry 4, Table 3). Finally, the 0.49P% PC sample showed asignificant overall decrease in both burn time and mass loss(Entry 4, Table 3) compared with the control, but relatively

similar to that of the SC sample. It is worth noting that there wasno significant difference in flame propagation between samplesor on replicates of the same sample (for images of samples pre-

and post-ignition, refer to the Supplementary Material).It would seem that from these data, a large immediate

decrease in resin flammability is observed due to the presence

of DDMP at very low phosphorus concentrations (0.16P%).This can be improved by adding more DDMP, but this quicklyplateaus. Regardless, the potential of a-aminophosphonates as

flame retardants is clearly highlighted by this work, and giventheir ease of derivatization, could lead to new chemical space toexplore.

Conclusion

This work shows the viability of integrating an a-aminopho-

sphonate moiety via rapid reaction with commercial epoxycuring agent to retard flammability in epoxy resins systems.TGA revealed that low P% induced significant decreases inflammability, with char yields increasing (up to 25.5 from

14.0%) and onset temperatures decreasing (313.88C from345.98C). Also observedwas a significant reduction in burn timefrom ignition (60 to 24 s) and a decrease of mass loss after

ignition (87.6 to 58.5%) with the introduction of DDMP. Fur-ther to this, the use of a secondary curing process of 5 h at 1508Cfurther improved any reduction in flammability. This work

suggests the potential for rapid access to a-aminophosphonate-functionalized versions of curing agents that are alreadycommercially available to imbue flame-retardant propertieseffectively and inexpensively.

Experimental

Materials

All chemicals, reagents and solvents were purchased fromSigma–Aldrich (Australia) and used as received.

Synthesis of (((4-(4-Aminobenzyl)phenyl)amino)(phenyl)methyl)phosphonate (DDMP)

A round-bottom flask was charged with DDM (0.05 g,

0.252 mmol), which was then dissolved in [Li(G3)]TFSI(0.5 mL) with gentle heating. To the resulting mixture, benz-aldehyde (0.026 mL, 0.252 mmol) was added; this was stirred

for 5 min before diphenyl phosphite was added (0.058 g,0.303 mmol) and the mixture was stirred at 238C for an addi-tional 25 min. At this time, the mixture was dissolved in diethyl

ether (,20 mL) and added to water. The organic phase wasremoved under reduced pressure, leaving the aqueous phase and

Table 2. Summary of flammability parameters for standard and post-cured samples (N2 atmosphere)

Values in parenthesis refer to samples post-cured (PC) at 1508C for 5 h

Entry P% T10%A DT10% [8C]B Char yield at 5308C [%] D Char yield [%]B

1 0.00 352.2 (353.9) – 4.5 (2.8) –

2 0.16 328.1 (337.2) 24.1 6.6 (3.8) 2.1 (1.0)

3 0.32 321.1 (336.9) 31.1 8.5 (12.5) 4.0 (9.7)

4 0.49 323.9 (344.4) 28.3 10.0 (15.1) 5.5 (12.3)

AThe temperature at which 10% weight loss occurred.BThe difference between the flame-retardant sample and the control.

Table 3. Summary of burn time and mass loss for standard-cure and

post-cured samples

Values in parentheses refer to post-cured samples. * denotes statistical dif-

ference (P, 0.05) compared with neat resin (0.00P%)

Entry P% LOIA Burn time [s]B Mass loss [%]C

1 0.00 20.3� 0.8% 60 (48) 83.6 (87.6)

2 0.16 20.8� 0.6% 33 (23) 69.2 (70.2)

3 0.33 21.4� 0.4% 27 (20) 61.5 (58.5)*

4 0.49 22.6� 0.8% 24 (24) 55.7 (58.7)*

ALOI determined only on post-cured samples.BTime to self-extinguish after 10 s of ignition.CMass lost after flame test.

