Copyright is owned by the Author of the thesis. Permission is given for a 
copy to be downloaded by an individual for the purpose of research and 
private study only. The thesis may not be reproduced elsewhere without 
the permission of the Author. 
 



 
 

The Synthesis and Chemistry of  

Quinolino[7,8-h]quinoline Derivatives 
 

 

A thesis presented in partial fulfilment of requirements for the degree of 

 

Doctor of Philosophy 

in 

Chemistry 

 

at 

Massey University, Manawatu, New Zealand 

 

by 

 

REBECCA J. SEVERINSEN 

 

 

 

 

2021 



 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



i 
 

Abstract 

Proton sponges are a class of neutral organic superbases. Quinolino[7,8-h]quinoline 

(QQ) is one such molecule. Structurally it has two closely positioned nitrogen atoms 

which cause a destabilising lone electron overlap which manifests as a helical torsional 

twist that can be relieved by monoprotonation or complexation. These compounds are 

highly basic and are chelators that can accommodate a variety of ion sizes. Exploration 

of the structural properties of QQ provides an avenue for non-symmetric compound 

synthesis. Research interest arose in developing original synthetic pathways and 

exploring the chemistry of this QQ moiety, and its potential uses. This work primarily 

focussed on the development of methods towards new derivatives containing the QQ 

core structure, of which several were developed. Exploration of their properties as bases 

was begun in the context of both experimental measurements and theoretical 

calculations, allowing some to be classified as superbases. Computational analysis also 

gave insight into structural changes taking place during the protonation process. 

Potential uses of QQ derivatives as chelators for metals were examined. An X-ray crystal 

structure of a beryllium containing 4,9-dihydroxyquinolino[7,8-h]quinoline was 

achieved, the 7th reported ion to be chelated by a QQ compound. 

 

 

 

 

 

 

 

 

 

 

 

 

 



ii 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



iii 
 

Contributions 

All the work in this thesis was completed by Rebecca Severinsen. 

Except: 

- In collaboration with The University of Marburg, Germany, Dr Magnus Buchner 

and his research group, including Nils Spang, characterised the complex including 

the beryllium-containing crystal structure discussed in Chapter 6, and that of 9-

methoxyquinolino[7,8-h]quinoline-4(1H)-one in Chapter 2. 

- In collaboration with the University of Tartu, Estonia, Prof. Ivo Leito and his 

research group obtained the experimental pKaH data discussed in Chapter 4. 

- In collaboration with the Ruđer Bošković Institute, Croatia, Dr. Robert Vianello 

and his research group obtained the computational basicity data also discussed 

in Chapter 4. 

- Computational calculations of Chapter 5 were performed by fellow group 

member Tyson Dais. 

Publications 

Two papers were published during the course of this project, including:  

 Rowlands, G. J.; Severinsen, R. J.; Buchanan, J. K.; Shaffer, K. J.; Jameson, H. T.; 

Thennakoon, N.; Leito, I.; Lõkov, M.; Kütt, A.; Vianello, R.; Despotović, I.; Radić, 

N.; Plieger, P. G., Synthesis and Basicity Studies of Quinolino[7,8-h]quinoline 

Derivatives. J. Org. Chem. 2020, 85 (17), 11297-11308. 

 Severinsen, R. J.; Rowlands, G. J.; Plieger, P. G., Coordination Cages in Catalysis. 

J. Inclusion Phenom. Macrocyclic Chem. 2020, 96 (1-2), 29-42. 

And contributions were made to: 

 Buchner, M. R.; Mueller, M.; Raymond, O.; Severinsen, R. J.; Nixon, D. J.; 

Henderson, W.; Brothers, P. J.; Rowlands, G. J.; Plieger, P. G., Synthesis of a 

Boronic Acid Anhydride Based Ligand and Its Application in Beryllium 

Coordination. Eur. J. Inorg. Chem. 2019,  2019 (34), 3863-3868. 

 

 

 



iv 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



v 
 

Acknowledgements 

Firstly, I would like to express my gratitude for my supervisors Prof. Paul Plieger and 

Assoc. Prof. Gareth Rowlands for the guidance, support, and patience they have 

provided that have enabled this goal to be reached.  

 

I would also like to thank the current, former, and honorary members of the Plieger 

Group for a great working environment and all the fun, support and help over the years: 

Jenna Buchanan, Michael Brown, Tyson Dais, Marryllyn Donaldson, Hossein Etemadi, 

Leonie Etheridge, Liam McGarry, Brodie Matheson, David Nixon, Suraj Patel, and Sidney 

Woodhouse.  

 

Thank you also to all the other Massey staff of the towers who have been instrumental 

in this process. This includes Dave Lun, Pat Edwards and Graham Freeman for assistance 

with unfamiliar techniques, equipment training and instrument use, and the 

Administration team for all that they do. 

 

Last, but certainly not least, my overwhelming gratitude to the family and friends who 

have been there for me during these years, you know who you are. Your love and 

support have kept me going and allowed me to make it this far.  

 

Thank you. 

 

 

 

 

 

 

 

 

 



vi 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



vii 
 

Contents 

Abstract ............................................................................................................................. i 

Contributions ................................................................................................................... iii 

Acknowledgements .......................................................................................................... v 

List of Figures .................................................................................................................... x 

List of Tables ................................................................................................................. xvii 

Abbreviations ............................................................................................................... xviii 

Chapter 1 - Introduction .................................................................................................. 1 

1.1 - Proton Sponges .................................................................................................... 1 

1.2 - Coordination potential of diamines and proton sponges .................................... 3 

1.3 - A New Type of Proton Sponge – quinolino[7,8-h]quinoline ................................ 8 

1.3.1 - Synthesis of Quinolino[7,8-h]quinoline ............................................................. 10 

1.3.2 - Naming and numbering of quinolino[7,8-h]quinoline derivatives ................. 14 

1.3.3 - Derivatisation of quinolino[7,8-h]quinoline ...................................................... 15 

1.3.4 - Other organic compounds with the QQ substructure ..................................... 21 

1.3.5 - QQ Coordination ................................................................................................... 23 

1.3.6 - Computational/Theoretical Studies ................................................................... 27 

1.3.7 - Patents – Organic Electronic Devices ................................................................. 28 

1.4 - Beryllium Coordination ...................................................................................... 28 

1.5 - Coordination cages ............................................................................................ 29 

1.6 - Summary ............................................................................................................ 30 

1.7 - Proposed Aims ................................................................................................... 30 

Chapter 2 - Synthesis of New Derivatives ...................................................................... 31 

2.1 - Overview ............................................................................................................ 31 

2.2 - Symmetrical QQ derivatives ............................................................................... 33 

2.2.1 - Challenges .............................................................................................................. 33 

2.2.2 - Suzuki-Miyaura Coupling ..................................................................................... 36 

2.2.3 - Other symmetrical substitution .......................................................................... 43 

2.2.4 - Synthesis of 9-(dimethylamino)quinolino[7,8-h]quinoline-4(1H)-one (Q12)
 ............................................................................................................................................. 45 

2.2.5 - Symmetrical QQ derivatives - Summary ............................................................ 46 

2.3 - Non-symmetrical QQ derivatives ....................................................................... 46 



viii 
 

2.3.1 - Synthesis of 9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinolin-4(1H)-one (Q10)
 ............................................................................................................................................ 47 

2.3.2 - Synthesis of 4-chloro-9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinoline (Q13)
 ............................................................................................................................................ 48 

2.3.3 - Synthesis of 9-(2-propyn-1-yloxy)-1,4,9,12-tetrahydro-4,9-dioxo-2,11-

dimethylester-quino[7,8-h]quinoline-2,11-dicarboxylic acid (Q15) .......................... 49 

2.3.4 - Synthesis of 4-bromo-9-(pyridin-4-yl)-quinolino[7,8-h]quinoline (Q14) ...... 51 

2.3.5 - Non-symmetrical QQ derivatives - Summary ................................................... 53 

2.4 - 9-methoxyquinolino[7,8-h]quinoline-4(1H)-one ................................................ 53 

2.5 - Selected Incomplete/unsuccessful QQ Transformations ................................... 54 

2.5.1 - Synthesis of 4,9-di(4-benzoic acid ethyl ester)quinolino[7,8-h]quinoline (Q8)
 ............................................................................................................................................ 54 

2.5.2 - Sonogashira Coupling .......................................................................................... 55 

2.5.3 - Transhalogenation ............................................................................................... 57 

2.5.4 - QQ boronic ester – Change of coupling partners ............................................ 58 

2.5.5 - 6,7-dinitroquinolino[7,8-h]quinoline-4,9(1H,12H)-dione ............................... 59 

2.5.6 - 4-bromo-9-chloro-quinolino[7,8-h]quinoline ................................................... 59 

2.6 - Non-QQ Synthesis ............................................................................................... 61 

2.6.1 - Synthesis and characterisation of a boronic acid anhydride-based ligand .. 61 

2.6.2 - Synthesis of 2-hydroxy-5-(3-pyridyl)-benzaldehyde oxime (L1) .................... 62 

2.7 - Conclusion .......................................................................................................... 64 

Chapter 3 - Experimental Synthesis Methods ................................................................ 65 

