Effects of structure on the acidity of heterocyclic carbon acids

271 Pages·2015·6.07 MB·English

Effects of structure on the acidity of
heterocyclic carbon acids:
Towards correlations with catalytic efficiency

This thesis is presented for the partial fulfilment
of the requirements for the degree of

Doctor of Philosophy
in the
School of Chemistry
by
Michelle Helen Dunn

November, 2014
i
THE UNIVERSITY OF NEW SOUTH WALES
Thesis/Dissertation Sheet

Surname or Family name: Dunn

First name: Michelle Other name/s:Helen

Abbreviation for degree as given in the University calendar:

School: Chemistry Faculty: Science

Title: Effect of structure on the acidity of heterocyclic carbon acids:
Towards correlations with catalytic efficiency

Abstract:

This thesis reports the determination of the pK values of 56 azolium salts in dimethyl sulfoxide using the bracketing indicator
a
method, where the change in concentration of a fluorene indicator of known pK value was monitored using UV-Vis
a
spectroscopy upon addition of aliquots of heterocyclic carbon. This methodology is explored within this thesis, along with the
synthesis, purification and testing of the required fluorene indicators. Each following chapter focuses on the synthesis,
measurement and subsequent analysis of a different class of carbon acid, with a particular emphasis on systematically modifying
structural and electronic properties of the carbon acid to understand the subsequent effects on acidity.

The first series investigated were the imidazolium salts containing N-alkyl and N-aryl substituents. The particular salts chosen
examined the effects of attaching electron withdrawing and electron donating groups directly to the azolium ring, the effect of
extending the π system and the effect of changing the electronic and steric nature of the N-substituent. The effect of
systematically changing the electronic nature of the 4'-substituent was also quantified through utilisation of Hammett parameters.
The effect of different anions on the N-aryl system was also considered.

These studies on imidazolium salts were followed by consideration of their more saturated counterparts with differing heterocylic
ring sizes and bulkier N-substituents, along with quantification of the effect of the 4'-substituent. Azolium salts containing
different heteroatoms were also considered. A set of triazolium salts was investigated with an emphasis on the effect of changing
the N-aryl and azolium ring substituents. While thiazolium salts were examined in terms of the effect of electron donating groups
attached directly to the ring, changing the 2',4' and 6'-aryl substituents.

This work also endeavours to make a direct correlation between pK values determined in dimethyl sulfoxide to those determined
a
in water and using computational methods. Correlation between acidity and existing data that quantify the electronic nature of
the deprotonated carbon acid (carbene) when coordinated to a metal was also attempted. Preliminary studies are also presented
that show a correlation between acidity of a heterocyclic carbon acid and catalyst efficacy of its corresponding carbene.

Declaration relating to disposition of project thesis/dissertation

I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in
part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all
property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation.

I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral
theses only).

…………………………………………………………… ……………………………………..……………… ……….……………………...…….…
Signature Witness Date

The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for
restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional
circumstances and require the approval of the Dean of Graduate Research.

FOR OFFICE USE ONLY Date of completion of requirements for Award:
Copyright Statement

‘I hereby grant the University of New South Wales or its agents the right to archive and to make available
my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here
after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as
patent rights. I also retain the right to use in future works (such as articles or books) all or part of this
thesis or dissertation.

I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract
International (this is applicable to doctoral theses only). I have either used no substantial portions of
copyright material in my thesis or I have obtained permission to use copyright material; where permission
has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or
dissertation.'

Signed

Date 18th March 2015

Authenticity Statement

‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version
of my thesis. No emendation of content has occurred and if there are any minor variations in formatting,
they are the result of the conversion to digital format.’

Signed

Date 18th March 2015
Originality Statement

‘I hereby declare that this submission is my own work and to the best of my knowledge
it contains no materials previously published or written by another person, or substantial
proportions of material which have been accepted for the award of any other degree or
diploma at UNSW or any other educational institution, except where due
acknowledgement is made in the thesis. Any contribution made to the research by
others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in
the thesis. Specifically the work undertaken by Mr Nicholas Konstandaras is noted of
which contributed towards the Results and Discussion in Chapter 7.