Decreasing Flammability in Polymers E

a yellow precipitate that was then filtered and collected, proving

to be the crude desired product. Dissolution in diethyl ether,addition to water, and removal of organic solvent were repeatedto analytical purity, providing the pure product as a yellow

precipitate (71%).

Preparation of Resin Samples

Control samples were prepared according to manufacturer’s

specifications using RIMR935 and RIMH937 and curing at1008C for 12 h (SC). Samples containing the flame retardantDDMP were prepared in the same manner, at the following

weight percentage loadings: 10, 20, and 30wt-%; correspondingto 0.16, 0.32, and 0.49P% respectively. These samples were alsocured for 12 h at 1008C. Owing to the different nature of theamine of DDMP to that of RIMH937 (aromatic versus alkyl), a

second post-curing procedure was employed on a replicate set ofsamples, whereby after the first curing process (12 h at 1008C),there was a second curing step of 5 h at 1508C (PC). This was

completed in order to promote the reactivity of the aromaticamine of DDMP, encouraging crosslinking with the epoxymatrix, and increase incorporation into the polymer network.

Note that we use wt-% and P% rather than mole ratio as thehardener used in this study is a proprietary mixture, and thusexact numbers of moles of amine are unknown. Amounts ofepoxy, hardener, and aminophosphonate are given here:

0P% (control): RIMR935, 4.34 g, 13.6mmol; RIMH935, 1.64 g,

13.8 mmol; DDMP, 0 mg, 0 mmol0.16P%: RIMR935, 4.34 g, 13.56 mmol; RIMH935, 1.49,12.6 mmol; DDMP, 165 mg, 0.6 mmol0.32P%: RIMR935, 4.34 g, 13.56 mmol; RIMH935, 1.32,

11.1 mmol; DDMP, 330 mg, 1.3 mmol0.49P%: RIMR935, 4.34 g, 13.56 mmol; RIMH935, 1.15,9.7 mmol; DDMP, 496 mg, 1.9 mmol

Thermogravimetric Analysis

TGA was carried out in both oxidative and non-oxidative

environments using a TA Instruments TGA Q50 analyzer. Forair atmospheres, a flow rate 60.0 mL min�1 was used, and forthose performed in nitrogen, a flow rate of 40.0 mL min�1 was

employed. Resin samples of,5–10 mg were heated from 208Cto 7008C in air and to 6008C in nitrogen at a constant heating rateof 208C min�1.

Flame Test

A piece of resin (12� 5� 3 mm, approx. 0.2 g) containing thegiven percentage ofmodified hardenerwas ignitedwith a butane

torch at a 458 angle for 10 s, and allowed to burn until self-extinguished. Each sample was weighed before and afterburning and the duration of burning timed.

Limiting Oxygen Index

Ignition was performed using a lighter flame applied to the endface of the sample. The flame was applied for 10 s in order to

induce uniform burning across the top. Sampleswere consideredignited when the flame lasted for more than 30 s. Pure oxygen(99.9%, O2) and nitrogen (99.99%, N2) streams in combination

with mass-flow controllers (Bronkhorst F-203AV) were used toachieve target oxygen concentrations. All tests were conductedwith a fixed flow velocity of 100 mm s�1. The test conditiontemperature was 23� 28C. Reported LOI values are defined as

the lowest oxygen concentration in which a given sample

extinguished within 180 s from the moment of ignition.

Supplementary Material

Images of the burnt specimens and NMR spectra of the syn-thesized compound are available on the Journal’s website.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgements

The authors gratefully acknowledge Deakin University and the Australian

Research Council (ARC) (grant numbers DP140100165, DP18010094) for

funding this project. This researchwas conducted by theARCTrainingCentre

for Lightweight Automotive Structures (project number IC160100032) and

the ARC Research Hub for Future Fibres (IH140100018) and funded by the

Australian Government. This work was funded in part by the Office of Naval

Research (N62909–18–1-2024), which is gratefully acknowledged.