3.1 - General QQ experimental and characterisation notes ....................................... 65 

3.2 - Experimental methods ........................................................................................ 69 

3.2.1 - Synthesis of tetramethyl-2,2’-(naphthalene-1,8-diylbis(azanediyl) 

difumarate (N) .................................................................................................................. 69 

3.2.2 - Synthesis of 4,9-dioxo-1,4,9,12-tetrahydroquinolino[7,8-h]quinoline-2,11-

dicarboxylate (Q1) ............................................................................................................ 70 

3.2.3 - Synthesis of quinolino[7,8-h]quinoline-4,9-(1H,12H)-dione (Q2) ................. 71 

3.2.4 - Synthesis of 4,9-dichloroquinolino[7,8-h]quinoline (Q3) ............................... 72 

3.2.5 - Synthesis of 4,9-dibromoquinolino[7,8-h]quinoline (Q4) ............................... 73 

3.2.6 - Synthesis of 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline (Q5) .................... 74 

3.2.7 - Synthesis of 4,9-di(pyridin-3-yl)quinolino[7,8-h]quinoline (Q5) .................... 75 

3.2.8 - Synthesis of N4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-diamine 76 

3.2.9 - Synthesis of 4-bromo-9-oxo-9,12-dihydroquinolino[7,8-h]quinoline (Q9) .. 77 



ix 
 

3.2.10 - Synthesis of 9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinolin-4(1H)-one 

(Q10) ................................................................................................................................... 78 

3.2.11 - Synthesis of 9-(dimethylamino)quinolino[7,8-h]quinoline-4(1H)-one (Q12)
 ............................................................................................................................................. 79 

3.2.12 - Synthesis of 4-chloro-9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinoline 

(Q14) ................................................................................................................................... 80 

3.2.13 - Synthesis of 4-bromo-9-(pyridin-4-yl)quinolino[7,8-h]quinoline (Q14) ...... 81 

3.2.14 - Synthesis of 9-(2-propyn-1-yloxy)-1,4,9,12-tetrahydro-4,9-dioxo-2,11-

dimethylester-quino[7,8-h]quinoline-2,11-dicarboxylic acid (Q15) .......................... 82 

3.2.15 - Synthesis of 4,9-dichloro-6,7-dinitroquinolino[7,8-h]quinoline (Q18) ........ 83 

3.2.16 - Synthesis of 3-pyridine boronic acid pinacol ester ........................................ 83 

3.3 - Other Experimental ............................................................................................ 84 

3.3.1 - Synthesis of a boronic acid anhydride-based ligand ........................................ 84 

3.3.2 - Synthesis of 2-hydroxy-5-(3-pyridyl)-benzaldehyde oxime (L1) ..................... 85 

Chapter 4 - Quinolino[7,8-h]quinoline pKaH  Research .................................................. 86 

4.1 - Introduction ....................................................................................................... 86 

4.2 - Results and Discussion ....................................................................................... 88 

4.2.1 - Theoretical QQ Derivatives ................................................................................. 94 

4.3 - Comparison to existing Proton Sponges ............................................................ 97 

4.4 - Conclusion .......................................................................................................... 99 

Chapter 5 - Structural insights using Computational Chemistry .................................. 100 

5.1 - Methods ........................................................................................................... 101 

5.2 - Results and Discussion ..................................................................................... 103 

5.2.1 - Gas Phase Basicity .............................................................................................. 107 

5.3 - Conclusion ........................................................................................................ 110 

Chapter 6 - Coordination ............................................................................................. 111 

6.1 - Quino[7,8-h]quinoline Coordination - General ................................................ 111 

6.1.1 - Results .................................................................................................................. 113 

6.2 - Beryllium Coordination .................................................................................... 116 

6.3 - Conclusion ........................................................................................................ 122 

Chapter 7 - Future Work .............................................................................................. 123 

Chapter 8 - Conclusion ................................................................................................. 126 

References ................................................................................................................... 128 

Appendices .................................................................................................................. 137 



x 
 

Appendix A – X-ray summary data for 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline 

(Q4) ........................................................................................................................... 137 

Appendix B – X-ray summary data for 9-methoxyquinolino[7,8-h]quinoline-4(1H)-

one ............................................................................................................................ 139 

Appendix C - Selected Experimental NMR Characterisation .................................... 141 

Appendix D - QQ Computational .............................................................................. 175 

Appendix E – Crystal data and refinement for [BeBr(MeCN)(QQ(OH)2)]Br .............. 177 

Appendix F - QQ Derivative names and codes .......................................................... 179 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



xi 
 

List of Figures 

Figure 1-1:  1,8-Bis(dimethylamino)naphthalene (DMAN) - The original Proton SpongeTM ... 1 

Figure 1-2:  X-ray structures of DMAN in neutral (left) and protonated (right) forms. Images 

generated in Olex28 from CCDC files DMANAP019 and CEJGUU10 with 50% 

ellipsoids. Counter-ion (CF3O3S-) omitted from DMANH+ (right) for clarity. ....... 2 

Figure 1-3:  Structures of triguanidinophosphazene (B) N4,N4,N5,N5-tetramethyl-1,8-dioxide-

arsenino[2,3-b]arsenin-4,5-diamine (C). .............................................................. 2 

Figure 1-4:  pKa values in acetonitrile for the conjugate acids of DMAN (A), TMGN (D) and 

HMPN (E).16-18 ...................................................................................................... 3 

Figure 1-5:  Example of a light-responsive coordination complex (F) involving bidentate 

diamine binding sites. Adapted with permission from Mobian et al.20 Copyright 

2004 Wiley-VCH. .................................................................................................. 4 

Figure 1-6:  Example of a multistep catalysis (right) by a hexahedral coordination cage (G)  

featuring a ligand (H) with bidentate diamine binding sites.36 ............................ 5 

Figure 1-7:  Coordination of a Pd(II) ion by DMAN (I), completed with a 1,3-diphenylpropane-

1,3-dionato-O,O'- ligand. Hydrogen and counter-ion (HFAC-) omitted for clarity. 

Image generated in Olex28 from CCDC file OBEJIP38 with 50% ellipsoids. ........... 6 

Figure 1-8:  Complexes of TMPN with Ga(III) (J) and Al(III) (K) in front (top) and side-plane 

(lower) views. Hydrogen omitted for clarity. Images generated in Olex28 from 

CCDC files BIXQEG and BIXQAC with 50% ellipsoids.40 ........................................ 7 

Figure 1-9:  Structures of DMAN (A), 1,10-phen (L) and quinolino[7,8-h]quinoline (QQ). ..... 8 

Figure 1-10:  4,9-dichloroquinolino[7,8-h]quinoline (Q3) structures in neutral (left) and 

protonated (right) forms. Images generated in Olex28 from CCDC files PANFOB 

and PANFUH with 50% ellipsoids.41 Counter-ion (BF4
-) omitted from (right) for 

clarity. .................................................................................................................. 9 

Figure 1-11:  All tautomers of quinolino[7,8-h]quinoline-4,9-(1H,12H)-dione (Q2). ................ 9 

Figure 1-12:  Skraup reaction (top) and mechanism (partial) to form quinoline.48 ................ 10 

Figure 1-13:  Attempted formation of QQ by Skraup condensation by Sauvage and coworkers 

that resulted in formation of 2-mdp (N).52 ........................................................ 11 

Figure 1-14:  Proposed mechanism of formation of 2-mdp (N) from 1,8-

diacetaminonapthalene (M). ............................................................................. 12 

Figure 1-15:  Initial quinolino[7,8-h]quinoline synthesis by Zirnstein and Staab, 1987.11,54 

Reaction conditions and yields: (i) DMAD, MeOH, RT, 71%; (ii) Ph2O, 240 °C, 64%; 

(iii) (a) KOH, 100 °C; (b) HCl, H2O, 93%; (iv) 370 °C, 10-5 torr 76%; (v) POCl3, 130 

°C, 81%; (vi) Pd/C, HOAc, NaOAc, 39%. ............................................................. 13 

Figure 1-16:  Total QQ structures (with assigned CAS numbers) published 1987-2019. Data 

points indicate years in which one or more QQ-derivative-containing 

publications were released. Data includes complexes and salts, and those 

present only in patent literature. Some of these publications are discussed in the 

following sections. ............................................................................................. 14 

Figure 1-17:  Nomenclature of quinolino[7,8-h]quinoline (left) and numbering scheme for 

atoms/substituents (right). ................................................................................ 15 

Figure 1-18:  Quinolino[7,8-h]quinoline substituent numbering. ........................................... 15 

Figure 1-19:  Selected examples of published 4,9-substituted QQ derivatives.11, 15 ............... 17 

Figure 1-20:  Crystal structures of dimethyl 4,9-dichloroquinolino[7,8-h]quinoline-2,11-

dicarboxylate (Q16) and N-[2-(methylthio)benzo[h]quinolin-10-yl]acetamide 



xii 
 

(U). Counter-ion (BF4
-) not shown for clarity (left). Images generated in Olex28 

using CCDC files FEJXID and FEJXEZ with 50% ellipsoids.15 ............................... 18 