I also declare that the intellectual content of this thesis is the product of my own work,
except to the extent that assistance from others in the project's design and conception or
in style, presentation and linguistic expression is acknowledged.’

Signed

Date 18th March 2015

iv
Table of Contents
Table of Contents ............................................................................................................ ii
Originality Statement..................................................................................................... iv
Acknowledgements .......................................................................................................... v
Abstract ......................................................................................................................... viii
Abbreviations .................................................................................................................. x
Introduction ..................................................................................................................... 1
Results and Discussion, Chapter One: ........................................................................ 36
Method development and indicator synthesis
Results and Discussion, Chapter Two: ........................................................................ 47
The pK values of N-alkyl imidazolium salts in dimethyl sulfoxide
a
Results and Discussion, Chapter Three: ..................................................................... 54
The pK values of N-aryl imidazolium salts in dimethyl sulfoxide
a
Results and Discussion, Chapter Four: ....................................................................... 79
The effect of changing the anion on the pK value of N-aryl imidazolium salts
a
in dimethyl sulfoxide
Results and Discussion, Chapter Five: ........................................................................ 85
The pK values of ring expanded N-aryl imidazolinium and formamidinium salts
a
in dimethyl sulfoxide
Results and Discussion, Chapter Six: ........................................................................ 102
The pK values of 1,2,4- triazolium salts in dimethyl sulfoxide
a
Results and Discussion, Chapter Seven: ................................................................... 109
The pK values of N-aryl thiazolium salts in dimethyl sulfoxide
a
Results and Discussion, Chapter Eight: .................................................................... 127
The relationship between pK values, nucleophilicity and catalytic outcomes
a
Conclusions .................................................................................................................. 148

ii
Experimental ............................................................................................................... 151
Experimental for Chapter One .............................................................................. 157
Experimental for Chapter Two.............................................................................. 171
Experimental for Chapter Three............................................................................ 176
Experimental for Chapter Four ............................................................................. 191
Experimental for Chapter Five .............................................................................. 198
Experimental for Chapter Six................................................................................ 208
Experimental for Chapter Seven ........................................................................... 213
Experimental for Chapter Eight ............................................................................ 226
Appendices ................................................................................................................... 231
Appendix One: Determination of pK values from titration data .......................... 232
a
Appendix Two: The effect of 2',6'-methyl substitution ........................................ 237
Appendix Three: Equation for the determination of the pK of different isomers 239
a
Appendix Four: Catalysis Data ............................................................................. 242
Appendix Five: XRD Data ........................................................ 244 and attached CD
Appendix Six: Titration Data ............................................................ see attached CD
References .................................................................................................................... 246

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Acknowledgements

Firstly to Jason…Thank you!
Over the past few years you have been an incredible source of support and
encouragement. As a supervisor you have always gone above and beyond expectations
and have given me the space to grow and develop into the scientist I am today. Thank
you for always having my back, always wanting me to do my best (even if it means you
just keep saying something about consistency) and always being a source of chocolate
and drinks. PS-You were right about my thesis; I believe I owe you a beer (and your
chair back)!

To my co-supervisor Marcus- thank you for really stepping up to the plate when my
thesis needed it. Your insight and wealth of knowledge just amazes me and has made
my project and thesis stronger. I appreciate that you take a genuine interest in my
project and always go out of your way to help me understand. Your antics in meetings
have made them more enjoyable especially the recent adventures with Mother
drinking/bogan chemist/trapped in a lolly dispenser Beanie.

To the Harper group, thank you for being incredibly supportive and keeping me
company in the lab. The random antics which kinda define our group have been a lot of
fun over the course of my thesis. Thank you for the group lunches, drinking sessions
and random laser tag outings. I really look forward to watching your projects develop
and I so bags being there when one of you win a Nobel Prize (my money is on Max for
his time machine).

In particular the current members whom have endured my writing phase Brad (for your
random knowledge of ‘all the things’ aka NMR and computers), Sinead (for the random
chats on the couch and this coffee I’m drinking), Nick (for always looking out for me
and for being my supplier of Aero bars), Will (for all the dinners ever and for not
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“mcjudging” me when it comes to ice cream), Beck (bringing cheer into the lab and the
free taxi ride to upper campus) and Max (for matching my crazy, I may have just called
you crazy…prepare for a Nerf Gun War!)