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POLYMDEGRADSTAB.2007.03.009

Decreasing Flammability in Polymers G

Ion-Tagged Prolinamide Organocatalysts for the Direct AldolReaction On-Water

Daniel J. Eyckens1 • Hannah L. Brozinski1 • Joshua P. Delaney1 • Linden Servinis1 •

Sahar Naghashian1 • Luke C. Henderson1,2

Received: 18 August 2015 / Accepted: 20 September 2015 / Published online: 29 September 2015

� Springer Science+Business Media New York 2015

Abstract A concise synthesis of two imidazolium ion-

tagged prolinamide organocatalysts 3 and 4, varying in

anionic component (CF3COO- and PF6

-, respectively) is

presented. The latter could be classified as an ionic liquid

with a melting point of 66.3 �C, and glass transition tem-

perature of 14.5 �C. The efficiency of each catalyst was

compared via a direct aldol reaction revealing a large

contrast in catalytic performance, with the catalyst bearing

the PF6- anion being superior. The optimal conditions

were determined to be an on-water reaction system, and

substrate scoping gave a range of desired aldol products in

high conversion (up to[99 %), dr (up to 98:2), and er (up

to 96:4). The application of these catalysts to beta-

nitrostyrene conjugate addition is also presented.

Graphical Abstract

N

TBDPSO

OH

O

Boc

Catalyst 1Anion = CF3COO-

Overall yield 57%3 steps

NH

TBDPSO

HN

ON

N Me

AnionCatalyst 2

Anion = PF6-Overall yield 64%

4 steps

+

catalyst 2(20 mol%), 24 hr,

O OH

X

O

X

O

water, r.t.n n

H

R R25 examples

Conversions up to 99%dr up to 98:2 (anti :syn)

er up to 96:4

Keywords Organocatalyst � Imidazolium � Aldol � On-water

1 Introduction

Widely recognised as the third pillar of catalysis,

organocatalysis has become a major field of research and a

viable means of installing asymmetry within complex

molecules [1–5]. While organic transformations carried out

by organocatalysis have become increasingly complex, so

too has the structure of the organocatalysts themselves [6–

10]. Efforts in recycling organocatalysts have heavily

centred on conjugation to a solid support, to remove the

tethered catalysts by filtration [11–15]. Recently, the

introduction of imidazolium salts into catalyst structures

has been used as a means to control solubility properties of

the catalyst allowing for separation of reaction products/

reagents from the catalyst by selective solubilisation [14,

Electronic supplementary material The online version of thisarticle (doi:10.1007/s10562-015-1630-4) contains supplementarymaterial, which is available to authorized users.

& Luke C. Henderson

luke.henderson@deakin.edu.au

1 Institute for Frontier Materials, Carbon Nexus, Deakin

University, Pigdons Road, Waurn Ponds Campus,

Geelong, VIC 3216, Australia

2 Strategic Research Centre for Chemistry and Biotechnology,

Deakin University, Locked Bag 20000, Geelong, VIC 3220,

Australia

123

Catal Lett (2016) 146:212–219

DOI 10.1007/s10562-015-1630-4

16–33]. Of the published imidazolium supported catalysts,

the majority are based on 4-hydroxyproline and incorporate

the imidazolium group via the oxygen at the 4 position

(Fig. 1 1 and 2). This approach leaves the amine and car-

boxylic acid of the proline scaffold unmodified and has

shown to be a successful strategy to develop efficient cat-

alysts of broad scope.

An exception to this trend was recently reported by

Zlotin [16], who synthesised a C2-symmetric bis-proli-

namide organocatalyst, which displayed good catalytic

activity and scope despite the absence of a-carboxylicacid. The focus of the current study was to explore the

effect, if any, on installing the imidazolium salt via the

C-terminus of trans-4-hydroxyproline scaffold. Given the

hydrogen bonding capabilities of the imidazolium group,

its presence in close proximity to the proline nitrogen

may lead to enhanced catalytic performance or partici-

pation in hydrogen bonding within the transition state [34,

35].