Figure 1-21:  Attempted synthesis of QQ from 1,8-diaminonapthalene (O) and 3-

bis(methylthio)acrolein by Skraup condensation, resulting in the formation of N-

[2-(methylthio)benzo[h]quinolin-10-yl]acetamide (U) instead of the desired 

disubstituted product (V). ................................................................................. 19 

Figure 1-22:  Nitration of 4,9-dichloroquinolino[7,8-h]quinoline (Q3).54 ............................... 19 

Figure 1-23:  X-ray structure of 4-chloro-9-oxo-9,12-dihydro-6,7-dinitroquino[7,8-h]quinoline 

(Q21).11 Generated in Olex28 with 50% ellipsoids. ............................................ 20 

Figure 1-24:  Resonance structures of QQ showing the partial positive character of positions 

5 and 8. .............................................................................................................. 21 

Figure 1-25:  Examples of other organic compounds with the QQ substructure, with a 

polycyclic 'croissant-like' compound (W) and acequinolino[7,8-h]quinoline 

(AceQQ). ............................................................................................................ 22 

Figure 1-26:  Proposed mechanism for the formation of aceQQ. .......................................... 23 

Figure 1-27:  Pt and Re complexes of 4,9-dichloroquinolino[7,8-h]quinoline (Q3). Hydrogen 

omitted for clarity. Images generated in Olex28 using CCDC files ACEQAA and 

ACEPUT with 50% ellipsoids.56 .......................................................................... 24 

Figure 1-28:  Boron-chelates of 4,9-dichloroQQ (left) and QQ (right). Hydrogen and counter-

ions (BF4
-) omitted for clarity. Images generated in Olex28 using CCDC files 

PANGES and PANGAO with 50% ellipsoids.41 .................................................... 25 

Figure 1-29:  QQ spatial changes associated with (left) coordination to large metal ions (M) 

such as Pt and Re and (right) protonation or coordination to smaller ions (Y) such 

as BF2.15 ............................................................................................................. 26 

Figure 1-30:  Cu(II) complexes of 4,9-dichloroquinolino[7,8-h]quinoline (Q3, left) and 

quinolino[7,8-h]quinoline (QQ, right). Hydrogen and counter-ions removed for 

clarity. Images generated in Olex28 using CCDC files NIBSOI and NIBSIC with 50% 

ellipsoids.58 ........................................................................................................ 26 

Figure 1-31:  Crystal structure of (Be(PhC(O)O)2)12 obtained by Müller and Buchner as an 

example of an existing beryllium complex.82 Image generated in Olex28 from the 

CCDC file YEZQAY. ............................................................................................. 28 

Figure 1-32:  Molecular mechanics representation of a potential QQ cage structure. ......... 29 

Figure 2-1:  Summarised QQ reaction scheme. .................................................................... 32 

Figure 2-2:  1H NMR of Q2 in d-trifluoroacetic acid (TFA-d) showing four aromatic proton 

signals, indicative of a symmetrical QQ structure ((a), with trifluoroacetate 

anion). ............................................................................................................... 33 

Figure 2-3:  Synthesis of Q9 from Q4. .................................................................................. 34 

Figure 2-4:  Proposed mechanism for partial hydroxyl substitution and tautomerisation from 

4,9-dibromoQQ. ................................................................................................ 36 

Figure 2-5:  Generalised Suzuki-Miyaura coupling mechanism showing the oxo-Pd pathway. 

Boronate pathway transmetalation proceeds by the reaction of ‘2’ directly with 

the boronate species without formation of ‘3’. ................................................ 37 

Figure 2-6:  Possible Suzuki-Miyaura coupling pathways for the formation of mono- and di-

substituted QQ derivatives. X = Cl or Br. ........................................................... 38 

Figure 2-7:  Synthesis of Q5 from Q4. .................................................................................. 39 

Figure 2-8:  Images of the X-ray structure of 4,9-dipyridylquino[7,8-h]quinoline (Q5), 

generated in Olex2 with 50% ellipsoids.8 .......................................................... 41 

Figure 2-9:  Successful synthesis of Q6 from Q4. ................................................................. 41 



xiii 

 

Figure 2-10:  Attempted synthesis of Q6 from Q3. ................................................................. 42 

Figure 2-11:  Synthesis of Q7 from Q4. ................................................................................... 44 

Figure 2-12:  Synthesis of Q12 from Q4. ................................................................................. 45 

Figure 2-13:  Synthesis of Q10 from Q2. ................................................................................. 47 

Figure 2-14:  Synthesis of Q13 from Q10. ............................................................................... 48 

Figure 2-15:  Synthesis of Q15 from Q1. ................................................................................. 50 

Figure 2-16:  Synthesis of Q14 from Q11. ............................................................................... 51 

Figure 2-17:  1H NMR spectra of Q14 taken after <1hr (top) ~30hrs (lower) in DMSO-d6. Note 

the appearance of many new peaks (e.g. 17.2 and 15.6 ppm, highlighted by ‘*’ 

symbols), some of which correspond to degradation to Q11. .......................... 52 

Figure 2-18:  Schematic (left) and crystal (right) structures of 9-methoxyquinolino[7,8-

h]quinoline-4(1H)-one showing two different viewpoints. Image generated in 

Olex2 with 50% ellipsoids.8 ................................................................................ 53 

Figure 2-19:  Crystal structure packing of 9-methoxyquinolino[7,8-h]quinoline-4(1H)-one. 

Images generated in Olex2 with 50% ellipsoids.8 .............................................. 54 

Figure 2-20:  Synthesis of Q8 from Q4. ................................................................................... 55 

Figure 2-21:  High-resolution mass spectrum of Q8 synthesis. .............................................. 55 

Figure 2-22:  Triple-cavity Pd4L4 cage constructed by Crowley and coworkers, where 

R=O(CH2)2O(CH2)2OCH3 Image adapted from Ref. [101]. For further permissions 

related to this image, contact the ACS. 

https://pubs.acs.org/doi/10.1021/jacs.6b11982. Copyright American Chemical 

Society (2017).101 ............................................................................................... 56 

Figure 2-23:  Synthesis of 4,9-di(X-ethynylpyridyl)quinolino[7,8-h]quinoline and 4-(X-

ethynylpyridyl)-9-oxo-9,12-dihydroquinolino[7,8-h]quinoline from Q4, where X 

= 3 or 4. .............................................................................................................. 56 

Figure 2-24:  Low-res mass spectrum of a Sonogashira coupling attempt showing three 

different products. ............................................................................................. 57 

Figure 2-25:  Attempted transhalogenation of Q3 to 4,9-diiodoquinolino[7,8-h]quinoline ... 58 

Figure 2-26:  Attempted formation of 4,9-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

quinolino[7,8-h]quinoline .................................................................................. 58 

Figure 2-27:  Synthesis of 6,7-dinitroquinolino[7,8-h]quinoline-4,9(1H,12H)-dione .............. 59 

Figure 2-28:  Synthesis of 4-bromo-9-chloro-quinolino[7,8-h]quinoline ................................ 59 

Figure 2-29:  Mass spectrum of attempted formation of 4-bromo-9-chloro-quinolino[7,8-

h]quinoline (left) and proposed mechanism (right). ......................................... 60 

Figure 2-30:  Synthesis of C3 from C1 ..................................................................................... 61 

Figure 2-31:  Synthesis of 2-hydroxy-5-(3-pyridyl)-benzaldehyde oxime (L1) from 4-

bromophenol. .................................................................................................... 62 

Figure 2-32:  Pt4L4 metallomacrocycle synthesised by MacLachlan and coworkers.114 .......... 63 

Figure 3-1:  1H NMR spectra comparison of Q7 showing the aromatic region. Upper 

spectrum is ~ 3-4x more concentrated (exact concentrations were not 

recorded). .......................................................................................................... 66 

Figure 3-2:  1H NMR signals corresponding to HA (left) and HB (right). Both proton signals 

should present as doublets, however this is not observed here. ...................... 67 

Figure 4-1:  Structure of the Proton SpongeTM DMAN (left) and quinolino[7,8-h]quinoline 

(right). ................................................................................................................ 86 

Figure 4-2:  Example of framework buttressing effects on organic bases (left) and hybridised 

N donor atoms  in DBU (right). .......................................................................... 87 



xiv 

 

Figure 4-3:  Relative strength of selected electron withdrawing and donating substituents.

 .......................................................................................................................... 88 

Figure 4-4:  Key to R1-R3 QQ substituent position codes. ..................................................... 89 

Figure 4-5:  Calculated pKaH values compared to degree of torsional twists of synthesised QQ 

derivatives. ........................................................................................................ 91 

Figure 4-6:  Variation of QQ basicity correlated with substituent electronic effects. .......... 94 

Figure 4-7:  Effects of substituent position on resulting pKaH .............................................. 96 

Figure 4-8:  Structural comparison of quinolino[7,8-h]quinoline (left), TMGN (middle) and 

HMPN (right) ..................................................................................................... 97 

Figure 5-1:  Structures explored in this chapter using Gaussian09 (G09) .......................... 100 

Figure 5-2:  Optimised gas-phase neutral geometries of A: 4,9-di(3-pyridyl)quinolino[7,8-

h]quinoline (Q6); B: 4,9-di(4-pyridyl)quinolino[7,8-h]quinoline (Q5); C: 4-chloro-

9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinoline (Q13); D: 4,9-

diaminoquinolino[7,8-h]quinoline; E: N
4,N4,N9,N9-tetramethylquinolino[7,8-

h]quinoline-4,9-diamine (left) and protonated geometries (right). ................ 103 

Figure 5-3:  Comparison between angle of torsional twist in QQ derivative neutral structures 

and magnitude of N···N distance change upon protonation .......................... 105 

Figure 5-4:  Change in bond lengths in QQ core of derivatives A-E upon protonation. Bonds 

associated with the ‘protonated’ quinoline side (N1) to the left and the ‘non-

protonated’ to the right. ................................................................................. 106 

Figure 5-5:  QQ core structure with bonds that significantly change upon protonation. 

