Approaches to the Synthesis of Chiral and Amino-substituted BODIPY Dyes

360 Pages·2016·15.6 MB·English

Approaches to the Synthesis of Chiral
and Amino-substituted BODIPY Dyes

By
Rua Bandar Alnoman

A thesis submitted in partial fulfilment of the requirements for the
degree of
Doctor of Philosophy

July 2016
Abstract

Abstract

Boron dipyrromethenes (BODIPYs) have attracted considerable attention due to their
fluorescence properties, including high fluorescence quantum yields and absorption
coefficients, good photochemical stability and narrow absorption and emission
bandwidths. Because of these properties, they have found extensive use for in vivo
imaging, analyte sensing, photodynamic therapy, solar cells and light harvesting arrays.
This thesis is divided in two parts. Part one covers the synthesis of functionalised chiral
BODIPYs whilst part two involves investigations into the synthesis and application of
aminoBODIPY via metal catalysed amination reactions.
Four approaches to the synthesis of novel chiral BODIPY dyes were investigated. The
axially chiral BODIPY dye with C2-symmetry I was synthesised via Suzuki coupling of
the corresponding 2,6-dibromoBODIPY with 2-methoxyphenyl boronic acid. The
unsymmetrical axially chiral BODIPY II was synthesized via Suzuki coupling of the
corresponding 2-bromoBODIPY with phenyl boronic acid. Unfortunately, attempted
resolution of these chiral systems by analytical chiral HPLC was unsuccessful.

The new helically chiral BODIPYs IIIa-c were synthesised. Resolution of racemic
helically chiral BODIPYs IIIa and IIIb was successfully accomplished by preparative
chiral HPLC.

i
Abstract

Electronic circular dichroism (ECD) spectra of both (M) and (P) isomers of IIIa and IIIb
were measured by Prof. W. Herrebout (University of Antwerp). Comparison of the
measured and computationally predicted ECD spectra allowed the absolute configuration
of each of the enantiomeric samples of IIIa-b to be established. The CPL spectra of both
(M) and (P) isomers of IIIa and IIIb were recorded by Prof. R. D. Peacock (University
of Glasgow). The |g | of IIIa at 637 nm is 0.0043 and IIIb at 675 nm is 0.0042, which
lum
are among the largest so far reported for a simple BODIPY fluorophore in solution.

We designed and synthesized the mono-strapped BODIPY V scaffold via sequential
regioselective functionalisation of the unsymmetrical BODIPY IV. Resolution of
N,N,F,O-BODIPY V by analytical chiral HPLC gave two peaks confirming that single
enantiomers of this compound should be accessible.

The 8-anisyl-substituted BODIPY VI was synthesized using a standard synthetic route,
regioselective iodination with ICl then gave the 2-iodo-substituted BODIPY VII. We
unexpectedly found that copper catalysed nucleophilic substitution of the 2-iodoBODIPY
VII produced the 3-amino BODIPYs VIIIa-n in good yield. The reactions occurred
successfully for a range of primary and secondary alkyl and aryl amines and even with
benzamide, albeit in low yield.

2-aminoBODIPYs Xa-e have been prepared successfully via Buchwald–Hartwig
amination of the 2-iodoBODIPY IX (fully blocked). The presence of the nitrogen group

ii
Abstract

in the 2-position gives a broadened red-shifted absorption maximum and quenched
fluorescence.

This palladium catalysed amination was used to prepare the 2-nitroaniline-substituted
BODIPY XI. Reduction of the nitro group by hydrogenation gave the novel fluorescence-
quenched 2-aminoaniline-substituted BODIPY XII. Reaction of this compound with
triphosgene gave the corresponding benzimidazolone-substituted BODIPY XIII. The
bright yellow fluorescence of the triphosgene reaction product XIII can be easily
visualized by the naked eye. The detection limit for phosgene was determined to be 160
nM in solution at room temperature.

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Dedication

Dedication

I would like to dedicate this work to my father, Bandar Alnoman; to my mother, Hedayat
Bokhari; to my brothers and sisters; to my wonderful husband, Moaz Zulali; and to my
children, Omar and Joanne.

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Acknowledgements

Acknowledgement

In the Name of Allah, the Most Gracious, the Most Merciful,

I would like to express my gratitude to Allah (God) for giving me the opportunity,
determination, and strength to do this work.
I would like to express my deepest appreciation to my supervisor, Dr. Julian Knight, for
his continuous support, guidance and encouragement over the course of my PhD and
related research. I could not have imagined having a better advisor and mentor for my
PhD study.
Many thanks also to my second supervisor, Dr. Michael Hall, for his support, guidance,
knowledge, and experience from which I benefited from so greatly. I would like to thank
Professor Anthony Harriman for his assistance with the measurements, Dr Corrine Wills
for assistance with NMR spectroscopy, and Dr Paul G. Waddell for X-ray crystallography
analysis. I would like to thank all the past and present members in the Dr. Julian Knight
research group, for all the good times and memories.
Special thanks are directed to the Taibah University for providing scholarship funds and
financial support. I also would like to thank Newcastle University for providing me with
all the necessary facilities.
Finally, I would like to thank my entire family for their love, support, extraordinary
encouragement, and assistance over the past few years. A special thank you goes to my
husband for supporting me through these times, as I could not have been as successful
without his flexibility and support.