We were also interested in how we may manipulate the

physical behaviour of these catalysts by variations of

anion (Fig. 1) in addition to their effectiveness as

organocatalysts. The target imidazolium tagged proli-

namides were to be decorated with a tert-butyldiphenyl

silyl group at the 4-position, a widely reported modifi-

cation that would allow for broad comparison of our

catalysts to published examples [36–38]. In this manu-

script we present the synthesis and evaluation of imida-

zolium supported organocatalysts which incorporate PF6-

and trifluoroacetate (F3CCOO-) anions. We compare the

physical properties and catalytic performance of these

compounds demonstrating their catalytic potential in both

the direct aldol reaction and conjugate addition to b-nitrostyrenes.

2 Results and Discussion

2.1 Synthesis of Organocatalysts 3 and 4

Our strategy for accessing target catalysts was based on

previous approaches used by Zlotin et al. and Maio et al.

where the heterocyclic amine is liberated at the last step,

typically by cleavage of Cbz, N-benzyl or Boc protecting

group. We initially chose the latter, incorporating a Boc

protecting group onto the proline nitrogen, in addition to a

tert-butyldiphenyl silane on the alcohol moiety at the

4-position (5) as we have had extensive experience with

this scaffold.

Amide formation using carboxylic acid 5 and

3-aminopropylimidazole gave 6 in excellent yield (99 %).

This was followed by treatment of 6 with methyl iodide

under microwave irradiation to generate the imidazolium 7

in good yield (79 %). Interestingly, the imidazolium salt 7

was able to be purified by column chromatography

(Scheme 1).

From 7, the removal of the Boc group was successfully

carried out using 10 % TFA/CH2Cl2 overnight. This was

accompanied by concomitant exchange of the anion from

iodide to trifluoroacetate, indicated by the shift of the H2

proton observed by 1H NMR spectroscopy. Isolation of 3

was achieved by careful organic extraction and washing

with NaHCO3 which gave 3 in good yield (73 %). Alter-

natively, prior to aqueous work up, a solution of KPF6could be added to the solution, executing anion metathesis

to give catalyst 4, also in good yield (82 %). This gave

excellent overall yields for both 3 and 4 (57 and 64 %,

respectively), the slightly depressed yield for 3, despite

having one less step, was attributed to a slight solubility in

water, thus a small amount being lost in work up.

2.2 Physical Characterization of 3 and 4

With imidazolium salts 3 and 4 in hand, our attention

turned to determining if these materials could technically

be classified as an ionic liquids. Ionic liquids are broadly

defined as molten salts which possess a melting point under

100 �C, have negligable vapour pressure, and excellent

thermal stability. We were pleased to see that the melting

point of 4 was 66.3 �C, well below the generally accepted

100 �C cut-off, while 3 was 118 �C and thus not techni-

cally defined as an ionic liquid. This observation was

attributed to the more charge diffuse nature of the PF6-

anion. Next we undertook isothermal thermogravimetric

analysis (TGA) at 100 �C, with 4 only, to determine

evaporation phenomena, if any. After 80 min at 100 �C no

major loss in weight was observed for this material, con-

sistent with the behaviour of ionic liquids.Fig. 1 Known imidazolium salt supported organocatalysts 1 and 2,with target organocatalysts for this study, 3 and 4

Ion-Tagged Prolinamide Organocatalysts for the Direct Aldol Reaction On-Water 213

123

The initial loss in sample weight is presumably water

being evaporated from the solid sample, as this occurrs

after the temperature reaches 100 �C (red line, Fig. 2). The

variation seen is typically\10 % of the sample weight and

most likely due to evaporation of residual moisture.

Additionally, differential scanning calorimetry (DSC) was

conducted on 4, giving a glass transition temperature (Tg)

of 14.5 �C.