Orange bonds increase length, blue decrease, and grey/black show little change.

 ........................................................................................................................ 107 

Figure 5-6:  Optimised structure images of protonated E with calculated plane (left) showing 

slight bowing. NMe2 side groups omitted from the left image for clarity of the 

plane. ............................................................................................................... 107 

Figure 5-7:  Calculated basicity (Gas Phase Basicity (GPB, circle) or Proton Affinity (PA, 

square)) compared with degree of torsional twist in the neutral structures. 109 

Figure 6-1:  QQ spatial changes associated with (a) coordination to large metal ions such as 

Pt and Re and (b) protonation or coordination to smaller ions such as BF2. (C): X-

ray structure of a Cu-QQ complex, produced in Olex2 with 50% ellipsoids from 

CCDC file NIBSIC.8 Anions and hydrogen removed for clarity. (a)/(b) reproduced 

from Shaffer et al., 2012.41 .............................................................................. 112 

Figure 6-2:  Mass spectra of attempted complex formation. A: Attempted Q5-B(III) 

complexation showing only the Q5 ligand. B: Attempted Q4-Cu(II) complexation, 

showing decomposition of Q4 to the mono-halide Q9. .................................. 114 

Figure 6-3:  Mass spectrum of complexation attempt between Pt(II) and Q6. ................. 115 

Figure 6-4:  QQ-BF2 complex with 50% ellipsoids.41 Image generated in Olex2 from CCDC 

deposition number PANGAO.8 ........................................................................ 116 

Figure 6-5:  [BeBr(MeCN)(QQ(OH)2)]Br crystal structure (Be-QQ(OH)2) in two different views 

with 50% ellipsoids. Images generated in Olex2.8 ........................................... 119 

Figure 6-6:  Be-QQ(OH)2 crystal structure showing a layer of packing (50% ellipsoids). Image 

generated in Olex2.8 ........................................................................................ 120 

Figure 7-1:  Structure of computationally calculated QQ derivatives with high pKaH values 

given in chapter 4. ........................................................................................... 123 

Figure 7-2:  Attempted synthesis of 4,9-di(dimethylamine)quinolino[7,8-h]quinoline ..... 123 

Figure 7-3:  Examples of possible transformations of Q10 and Q13 (R1 = OH (tautomer) or Cl 

respectively). R2/R3 = alkyl group. ................................................................... 124 



xv 

 

Figure 7-4:  A: Acequinolinoquinoline (aceQQ), also called dipyrido[3,2-e:2’,3’-h] 

acenaphthene.59 B: AceQQ with possible functionalisation positions from 

synthesis by QQ methods. ............................................................................... 125 

Figure C-1:  1H NMR spectrum of 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline (Q5) ........ 141 

Figure C-2:  13C NMR spectrum of 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline (Q5) ....... 142 

Figure C-3:  COSY (top) and HMQC (lower) spectra of 4,9-di(pyridin-4-yl)quinolino[7,8-

h]quinoline (Q5) ............................................................................................... 143 

Figure C-4:  1H NMR spectrum of 4,9-di(pyridin-3-yl)quinolino[7,8-h]quinoline (Q6) ....... 144 

Figure C-5:  13C NMR spectrum of 4,9-di(pyridin-3-yl)quinolino[7,8-h]quinoline (Q6) ....... 145 

Figure C-6:  HMQC (top) and COSY (lower) spectra of 4,9-di(pyridin-3-yl)quinolino[7,8-

h]quinoline (Q6) ............................................................................................... 146 

Figure C-7:  1H NMR spectrum of N
4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-

diamine (Q7) .................................................................................................... 147 

Figure C-8:  13C NMR spectrum of N
4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-

diamine (Q7) .................................................................................................... 148 

Figure C-9:  HMQC (top) and COSY (lower) spectra of N4,N4,N9,N9-tetraethylquinolino[7,8-

h]quinoline-4,9-diamine (Q7) .......................................................................... 149 

Figure C-10:  1H NMR spectrum of 4-bromo-9-oxo-9,12-dihydroquinolino[7,8-h]quinoline 

(Q9) .................................................................................................................. 150 

Figure C-11:  13C NMR spectrum of 4-bromo-9-oxo-9,12-dihydroquinolino[7,8-h]quinoline 

(Q9) .................................................................................................................. 151 

Figure C-12:  HMQC (top) and COSY (lower) spectra of 4-bromo-9-oxo-9,12-

dihydroquinolino[7,8-h]quinoline (Q9). .......................................................... 152 

Figure C-13:  1H NMR spectrum of 9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinolin-4(1H)-one 

(Q10) ................................................................................................................ 153 

Figure C-14:  13C NMR spectrum of 9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinolin-4(1H)-one 

(Q10) ................................................................................................................ 154 

Figure C-15:  HMQC (top) and COSY (lower) spectra of 9-(2-propyn-1-yloxy)-quinolino[7,8-

h]quinolin-4(1H)-one (Q10) ............................................................................. 155 

Figure C-16:  1H NMR spectrum of 9-(dimethylamino)quinolino[7,8-h]quinoline-4(1H)-one 

(Q12) ................................................................................................................ 156 

Figure C-17:  13C NMR spectrum of 9-(dimethylamino)quinolino[7,8-h]quinoline-4(1H)-one 

(Q12) ................................................................................................................ 157 

Figure C-18:  Overlay of 13C and DEPT-135 NMR spectra of 9-(dimethylamino)quinolino[7,8-

h]quinoline-4(1H)-one (Q12) ........................................................................... 158 

Figure C-19:  1H NMR spectrum of 4-chloro-9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinoline 

(Q13) ................................................................................................................ 159 

Figure C-20:  13C NMR spectrum of 4-chloro-9-(2-propyn-1-yloxy)-quinolino[7,8-h]quinoline 

(Q13) ................................................................................................................ 160 

Figure C-21:  HMQC (top) and COSY (lower) spectra of 4-chloro-9-(2-propyn-1-yloxy)-

quinolino[7,8-h]quinolin-4(1H)-one (Q13) ...................................................... 161 

Figure C-22:  1H NMR of 4-bromo-9-(pyridin-4-yl)quinolino[7,8-h]quinoline (Q14) ............. 162 

Figure C-23:  13C NMR of 4-bromo-9-(pyridin-4-yl)quinolino[7,8-h]quinoline (Q14) ............ 163 

Figure C-24:  HSQC (top) and COSY (lower) spectra of 4-bromo-9-(pyridin-4-yl)quinolino[7,8-

h]quinoline (Q14) ............................................................................................. 164 

Figure C-25:  HMBC (top) spectrum of 4-bromo-9-(pyridin-4-yl)quinolino[7,8-h]quinoline 

(Q14) ................................................................................................................ 165 



xvi 

 

Figure C-26:  1H NMR spectrum of 9-(2-propyn-1-yloxy)-1,4,9,12-tetrahydro-4,9-dioxo-2,11-

dimethylester-quino[7,8-h]quinoline-2,11-dicarboxylic acid (Q15) ................ 166 

Figure C-27:  13C NMR spectrum of 9-(2-propyn-1-yloxy)-1,4,9,12-tetrahydro-4,9-dioxo-2,11-

dimethylester-quino[7,8-h]quinoline-2,11-dicarboxylic acid (Q15) ................ 167 

Figure C-28:  HMQC (top) and COSY (lower) spectra of 9-(2-propyn-1-yloxy)-1,4,9,12-

tetrahydro-4,9-dioxo-2,11-dimethylester-quino[7,8-h]quinoline-2,11-

dicarboxylic acid (Q15) .................................................................................... 168 

Figure C-29:  1H NMR spectrum of a boronic anhydride-based ligand (compound 3) ......... 169 

Figure C-30:  11B NMR spectrum of a boronic anhydride-based ligand (compound 3) in CDCl3. 