A special to mention to previous PhD students Honie, Dom and Steve for their
guidance, especially when I was lost and needed inspiration to find my way.

Now to a small, and way more awesome, carbene group of Max, Nick, Chris and Beanie
(who may or may not be the squirrel mascot). I still find it crazy that someone thought
my project was cool, let alone 3 people! Thank you for trusting me (even when I would
have no reason behind madness) and encouraging me to continue my research (aka keep
me company in front of the UV machine).

To our lab colleagues of the Morris Group, thank you for the chemicals (all the
chemicals!!!!), your organic chemistry wisdom (my DIBAL-H reaction is all the better
for it) and company in the lab (I’m sure one day we could get a bouncer).

To the staff in the school, who have been hugely supportive. A particular mention
should go to the Lab Techies (Nancy, Peta and Ruth) for teaching me all the instrument
things and keeping me updated on all the gossip. A huge thank you to the NMR facility
staff of whom always happen to be there when I break things.

To some of my fellow PhD students- Chris (for all the breakfast outings, and letting me
steal your chemicals), Sandy (for always being up for a chat and roping me into netball),
and Mark (for reading some parts of my thesis and giving me guidance on how to save
time).

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To Will and Pitch-thank you for providing me with a second home over the past 3
months, without your selflessness I wouldn’t have a thesis, nor would I not know the
wonders of Ally McBeal or the Lego games.

To my dear friends Loz (Dumplings!) and Cat, thank you for being understanding with
me (even when I’m being all thesis brained) and making me get out of the lab and
do/eat/drink some incredible things (like Chai Tea). To my board games friends for
their constant encouragement and thinking I am awesome before I even say anything
(I’m sure the “You can do it” video will become a YouTube sensation). To Meg for
your amazing friendship, our weekly lunches and random catch-up sessions have
always been the highlights of my day. I can’t believe we both finished our theses and I
can’t wait to catch up with you when we are both doctors.

Finally the biggest thank you needs to go to my parents; you are both incredible sources
of inspiration for me. I’m really sorry for all the late night phone calls and freaking you
out about my wellbeing. Knowing that you 100% support me in everything I do, means
the world to me and has really helped me in the completion of my thesis.

vii
Abstract

Heterocyclic carbon acids, such as azolium cations, are synthetically useful precursors
for N-Heterocyclic Carbenes (NHCs). These carbenes have attracted interest as
organocatalysts for a large number of nucleophilic/Brønsted base transformations.
However despite their widespread use, choosing an appropriate NHC for a specific
organocatalytic process remains difficult. Through understanding the acidity of the
heterocyclic carbon acids, and hence their nucleophilicity, there is the potential to
introduce a rationale to catalyst selection.

This thesis reports the determination of the pK values of 56 azolium salts in dimethyl
a
sulfoxide using the bracketing indicator method, where the change in concentration of a
fluorene indicator of known pK value was monitored using UV-Vis spectroscopy upon
a
addition of aliquots of acid, in this case an azolium salt. This methodology is explored
in Chapter 1, along with the synthesis, purification and testing of the required fluorene
indicators. Each subsequent chapter focuses on the synthesis, measurement and
subsequent analysis of a different class of carbon acid, with a particular emphasis on
systematically varying structural and electronic properties of azolium cations to
understand the subsequent effects on acidity.

The first series investigated, in Chapter 2, was the imidazolium salts containing N-alkyl
substituents. The particular members within this series were chosen to examine the
effects of attaching electron withdrawing and electron donating groups directly to the
azolium salts, the effect of extending the π system and the effect of changing the
electronic and steric nature of the N-substituent.

This investigation of imidazolium systems was further extended to N-aryl systems in
Chapter 3, whereupon the effect of changing the nature of the aromatic group was
considered. This was done with a particular focus on systematically changing the
electronic nature of the 4'-substituent in an attempt to quantify the effect through
utilisation of Hammett parameters, variation of substituents at the 2'- and 6'-positions
and modification of the substituents in the 4- and 5-positions allowing direct
viii