2.2.1 Evaluation of Organocatalysts 3 and 4

as Organocatalysts

Our attention now turned to evaluation of 3 and 4 as

organocatalysts. We chose the direct asymmetric aldol

reaction for catalyst evaluation as it is a benchmark reac-

tion for catalyst evaluation in the literature and we have

previous experience with this system. The optimisation

began using catalyst 3 (bearing the trifluoroacetate anion)

in neat reaction conditions (Table 1, Entry 2). We were

pleased to see that full conversion to 9 had taken place,

though the product showed no diastereoisomeric enrich-

ment, an outcome that may have been due to the extended

reaction times (72 h) in the presence of a basic counter ion

(F3COO-).

Repeating the reaction on water at a reduced reaction

time (Table 1, entry 3) gave only a slightly depressed

conversion (93 %) and a dr of 71:29 (anti:syn). Unfortu-

nately, the product was found to possess minimal enantio-

enrichment (5 %). When using the same reaction duration

under neat reaction conditions (Table 1, Entry 4), a

depressed conversion (88 %) and dr 68:32 (anti:syn) was

observed. This is consistent with literature whereby neat

reaction conditions result in a homogenous mixture while

the addition of water creates an emulsion giving an ‘on-

water’ effect that enhances reaction outcomes [36–49].

This phenomena was supported when reacting 3 in an

organic solvent (Table 1, Entry 5) which gave very poor

conversion to the desired product.

Scheme 1 Synthesis of target

organocatalysts 3 and 4

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 8030

40

50

60

70

80

90

100

110

120

130

140

Sam

ple

wei

ght %

Tem

pera

ture

OC

Time mins

30

40

50

60

70

80

90

100

110

120

130

140

Isothermal degradation profile

-50 0 50 100 150 200-2

-1

0

1

2

3

4

5

0 5 10 15 20 25

-0.2

-0.1

0.0

0.1

0.2

He

at

Flo

w (

W/g

)

Temperature (degrees Celcius)

Hea

t Flo

w (

W/g

)

Temperature (degrees Celcius)

Fig. 2 Isothermal TGA showing no evaporation of 4 when in the liquid state (left) and DSC showing Tg (right) with key curve (inset)

214 D. J. Eyckens et al.

123

Our focus then moved to the use of catalyst 4 under the

same reaction conditions to determine the effect, if any, of

the IL counter ion. Employing 4 in the direct aldol reaction

using neat reaction conditions (Table 1, Entry 6) gave

improved dr 80:20 (anti:syn) and er of 77:23 compared to

those furnished by 3. The addition of water to the reaction

system (Table 1, Entry 7) gave a slightly depressed yield,

though an improved dr, 85:15 (anti:syn), and good er

(76:24). It is worth noting that the ‘on-water’ reactions

were much easier from a practical standpoint as the small

amount of cyclohexanone 7 used in the neat reactions (100

lL) made solvation of all reaction components difficult. To

ensuring total solvation of reagents, the neat asymmetric

aldol reaction (Table 1, Entry 8) was carried out a vast

excess of 7, affording excellent outcomes in yield (96 %),

very high dr 96:4 (anti:syn) and er 92:8. Finally, assessing

4 in an organic solvent (Table 1, Entry 9), gave poor

conversion (18 %) and moderate dr 82:18 (anti:syn), sim-

ilar to that provided by catalyst 3.

This preliminary evaluation of catalysts 3 and 4 high-

lights the variability in reaction outcome and catalyst

performance by simply changing the anionic component of

the catalyst. The influence of counter ions on catalyst

performance has been observed in other work, though in

this instance the performance of the catalyst is extremely

pronounced [33, 50, 51].

The optimal conditions were determined to be the on

water process using catalyst 4 (Table 1, Entry 7). Though,

the best stereochemical outcome for catalyst 4 employed a

vast excess of cyclohexanone 7 (Table 1, Entry 8), the use

of the ketone 7 as the reaction solvent on such a scale was

considered impractical and thus was not considered. The

scope of catalyst 4 was investigated with a range of ketones

and aldehydes, the latter of which possess a cross-section

of substituents on the aromatic portion, representing a

variety of electronic effects on the aldehyde.