External BF3.Et2O standard used. .................................................................... 170 

Figure C-31:  IR spectrum (ATR) of a boronic anhydride-based ligand (compound 3) ......... 171 

Figure C-32:  1H NMR spectrum of 2-hydroxy-5-(3-pyridyl)-benzaldehyde oxime (L1) ........ 172 

Figure C-33:  13C spectrum of 2-hydroxy-5-(3-pyridyl)-benzaldehyde oxime (L1) ................ 173 

Figure C-34:   HMQC (top) and COSY (lower) spectra of 2-hydroxy-5-(3-pyridyl)-benzaldehyde 

oxime (L1)…………………………………………………………………………………………………….174 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



xvii 
 

List of Tables 

Table 1-1:  Calculated N···N distances (neutral structures) and pKa (conjugate acids) of QQ 

(left) and coordination compound 623559-12-6 (right). Data published in Bucher 

et al.76 ................................................................................................................ 27 

Table 4-1:  Experimentally determined pKaH, calculated proton affinities (PA), gas-phase 

basicities (GB) calculated pKaH and helical torsional twists of quinolino[7,8-

h]quinoline derivatives (in their neutral states). ............................................... 90 

Table 4-2:  Comparison of QQ basicity and sum of electron withdrawing effects using the 

quantity ΔVc. *Experimental pKaH values are listed for all except compound Q18, 

which is computationally derived. ..................................................................... 93 

Table 4-3:  Calculated data for theoretical QQ derivatives. ................................................ 95 

Table 5-1:  Selected structural properties of calculated QQ structures. Angles and distances 

calculated using Olex2. .................................................................................... 104 

Table 5-2:  Calculated gas phase basicities (GPB) and proton affinities (PA) of calculated QQ 

derivatives, where QQ represents quinolino[7,8-h]quinoline. The substituents 

are attached at the 4 and 9 positions. Sorted in order of descending GPB. .... 109 

Table 6-1:  Summary of all complexes published to date involving quinolino[7,8-h]quinoline 

derivatives (excluding those only published in patents).79, 133-134 .................... 112 

Table 6-2:  Selected QQ derivative complexation attempts .............................................. 113 

Table 6-3:  QQ derivatives sent to Germany for Beryllium coordination .......................... 118 

Table 6-4:  Angles and distances associated with halogen bonding in Be-QQ(OH)2 and 

complex naming key (right) ............................................................................. 120 

Table 6-5:  Selected Distances (in Å) of QQ Complexes. Blue represents distances shorter 

than (or equal to) the corresponding distance in neutral QQCl2 (4,9-

dichloroquinolino[7,8-h]quinoline, Q3) while orange represents greater length. 

The ‘NCCCN plane’ represents the plane formed by the 5 atoms of the central Q 

derivative binding pocket. ............................................................................... 121 

Table A-1:  Crystal data and structure refinement for 4,9-di(pyridin-4-yl)quinolino[7,8-

h]quinoline. ...................................................................................................... 137 

Table A-2:  Bond Lengths for 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline ...................... 138 

Table A-3:  Bond Angles for 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline ....................... 138 

Table B-1:  Crystal data and structure refinement for 9-methoxyquinolino[7,8-h]quinoline-

4(1H)-one. ........................................................................................................ 139 

Table B-2:  Bond Lengths for 9-methoxyquinolino[7,8-h]quinoline-4(1H)-one ................. 140 

Table B-3:  Bond Angles for 9-methoxyquinolino[7,8-h]quinoline-4(1H)-one ................... 140 

Table D-1:  Bond lengths and changes of neutral and protonated structures of Chapter 5. 

Lengths and length changes given in Å. ........................................................... 175 

Table D-2:  Free energies and enthalpies of computational structures (Chapter 5) used for 

gas phase basicity and proton affinity calculations. ........................................ 176 

Table E-1:  Crystal data and structure refinement for [BeBr(MeCN)(QQ(OH)2)]Br. .......... 177 

Table E-2:  Selected bond lengths of the Be-QQ(OH)2 crystal structure ........................... 178 

Table E-3:  Selected angles of Be-QQ(OH)2 structure ........................................................ 178 

 

 



xviii 
 

Abbreviations 

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

B3LYP 3-parameter hybrid Becke exchange/Lee-Yang-Parr 

CCDC Cambridge Crystallographic Data Centre 

COSY Correlation Spectroscopy 

DCE Dichloroethane 

DCM Dichloromethane 

DEPT Distortionless Enhancement by Polarisation Transfer 

DMAD Dimethyl acetylenedicarboxylate 

DMAN 1,8-Bis(dimethylamino)naphthalene 

DMF Dimethylformamide 

DMSO-d6 Deuterated dimethylsulfoxide 

ESI Electrospray Ionisation 

G09 Gaussian 09 version: ES64L-G09RevD.01 

HFAC 1,1,1,5,5,5-Hexafluoropentane-2,4-dionate 

HMPN 1,8-Bis(hexamethyltriaminophosphazenyl)naphthalene 

HMQC Heteronuclear Multiple Quantum Coherence 

HR High resolution 

IHB Intramolecular Hydrogen Bond 

IR Infrared 

LR Low resolution 

Me Methyl Group 

MESP Molecular Electrostatic Potential 

MS Mass spectrometry 

NOESY Nuclear Overhauser Effect Spectroscopy 

QQ Quinolino[7,8-h]quinoline 

RT Room Temperature 

TFA-d Deuterated trifluoroacetic acid 

TMGN 1,8-Bis(tetramethylguanidino)naphthalene 

TMPN Dimethyl-((naphthalene-1,8-diyldi(nitrilo))bistrimethyl 

phosphorane)) 

XPhos 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl 

 

 

 

 

 



xix 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 





1 
 

Chapter 1 -  Introduction  

1.1 -  Proton Sponges 

In 1968 Alder et al. published a paper on 1,8-bis(dimethylamino)napthalene (DMAN), 

which promoted a new field of basic-compound studies.1-3 This compound was 

designated the first Proton SpongeTM,4 a neutral organic superbase with a pKa (of the 

conjugate acid) of ~ 12.2 in water and 18.63 in acetonitrile.5-6 
 

 

Figure 1-1: 1,8-Bis(dimethylamino)naphthalene (DMAN) - The original Proton SpongeTM 

The relatively simple structure of DMAN is shown in figure 1-1, where the structural 

aspects that impart its superbasic properties may not be immediately apparent. The 

lone pairs of electrons on the two nitrogen atoms are in close proximity, which results 

in electrostatic repulsion and a significant strain on the neutral molecule. Protonation 

effectively reduces this strain and flattens the helical-twisted neutral structure (19.9° 

torsion) into a planar conformation (fig. 1-2). This is accompanied by a reduction in N···N 

distance from 2.804 Å to 2.574 Å. The hydrogen bond is strongly shielded by the methyl 

groups, so although DMAN has a high thermodynamic basicity, both its kinetic basicity 

and N-nucleophilicity are low – the latter an advantage for avoiding reaction 

interference by base coordination, such as in transition metal catalysed reactions or 

those with components sensitive to Lewis bases.1, 7   

 

 



2 
 

 

Figure 1-2: X-ray structures of DMAN in neutral (left) and protonated (right) forms. Images 

generated in Olex28 from CCDC files DMANAP019 and CEJGUU10 with 50% ellipsoids. Counter-

ion (CF3O3S-) omitted from DMANH+ (right) for clarity. 

The discovery of this structural phenomenon led to the development of new neutral 

organic superbases - the definition used here is of ‘a base with a pKa of the conjugate 

acid greater than that of the proton sponge DMAN’3, 11 - with varied chemical moieties. 

For example some, like triguanidinophosphazene (fig. 1-3B) and N4,N4,N5,N5-

tetramethyl-1,8-dioxide-arsenino[2,3-b]arsenin-4,5-diamine (fig. 1-3C), feature 

phosphazene and aromatic pnictogen oxide groups respectively.11-14  
 

 

Figure 1-3: Structures of triguanidinophosphazene (B) N4,N4,N5,N5-tetramethyl-1,8-dioxide-

arsenino[2,3-b]arsenin-4,5-diamine (C).  

This new subset of organic superbases are, like the parent DMAN, known as proton 

sponges. The exact parameters defining the category of ‘proton sponges’ varies,1, 15 

however molecules are commonly classed as such with a superbasic pKa (as above) 

combined with the feature enhanced basicities resulting from the formation of 

intramolecular hydrogen bonds upon protonation, often with the “destabilising overlap 

of the lone pair of electrons on adjacent nitrogen atoms within the molecule”15.16 The 

pKa values of the conjugate acids of two newer proton sponges, TMGN17 and HMPN18, 

are shown in figure 1-4. As in DMAN (fig. 1-4A), these are also derivatives of 1,8-



3 
 

diaminonapthalene, however the structural alterations resulted in significantly 

increased basicities: In TMGN (fig. 1-4D), this is contributed to by the inherent basicity 

of the guanidinium moieties, and high strength of the resulting intramolecular hydrogen 

bond (IHB). The conjugate acid of HMPN also has a strong IHB, and this combines with 

the reduction of the significant steric strain of the bulky groups of the neutral molecule 

to give a pKa of 29.9 (fig. 1-4E).  

 

Figure 1-4: pKa values in acetonitrile for the conjugate acids of DMAN (A), TMGN (D) and HMPN 

(E).16-18  

See chapter 4 for more information on TMGN and HMGN. 