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List of Publications

Publications from this work

1. J. G. Knight, R. B. Alnoman, and Paul G. Waddell, Org. Biomol. Chem., 2015, 13,
3819-3829.
2. R. B. Alnoman, S. Rihn, D. C. O’Connor, F. A. Black, B. Costello, P. G. Waddell,
W. Clegg, R. D. Peacock, W. Herrebout, J. G. Knight, and M. J. Hall, Chem. Eur. J.,
2016, 22, 93-96.

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List of Abbreviations

List of Abbreviations

Ar Aryl
atm Atmosphere(s)
BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene
Boc Di-t-butyl dicarbonate
BODIPY Boron dipyrrin, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
°C Degree Celsius
cat Catalytic
CD Circular dichroism
cm-1 Wavenumber(s)
CPL Circularly polarized luminescence
DCE Dichloroethane
DCM Dichloromethane
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DMF N,N-Dimethyl formamide
DMSO Dimethylsulfoxide
d-PET Donor photoinduced electron transfer
ee Enantiomeric excess
eq Equivalent
Et O Diethyl Ether
2
EtOAc Ethyl acetate
EtOH Ethanol
ε molar extinction coefficient
g Gram
H-KITPHOS 11-dicyclohexylphosphino-12-phenyl-9,10-dihydro-9,10-
ethenoanthracene
h Hour/s
HPLC High-performance liquid chromatography
IR Infra-red
i-Pr NEt N,N-Diisopropyethylamine
2
MeOH Methanol

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List of Abbreviations

mg Milligram
mL Millilitre
mmol Millimole
N Nitrogen
2
NMR Nuclear magnetic resonance
NBS N-bromosuccinimide
PeT Photoinduced electron transfer
Pd (dba) Tris(dibenzylideneacetone)dipalladium(0)
2 3
Pd(OAc) Palladium(II) acetate
2
ɸ Quantum yield
S Ground state
0
S First excited state
1
SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl
S Ar Nucleophilic aromatic substitution
N
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin layer chromatography
UV Ultraviolet
XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

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Table of contents

Table of contents

Abstract ............................................................................................................................. i
Dedication ....................................................................................................................... iv
Acknowledgement ........................................................................................................... v
Publications from this work .......................................................................................... vi
List of Abbreviations .................................................................................................... vii
Table of contents ............................................................................................................ ix
Chapter 1: Introduction ................................................................................................. 1
1.1. General introduction to fluorescence ................................................................. 1
1.2. General introduction to fluorophores ................................................................. 3
1.3. Borondipyrromethene Difluoride (BODIPY) .................................................... 4
1.3.1. Background and structure ........................................................................... 4
1.3.2. General properties of BODIPY ................................................................... 6
1.3.3. General synthetic routes to BODIPY dyes ............................................... 10
1.3.3.1. From aldehyde ...................................................................................... 11
1.3.3.2. From carboxylic acid ............................................................................ 13
1.3.3.3. From a ketopyrrole ................................................................................ 14
1.4. Some applications of functionalized BODIPYs ............................................... 16
1.5. Goals and objectives ......................................................................................... 23
Chapter 2: Synthesis of chiral BODIPY dyes ............................................................. 24
2.1. Introduction ...................................................................................................... 24
2.2. Axially chiral BODIPYs .................................................................................. 29
2.2.1. Synthesis of axially chiral BODIPY dyes with C2-symmetry .................... 31
2.2.1.1. Chiral resolution .................................................................................... 37
2.2.1.2. Chiral HPLC separation .................................................................... 37
2.2.1.3. Photophysical data for 2,6-bis(2-methoxyphenyl) BODIPY 2.6 .......... 39
2.2.2. Synthesis of unsymmetrical axially chiral BODIPY dyes ........................... 40
2.2.2.1. Photophysical data of the 2-phenyl BODIPY 2.15. .............................. 44
2.3. Helically chiral BODIPY ................................................................................. 46
2.3.1. Approach to synthesis of functionalized Aza BODIPY dyes ...................... 46
2.3.2. Synthesis of helically chiral N,N,O,O-BODIPY dyes. ................................ 54
2.3.2.2. Photophysical properties of helically chiral N,N,O,O-BODIPYs ......... 70

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