Using cyclopentanone 10 with the chosen aldehydes

showed excellent conversions in all cases (Table 2, Entries

1–4) which is consistent with our previous work [36–38].

Also consistent when employing 10 predominant formation

of the syn-diastereomer in preference to the anti-diastere-

omer. The dr and er values observed for these reactions

varied from poor to moderate (Table 2, Entries 1 and 3,

respectively). This has again been observed in our work

published by this group where cyclopentanone typically

gives excellent yields, but poor stereo-discrimination of the

ultimate aldol product. We believe that the low ee values

obtained when employing cyclopentanone 10 are a result of

epimerisation of the products due to the presence of the

catalyst reforming then substituted enamine and thus

scrambling the enantiomeric centre, a more detailed dis-

cussion of this point has been provided below. Moving on

to tetrahydropyranone 11 gave much better reaction out-

comes across all parameters (Table 2, Entries 5–8).

Though conversions varied from 55–99 %, good to high dr

and er values were observed, especially when using

Table 1 Optimisation of organocatalyst 3 and 4

Entry Cat. Solvent Time (h) Conversiona (%) dra (anti:syn) erb

1 – Neat 24 0 0 0

2 3 Neat 72 97 1:1 –

3 3 H2O 24 93 71:29 60:40

4 3 Neat 24 88 68:32 53:47

5 3 CHCl3 24 15 72:28 –

6 4 Neat 24 99 80:20 76:24

7 4 H2O 24 71 85:15 76:24

8 4 Neatc 24 96 96:4 92:8

9 4 CHCl3 24 18 82:18 –

a Determined by 1H NMR spectroscopyb Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95)c Reaction carried out in 0.25 mL (12.5 eqivalents) of 7. Reaction conditions: Aldehyde (0.1 mmol), ketone (0.5 mmol), and catalyst (20 lmol),

in water (250 lL) were stirred for 24 h at room temperature, followed by aqueous work-up Note: no HPLC was conducted when conversion was

\20 %

Ion-Tagged Prolinamide Organocatalysts for the Direct Aldol Reaction On-Water 215

123

4-nitrobenzaldehyde (Table 2, Entry 5), giving er value of

85:15, and benzaldehyde (Table 2, Entry 7), with an er of

96:4. Replacement of the oxygen heteroatom of 11 for

sulphur (12) (Table 2, Entry 9) gave excellent conversion

(99 %) and diastereoselectivity (97:3), and an excellent er

of 85:15. Similarly, employing cyclohexanone 7 for the

remaining aldehydes (Table 2, Entries 9–11) gave excel-

lent stereochemical outcomes. We also examined substi-

tution on the aryl ring and the effects on stereochemical

outcome by employing 3- and 2-nitrobenzaldehyde to give

16e and 16f, respectively. In both cases (Table 2, Entries

13 and 14) excellent conversion and dr were observed. This

was complemented in the er with very high enantiomeric

ratios of 85:15 in each case.

We were interested in determining if 4 could be recycled

for multiple uses in the same reaction system. This was

undertaken by repeating the on-water reaction of cyclo-

hexanone 7 and 4-bromobenzaldehyde, giving product 14d.

The full aqueous work-up was replaced by simple addition

of a diethyl ether:hexane (1:1) solution to extract the aldol

products only, which we had previously determined that

catalyst 4 was not soluble in. It was therefore surprising to

see catalyst 4 had leeched into the extraction solvent, albeit

in small quantity. This may be due to the solubility of

catalyst 4 in the ketone reaction partner of this aldol

reaction. In the interest of thoroughness, we continued the

recycling study by re-addition of fresh cyclohexanone 7

and 4-bromobenzaldehyde to the aqueous phase containing

the majority of catalyst 4. The extraction of products and

addition of fresh reagents was repeated again, and it was

seen that after each extraction catalyst 4 was lost in this

process and the subsequent reaction gave progressively

lower yields. For this data please refer to the supplemen-

tary information.