 

1.2 -  Coordination potential of diamines and proton sponges 

Proton sponges containing nitrogen proton accepters that form intramolecular N-H···N 

hydrogen bonds are typically stronger bases than the O-H···O equivalents, so diamines 

are a common feature.16  

 

Throughout literature, diamines of various forms are one of the most common bidentate 

metal-binding moieties in a range of chemical fields, from 2,2’-bipyridine in luminescent 

compounds to the salen ligands widespread in catalysis. They are also present in large 

coordination structures that show structural and/or functional changes in response to a 

series of stimuli, such as light (fig. 1-5), mechanical or pH.19 
 



4 
 

 

Figure 1-5: Example of a light-responsive coordination complex (F) involving bidentate 

diamine binding sites. Adapted with permission from Mobian et al.20 Copyright 2004 Wiley-

VCH. 

Coordination cages are a type of large, multinuclear coordination structure in which 

bidentate, diamine ligands are a common feature. They consist of organic linkers 

connected by metallic components to form discrete structures with well-defined 

cavities. This is a growing field and several excellent reviews have been published 

showcasing recent developments.21-33 Methods of construction are being developed to 

widen the functionality of coordination cages, with applications of these including: 

research into uses of cages from elucidation of reaction mechanisms,34 potential drug 

delivery systems,35 to a more recent focus on catalysis (fig. 1-6).36-37 The unique 

microenvironments within cages provide a wealth of opportunities37 – these include  

effects of increased local concentrations by enclosing reaction components within the 

cage ‘walls’ of a cage and manipulation of components into orientations that may 

otherwise be unfavourable in solution, and thus induce the formation of uncommon 

synthetic conformations. Research into the addition of stimuli-responsive properties is 

ongoing, and has the potential to significantly enhance cage function.19 
 



5 
 

 

Figure 1-6: Example of a multistep catalysis (right) by a hexahedral coordination cage (G)  

featuring a ligand (H) with bidentate diamine binding sites.36 

Given the significant structural changes observed during protonation in proton sponge 

materials, there is interest in finding proton sponge organic superbases that could also 

act as ligands, as these could be used to create stimuli-responsive metal complexes.11 

 

Although numerous proton sponges contain bidentate diamine moieties similar to those 

used in coordination structures, the ability of many of them to chelate metal ions is as 

yet in the early stages of exploration, and has been hampered by obstacles. Sixteen years 

passed after the synthesis of DMAN before a transition metal complex involving the 

molecule (with Pd(II)) was published - to date it is the only one reported (fig. 1-7).38 In 

part, the lack of complexes is caused by the very aspects of DMAN that contribute to the 

high pKa. The N-methyl groups that provide hydrophobic shielding to the hydrogen bond 

that forms also sterically hinder the coordination process, significantly reducing this 

diamine’s coordination potential. 

 

In contrast to the reduced N···N separation and planar conformation of DMAN observed 

on protonation (fig. 1-2), the Pd(II)-coordinated DMAN showed significant increases in 

both the torsional twist (34.7° vs. 19.9°) and N···N distance (2.94 Å vs. 2.80 Å) while the 

  

 

G 

H 



6 
 

metal ion is located 0.862 Å above the NCCCN plane (fig. 1-7). The complex has low 

thermodynamic stability, and the metal ion can be displaced by water.  
 

 

Figure 1-7: Coordination of a Pd(II) ion by DMAN (I), completed with a 1,3-diphenylpropane-

1,3-dionato-O,O'- ligand. Hydrogen and counter-ion (HFAC-) omitted for clarity. Image 

generated in Olex28 from CCDC file OBEJIP38 with 50% ellipsoids.  

Publications featuring a metal ion coordinated to the proton binding site of ‘proton 

sponges’ are relatively few.39-40 Several of these chelating sponges are derivatives of 

DMAN with the foundation 1,8-diaminonapthalene core, such as TMPN (conjugate acid 

pKa 29.3 in MeCN), which has formed the Ga(III) and Al(III) TMPN metal complexes in 

figure 1-8. These show the coordinated ions to be sitting similarly out of plane ((1.207 Å 

and 1.11 Å) above the NCCCN plane respectively) but showing significantly more planar 

ligand structures than the Pd(II) DMAN complex (fig. 1-7) with only slight torsional twists 

(1.47° and 2.64°, fig. 1-8).40 
 

I 



7 
 

 

Figure 1-8: Complexes of TMPN with Ga(III) (J) and Al(III) (K) in front (top) and side-plane 

(lower) views. Hydrogen omitted for clarity. Images generated in Olex28 from CCDC files 

BIXQEG and BIXQAC with 50% ellipsoids.40 

Towards the opposite end of the scale of coordination publication numbers to DMAN 

and other proton sponges is the aromatic bidentate diamine 1,10-phenanthroline 

(phen) (fig. 1-9L). Derivatives of this are ubiquitous in coordination chemistry: A 

SciFinder structural search featuring the phen substructure with a centrally-bound metal 

ion produces more than 83000 results.41 However, unsubstituted phen only has a pKa of 

4.27, falling far short of the basicity required for the classification of a ‘proton sponge’. 

 

This gap between proton-sponges and coordinating ligands could be bridged with other 

promising aromatic diamines: such as derivatives of the proton sponge quinolino[7,8-

h]quinoline (<20 SciFinder metal complex hits, fig. 1-9QQ).41  

 

J K 



8 
 

1.3 -  A New Type of Proton Sponge – quinolino[7,8-h]quinoline 

 

Figure 1-9: Structures of DMAN (A), 1,10-phen (L) and quinolino[7,8-h]quinoline (QQ). 

This new structure was the first example of a proton sponge that lacks the type of steric 

alkyl shielding observed in the original DMAN proton sponge (1,8-

bis(dimethylamino)naphthalene) and many the same that have been developed on that 

naphthalene structure. As the shielding contributed to reduced proton exchange rates, 

the usefulness and potential of QQ, a kinetically active organic superbase, in chemical 

reaction applications is increased.42 The ring structure of QQ allows for a wide range of 

functionalisation, and thus potential applications, such as: development of synthons for 

supramolecular chemistry,37 with inclusion of multiple binding sites; small ion 

chelation;43 or novel compound synthesis.  

 

As described in 1.1, the molecule DMAN has a N···N separation of 2.804 Å;44 whereas 

the two nitrogen atoms of QQ are forced into an even closer proximity at 2.7271(18) Å45 

by the rigid ortho-fused ring structure. This causes a destabilising overlap of electron 

lone pairs; which manifests as a significant helical distortion that disrupts the planarity, 

and thus aromaticity. The binding of a single proton in the central cavity reduces the 

repulsion and removes the strain, flattening the rings into a planar formation and thus 

some of the QQ derivatives are considered superbasic, placing them in the category of 

proton sponges.41 Computational analysis gives the helical distortion of derivative 4,9-

dichloroquinolino[7,8-h]quinoline (Q3) to be 21.1˚, which is closely matched to the 

observed single crystal X-ray experimental data of 20.02(9)˚ for crystals grown under 

anhydrous conditions (fig. 1-10). Once singly-protonated, planarity in the crystal 

structure is observed (fig. 1-10).41   

 



9 
 

 

 

Figure 1-10: 4,9-dichloroquinolino[7,8-h]quinoline (Q3) structures in neutral (left) and 

protonated (right) forms. Images generated in Olex28 from CCDC files PANFOB and PANFUH 

with 50% ellipsoids.41 Counter-ion (BF4
-) omitted from (right) for clarity. 

The structure of unsubstituted, non-protonated quino[7,8-h]quinoline was initially 

reported to exist as planar,45 but further data analysis of the X-ray crystal data suggested 

a hydrogen-bonded bridging water molecule acted in a similar role to a proton, reducing 

the strain and flattening the compound.11 

 

The drive to stabilise the N···N interaction also gives rise to stabilised keto-enol 

tautomerism in QQ derivatives containing oxo groups in 4 and/or 9 positions. Although 

the initial QQ synthesis reported the diketo structure of Q2 as seen in figure 1-11, IR 

spectroscopic evidence supports the keto-enol tautomer (fig. 1-11) as the major form.41 

This is supported by calculations that have also shown this tautomer being more stable 

than both the 4,9-dihydroxy and diketo tautomers (fig. 1-11) by 17.6 and 12.0 kcal mol-

1 respectively (B3LYP/6-31+G(d,p)).11 
 

 

Figure 1-11: All tautomers of quinolino[7,8-h]quinoline-4,9-(1H,12H)-dione (Q2).  

The analogous keto-enol tautomers are also present in equilibrium for Q1 (fig. 1-15), 

however this compound is depicted as the diketone tautomer for consistency with 

literature.42, 46  

 

Further effects of the keto-enol tautomerism of QQ derivatives are discussed in chapter 

2. 