Finally, we were curious the effects observed in the

aldol reaction were similar for other reaction systems.

Therefore we employed catalysts 3 and 4 in the conjugate

addition of cyclohexanone 7 with trans-b-nitrostyrene 17,

another commonly used reaction to evaluate organocata-

lysts [52–55].

We were pleased to see that catalyst 3 was able to

effectively catalyse the formation of 18, though the yield

was excellent the dr was very low (53:47, anti:syn), and as

such an er was not determined for this material (Table 3,

Table 2 Substrate scoping for catalyst 3

Entry R X Prod Conversiona (%) dra (anti:syn) erb

1 4-NO2 – 13a 99 27:73 54:46

2 H – 13b 99 30:70 66:34

3 4-Me – 13c 83 34:66 76:24

4 4-Br – 13d 99 35:65 74:26

5 4-NO2 O 14a 99 69:31 85:15

6 H O 14b 55 84:16 96:4

7 4-Me O 14c 65 89:11 80:20

8 4-Br O 14d 84 71:29 81:19

9 4-NO2 S 15a 99 97:3 85:15

10 H (CH2) 16b 54 89:11 77:23

11 4-Me (CH2) 16c 29 86:14 90:10

12 4-Br (CH2) 16d 87 88:12 92:8

13 3-NO2 (CH2) 16e 91 96:4 85:15

14 2-NO2 (CH2) 16f 83 98:2 85:15

a Determined by 1H NMR spectroscopy, dr reported for major distereomer onlyb Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95. Reaction conditions: Aldehyde (0.1 mmol), ketone (0.5 mmol), and catalyst

(20 lmol), in water (250 lL) were stirred for 24 h at room temperature, followed by aqueous work-up Note: no HPLC was conducted when

conversion was\20 %

216 D. J. Eyckens et al.

123

Entry 2). Repeating the reactions in organic solvents,

toluene and THF, gave promising results as conversions

and drs were high (Table 3, Entries 3 and 4). Of these two

reactions the one performed in THF gave a superior

enantioenrichment (er (67:33) versus toluene (52:48)).

Interestingly, and in contrast to previous results pre-

sented in this manuscript, inferior stereochemical outcomes

resulted when the reaction was carried out on-water or neat

(Table 3, Entries 6 and 7) when compared to THF. This

same preference for THF for organocatalyzed nitro-con-

jugate addition was also observed by Lin et al. [55].

Nevertheless, dr could be improved under neat reaction

conditions by extended reaction times (Table 3, Entry 7), at

the expense of er. Nevertheless, decreasing the catalyst

loading to 5 mol% showed minimal effect on reaction

outcome giving similar conversion, diastereo- and enantio-

enrichment when 20 mol % was employed (Table 3,

Entries 8 and 9). In an effort to bolster the reaction out-

comes in THF, we repeated the reactions in this solvent

with additives present in the reaction mixture, which is

common for this class of reaction. Unfortunately, in each

case (Table 3, Entries 8–10) the conversions were depres-

sed, and no gain in er was observed in any case, though

improvements in dr were observed for benzoic acid derived

additives. Despite these moderate results we are encour-

aged that with further examination of this system and

investigation into a broader range of anions, may improve

these preliminary values.

2.3 Regarding the Effect of the Trifluoroacetate

anion on Reaction Outcome

Within this study we have attributed the poor stereoselec-

tivities observed when employing catalyst 3, to the effect

of the trifluoroacetate anion. This is especially evident

when using cyclopenanone 10 as the ketone donor in the

aldol reaction (compounds 13a–13d). In our hands, it is

common to observe lower diastereo- and enantioenrich-

ment when using cyclopentanone [36–38], which we have

previously attributed to epimerisation at the a-carbon due

to reformation of the enamine in the presence of the

organocatalyst. The propensity of cyclopentanone to

undergo epimerisation may be due to the Keq of the ketone-

enamine equilibrium being markedly higher (Keq 2.3) than

that of the cyclohexanone-enamine pair (Keq = 0.8), as

reported by Vilarrasa et al. (Scheme 2) [56].

Table 3 Application of catalysts 3 and 4 to the conjugate addition of cyclohexanone 7 with trans-b-nitrostyrene 17

Entry Cat. Solvent Time (h) Conversiona (%) dra (anti:syn) erb

1 – Neat 24 0 0 0

2 3 Neat 72 99 53:47 –

3 4 PhMe 24 87 83:17 52:48

4 4 THF 24 88 88:12 67:33

5 4 Water 24 83 75:25 63:37

6 4 Neat 24 95 81:19 63:37

7 4 Neat 96 90 91:9 66:34

8f 4 Water 24 90 93:7 67:33

9f 4 Neat 24 95 91:9 65:35

10 4 THFc 24 75 95:5 57:43

11 4 THFd 24 83 97:3 56:44

12 4 THFe 24 76 84:16 60:40

a Determined by 1H NMR spectroscopyb Determined by chiral HPLC (Diacel AD-H, iPA/n-Heptane, 5:95) for major diastereoisomer onlyc Benzoic acid additive at 20 mol%d p-nitrobenzoic acid additive at 20 mol%e Trifluoroacetic acid additive at 20 mol%f 5 mol% of catalyst was used in this reaction. Reaction conditions: Nitrostyrene (0.1 mmol), ketone (0.5 mmol), and catalyst (20 lmol), in

water (250 lL) were stirred for 24 h at room temperature, followed by aqueous work-up

Ion-Tagged Prolinamide Organocatalysts for the Direct Aldol Reaction On-Water 217

123

Nevertheless, the stereochemical outcomes for any aldol

product, regardless of donor ketone, from this study seem

unusually low when catalyst 3 was employed. We propose

that the deleterious role of the trifluoroacetate anion is via

encouraging epimerization at the a-position of the aldol

products. The poor basicity and high dilution of a trifluo-

roacetate anionic additive would normally prevent this

effect from occurring to a substantial degree, but in this

case the anion is held in close proximity to the

organocatalyst. Thus when imine formation occurs, causing

the subsequent decrease in pKa of the a-protons, enamine

(and thus epimerisation) is promoted by the trifluoroacetate

counterion associated to the organocatalyst.

3 Conclusion

Presented herein is a concise and high yielding synthesis of

two ionic liquid supported organocatalysts 3 and 4,

accessed in three synthetic steps. Variation of the anionic

component of the cationic imidazolium partner, CF3CCO-

(catalyst 3) and PF6- (catalyst 4) had a pronounced effect

on both the physical properties and catalytic behaviour of

these compounds. The latter catalyst (4) being technically

classified as a chiral ionic liquid, possessing a melting

point below 100 �C and exhibiting no evaporation phe-

nomena by isothermal TGA and a Tg of 14.5 �C. Evalua-tion of these catalysts in the direct asymmetric aldol

reaction revealed a significant contrast in catalytic perfor-

mance between 3 and 4, with the former giving good

reaction conversion but very poor stereochemical outcome

for both dr and er, attributed to the presence of the triflu-

oroacetate anion in solution. We have proposed that the

unsuitability of the trifluoroacetate anion is a result of

encouraging epimerisation of the aldol products. Con-

versely, catalyst 4 performed well in the direct aldol

reaction and showed excellent application across a range of

ketones and aldehydes.

Acknowledgments The authors acknowledge the Institute for

Frontier Materials, Strategic Research Centre for Chemistry and

Biotechnology, and the Faculty of Science, Engineering, and Built

Environment for funding. We acknowledge the Institute for Frontier

Materials for the postgraduate scholarship to DE.

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