Q3 



10 

 

1.3.1 - Synthesis of Quinolino[7,8-h]quinoline 

The first structurally confirmed synthesis of the proton sponge quinolino[7,8-

h]quinoline (QQ) was published in 1987 by Zirnstein and Staab.42  Following the synthesis 

of DMAN, this research group was one of several that explored the base potential of 

other aromatic backbones with reduced N···N distances (such as 4,5-

bis(dimethylamino)phenanthrene) that could be capable of forming intermolecular N-

H···N bonds with an optimised geometry (linear).3, 47  

 

Prior to the Staab synthesis, however, two other QQ syntheses were reported, both by 

attempts at double Skraup condensation, the well-established methodology used for 

the synthesis of quinolines. The Skraup reaction involves several steps, shown in figure 

1-12. These include glycerol dehydration to give acrolein, which then undergoes 

nucleophilic addition to the aniline derivative (fig. 1-12(i)). This precedes protonation, 

electrophilic attack of the aromatic ring by the aldehyde, cyclisation  (fig. 1-12(ii - iv)), 

and aromatisation (fig. 1-12(v)).48 

 

 

Figure 1-12: Skraup reaction (top) and mechanism (partial) to form quinoline.48 



11 
 

The first, reported in 195049, utilised 1,8-diaminonapthalene, however this was later 

noted by the authors to be an incorrect product identification.50 Dufour et al. (1967) also 

tried to replicate the 1950 procedure, and, when that was unsuccessful, reported the 

synthesis of quinolino[7,8-h]quinoline from 1,8-diacetaminonapthalene: however 

elemental analysis, a melting point and the formation of a picrate salt was the only 

characterisation provided.51  

 

Attempts were made to use the 1967 research methods for QQ synthesis by Sauvage 

and coworkers in 1985, however successful replication was not achieved. Researchers 

found that instead of the desired double Skraup condensation, addition across the two 

diamide nitrogen atoms occurred, along with the C-C bond formation to produce 2-

methyl-diazapyrene (2-mdp), with confirmation of identity by mass and 1H NMR 

spectroscopies (fig. 1-13N).52  
 

 

Figure 1-13: Attempted formation of QQ by Skraup condensation by Sauvage and coworkers 

that resulted in formation of 2-mdp (N).52   

The reaction to form 2-mdp from 1,8-diacetaminonapthalene (fig. 1-13) involves the 

formation of a 6-membered perimidine ring, then a Bally-Scholl type reaction.52 This 

begins with the conjugate addition of acrolein (formed by glycerol dehydration in the 

first step of the Skraup condensation), then cyclisation, water loss and aromatisation 

(fig. 1-14).53 



12 
 

 

Figure 1-14: Proposed mechanism of formation of 2-mdp (N) from 1,8-diacetaminonapthalene 

(M). 

 



13 
 

1.3.1.1 -  Staab (1987) and Plieger (2012) QQ syntheses 

 

Figure 1-15: Initial quinolino[7,8-h]quinoline synthesis by Zirnstein and Staab, 1987.11,54 

Reaction conditions and yields: (i) DMAD, MeOH, RT, 71%; (ii) Ph2O, 240 °C, 64%; (iii) (a) KOH, 

100 °C; (b) HCl, H2O, 93%; (iv) 370 °C, 10-5 torr 76%; (v) POCl3, 130 °C, 81%; (vi) Pd/C, HOAc, 

NaOAc, 39%.  

The confirmed synthesis by Zirnstein and Staab, as presented in figure 1-15, took seven 

steps, starting from 1,8-diaminonapthalene (O) and dimethyl acetylenedicarboxylate 

(DMAD) (fig. 1-15). 

 

The product (P) of the first reaction (fig. 1-15(i)) was thermally cyclised and subject to 

an alkaline hydrolysis (Q1”) before undergoing a high temperature low pressure 

decarboxylation to produce 9-hydroxyquino[7,8-h]quinolin-4(1H)-one (Q2). 

Subsequently, Q2 was subject to halogenation with concomitant aromatisation of the 

second ring to produce the dihalide Q3, which was converted into pure unsubstituted 

quinolino[7,8-h]quinoline (QQ) by catalytic hydrogenation. The first two steps modified 

methodology developed by Honda et al. (1983)46  

 

Subsequent research by other groups was slow. Zewge et al.55 synthesised 

quinolino[7,8-h]quinoline-4,9-(1H,12H)-dione (fig. 1-15, Q2) as part of a wider study 

looking at quinolone heterocycle synthesis in 2007, but that, and a study by Wüstefeld 

et al.56 on metal complexes, were the only new non-theoretical papers involving QQ 

published for 25 years after the initial Staab synthesis.42 

Q3: R=Cl, QQ: R=H                                                         Q2 

     Q1: R=Me, Q1”: R=H  



14 
 

 

A breakthrough in quinolino[7,8-h]quinoline research was made by the Plieger group, 

with a change in the synthetic procedure published in 2012 that improved research 

accessibility to the derivatives.41 Amongst modifications that improved several steps in 

the pathway, the bottleneck two-step low pressure/high temperature de-esterification 

was altered to a milder synthetic route, based on the work of Strauss and Trainor.57 The 

introduction of hydrothermal methods with a pressurised reaction vessel removed a 

synthetic step, resulting in a reliable ‘one-pot’  reaction (fig. 1-15, Q1Q2) with 

comparable yields and reduced time cost. Smaller amounts of Q2 could also be obtained 

in microwave reactor reaction, however the scale was much more limited (0.1 g of Q1 

vs. 0.8 g).41 

 

Following this publication, both the frequency of publications involving QQ, and the 

number of overall QQ structures published has increased (fig. 1-16).  
 

 

Figure 1-16: Total QQ structures (with assigned CAS numbers) published 1987-2019. Data 

points indicate years in which one or more QQ-derivative-containing publications were 

released. Data includes complexes and salts, and those present only in patent literature. Some 

of these publications are discussed in the following sections.  

 

1.3.2 - Naming and numbering of quinolino[7,8-h]quinoline derivatives 

IUPAC regulations prior to 2013 described the prefix quino- as an acceptable short form 

of quinoline for the ortho-fused substituent heterocycle,15, 41-42, 45-46, 52, 56, 58-59 and this is 

0

50

100

150

200

250

1987 1992 1997 2002 2007 2012 2017

N
u

m
b

er
 o

f 
u

n
iq

u
e 

Q
Q

 s
tr

u
ct

u
re

s

Publication Year



15 

 

commonly used in past publications involving QQ. Updated regulations state this prefix 

to be no longer accepted nomenclature:60 Quinolino- will be used hereafter. 

Quinolino[7,8-h]quinoline naming and numbering is shown in Figure 1-17.  

 

 

Figure 1-17: Nomenclature of quinolino[7,8-h]quinoline (left) and numbering scheme for 

atoms/substituents (right).  

Described by Rowlands et al., the naming system is based on the fused quinoline 

substituent and parent ring structures, with the fusion locant described as 7,8-h: they 

are joined across the h-face between atoms 7 and 8. For the correct numbering of this 

type of fused-ring system, the compound is positioned to give the greatest number of 

rings first laterally, then turned so the maximum number of rings are above and to the 

right of this row. Numbering is assigned clockwise from the top right ring, other than the 

bridgehead atoms which are labelled with letters and the number of the preceding 

numbered atom as shown, beginning at the most counter clockwise atom (nitrogen 

atom).11, 61-63  

 

1.3.3 - Derivatisation of quinolino[7,8-h]quinoline 

 

Figure 1-18: Quinolino[7,8-h]quinoline substituent numbering. 



16 
 

A substructure search of the SciFinder database revealed a total of 33 structures with 

the QQ core published (outside of patents) across 14 publications from 1987-2019. 

These 33 are based on ~ 14 organic derivatives in a variety of complex and salt forms. 

Structures containing the QQ substructure but with additional fused rings (2 or more 

bridging atoms) are discussed in 1.3.4. 

 

A further ~178 QQ structures can be found in the patent literature. These are not 

detailed in this section. Additionally, derivatives first published in Rowlands et al. are 

generally excluded from this chapter as the majority were produced in the course of this 

project.11 

 

Quinolino[7,8-h]quinoline shows similarities to its components, the aromatic 

heterocycle quinoline, with reflected regioselectivity and substitution patterns, making 

the wealth of quinoline chemistry a useful resource in the development of quinolino[7,8-

h]quinoline pathways. However, there are important differences that affect the 

synthetic chemistry involved - including the basicity of QQ. Without the structural 

factors (discussed earlier) that give QQ the properties of a proton sponge, quinoline is a 

weak base, with a pKa (conjugate acid) of only 4.9, affecting comparative interactions 

with protic or base-sensitive reaction components.64 This structure also makes quinoline 

a better nucleophile, as the nitrogen atom of quinoline is less sterically hindered than 

those in QQ. Additionally, the solubility of QQ derivatives are often more limited than 

those of quinoline, of which the core structure is soluble in many organic solvents as 

well as alcohols and, to a slight extent, water.65  

 

1.3.3.1 -  4,9-Derivatisation 

Research has shown the 4- and 9- positions of the QQ ring are the easiest places for 

functionalisation and the formation of new derivatives. The first quinolino[7,8-

h]quinoline derivative synthesised was by Staab et al. in 198742 - 4,9-

dichloroquinolino[7,8-h]quinoline (Q3), which was formed during the penultimate 

reaction of the QQ synthetic pathway.  

 



17 
 

Along with other halogen equivalents, in particular 4,9-dibromoQQ, this is an effective 

and versatile starting point for many other reactions, including Suzuki–Miyaura 

coupling, simple substitutions, amine formation etc. 11 

 

The Plieger Group, with the altered core synthetic route, synthesised several different 

derivatives in this manner, ranging from tertiary amines to methoxides such as 4,9-

dimethoxyquinolino[7,8-h]quinoline (Q20).15 A number of different 4,9-QQ derivatives 

have also been synthesised (under CN patent) by Qiu, Tang, Li, Fan, Duan, Ren and 

Xueyan who focussed on tertiary amines with large bulky aromatic groups and utilised 

the methodology of the Plieger Group.15, 66 
 

 

Figure 1-19: Selected examples of published 4,9-substituted QQ derivatives.11, 15 

During some of the attempted 4,9-halogen substitution reactions, side products were 

observed in which one of the halogen atoms was unexpectedly substituted with an oxo 

group.15 Researchers hypothesised this was due to the proton sponge properties (strong 

basicities) of the compounds giving rise to stabilised keto-enol tautomerism following 

hydroxyl group substitution.  

 

Consequently, this stability means kinetically less favourable 4,9-substitution reactions 

often result in non-symmetric compound formation, with one halogen group reacting as 

desired while the other is converted back to an oxo- group, allowing the tautomer of the 

type figure 1-11 (keto-enol) to form. This behaviour creates an opportunity;  an exciting 

new avenue of research for the synthesis of non-symmetric derivatives is opened up, 



18 
 

with the second position able to be substituted by a different group - something that is 

typically difficult to achieve with symmetrical starting materials.  

 

The opportunities and complications arising from this phenomenon of keto-enol 

tautomerism, and from the high basicity of QQ derivatives, are discussed further in the 

synthesis section (chapter 2).  

 

1.3.3.2 -  2,11-Derivatisation 

Functionalisation of the 2 and 11 positions of quinolino[7,8-h]quinoline can be achieved 

by forgoing the de-esterification step (fig. 1-15, Q1Q2) to leave the methyl esters 

attached, while the remaining ring positions can theoretically still be accessed by the 

aforementioned methods. A crystal structure was obtained of such a compound (fig. 1-

20, 2,11 = COOMe, 4,9 = Cl),15 however subsequent alteration of either the ester or 

chloride groups is as yet unsuccessful.54  
 

 

Figure 1-20: Crystal structures of dimethyl 4,9-dichloroquinolino[7,8-h]quinoline-2,11-

dicarboxylate (Q16) and N-[2-(methylthio)benzo[h]quinolin-10-yl]acetamide (U). Counter-ion 

(BF4
-) not shown for clarity (left). Images generated in Olex28 using CCDC files FEJXID and 

FEJXEZ with 50% ellipsoids.15  

In 2004 Panda et al. reported a new pathway to 2-(methylthio)quinolines by a double 

Skraup cyclisation,67 which could have provided an alternate functionalisation option, 

however the chemistry was unable to be repeated despite several attempts – it was 

suspected that the reaction does not proceed further than single cyclisation and 

acetylation to produce N-[2-(methylthio)benzo[h]quinolin-10-yl]acetamide (fig. 1-21U), 

Q16 U 



19 

 

made favourable by the formation of the intramolecular hydrogen bond bridged 

between the central nitrogen atoms of this product. This compound was obtained in 

small amounts and was confirmed by X-ray crystallography (fig. 1-20U).11, 15 As the 

purification methods described by the authors are incompatible with those typically 

successful for QQ, and as no analytical data was presented, the initial reported QQ 

synthesis may have been incorrect.54 

 

 

Figure 1-21: Attempted synthesis of QQ from 1,8-diaminonapthalene (O) and 3-

bis(methylthio)acrolein by Skraup condensation, resulting in the formation of N-[2-

(methylthio)benzo[h]quinolin-10-yl]acetamide (U) instead of the desired disubstituted 

product (V). 

 

1.3.3.3 -  6,7-derivatisation 

The 6,7 positions on the QQ ring can be functionalised by a standard HNO3/H2SO4 

nitration of 4,9-dichloroquinolino[7,8-h]quinoline (fig. 1-22, Q3), which occurs with 

good regioselectivity54 – a substitution pattern that matches that of the nitration of 4-

hydroxyquinoline.68 

 

 

Figure 1-22: Nitration of 4,9-dichloroquinolino[7,8-h]quinoline (Q3).54 



20 
 

However, although NMR and mass spectroscopic evidence very strongly supported the 

formation of 4,9-dichloro-6,7-dinitroquino[7,8-h]quinoline (fig. 1-22, Q18), X-ray 

crystallographic data collected on crystals grown in CH3CN revealed that over some time 

period this compound had partially hydrolysed to 4-chloro-9-oxo-9,12-dihydro-6,7-

dinitroquino[7,8-h]quinoline (fig. 1-23), made favourable by the keto-enol tautomerism 

(discussed in chapter 2).11  
 

 

Figure 1-23: X-ray structure of 4-chloro-9-oxo-9,12-dihydro-6,7-dinitroquino[7,8-h]quinoline 

(Q21).11 Generated in Olex28 with 50% ellipsoids.  

 

1.3.3.4 -  5,8-derivatisation 

To date, no QQ structures containing modifications at the 5 and 8 positions have been 

published (excluding fused ring systems).41 As with quinoline, nucleophilic substitution 

occurs more readily on the electron poor pyridine ring, and electrophilic aromatic 

substitution on the benzene ring. However, resonance structures can be drawn that give 

the 5 and 8 positions partial positive character, thus reducing the favourability of 

electrophilic attack (fig. 1-24).  



21 
 

 

Figure 1-24: Resonance structures of QQ showing the partial positive character of positions 5 

and 8. 

This is reflected in published quinoline structures – SciFinder substructure searches of 

quinoline derivatives with single non-hydrogen ring substitutions gives the lowest 

number of results for the 5 position (followed by the 3<6<4<2 positions).69  

 

1.3.4 - Other organic compounds with the QQ substructure  

Selected publications outside of patent literature feature compounds with a QQ 

substructure, but not classed as QQ derivatives for the purposes of this project, which 

show one or more of the core ring positions fused to another ring. These include large 

extended polycyclic aromatic hydrocarbons, where the substructure is a small part of a 

larger system with covalent carbon links between the nitrogen positions and across ring 

carbons,70 or aza-fullerenes.71 A DFT study published Peran et al. examined the 

superbasic properties of smaller polycyclic ‘croissant-like’ compounds like the example 

shown in figure 1-25 (W), which have the QQ core but contain rings across the 2,3 and 

10,11 carbon atoms of QQ. The synthesis of these compounds was not reported.72 



22 
 

 

Figure 1-25: Examples of other organic compounds with the QQ substructure, with a polycyclic 

'croissant-like' compound (W) and acequinolino[7,8-h]quinoline (AceQQ). 

Of the other QQ  substructure-containing compounds in literature, the one with the 

most similar structure to QQ, is acequinolinoquinoline (fig. 1-25), a strong base with a 

conjugate acid pKa  of 7.9 in DMSO, greater than DMAN at 7.5  (in DMSO). The synthesis 

of this compound was first reported in 1968 by Dufour et al. by a Skraup synthesis,73 but 

the compound captured little research interest until the recent modified procedure 

published by Pozharskii et al. (2019).59 Researchers used a Skraup reaction with glycerol, 

sodium m-nitrobenzenesulfonate, FeSO4.7H2O and H2SO4 to form aceQQ in 58% yield 

(purified by column chromatography). A mechanism for this procedure is given in figure 

1-26. 

 

The ethyl ring carbon linker significantly increases the rigidity of the heterocycle, which 

increases fluorescence over the more flexible QQ, however may reduce metal ion 

coordination potential. While the more direct synthesis of aceQQ is more efficient than 

QQ’s, the pathway means avenues for ring functionalisation are reduced, with no 

derivatives yet reported outside of patent literature.59  



23 
 

 

Figure 1-26: Proposed mechanism for the formation of aceQQ. 

 

1.3.5 - QQ Coordination 

The early synthetic difficulties of the original de-esterification (fig. 1-15) are likely one of 

the reasons for the enormous gap between publications involving phen and of QQ, and 

why 14 years passed between the initial synthesis of QQ by Staab et al.42 and the 

publication of the first QQ coordination complex – which was also reported to be the 

first successful attempt to make stable coordination complexes with any proton 

O 



24 
 

sponge.56 The Wüstefeld group published transition metal complexes of 4,9-

dichloroquinolino[7,8-h]quinoline (Q3) in 2001.56 They synthesised and obtained crystal 

structures of platinum and rhenium QQ complexes (fig. 1-27) with interesting structural 

insights.  

 

The short N···N distance (2.7683(16) Å)41 of 4,9-dichloroquinolino[7,8-h]quinoline (Q3) 

creates a significantly different coordination environment to the much more spacious 

phen. Unlike phen, complexation of the large metal ions Pt(II) and Rh(II) required 

significant bowing of the core ring structure (0.742 Å and 0.498 Å respectively), and the 

ions were forced out of the plane at distances of 1.43 and 1.42 Å.56  
 

 

Figure 1-27: Pt and Re complexes of 4,9-dichloroquinolino[7,8-h]quinoline (Q3). Hydrogen 

omitted for clarity. Images generated in Olex28 using CCDC files ACEQAA and ACEPUT with 

50% ellipsoids.56 

The aforementioned lack of hydrophobic methyl shielding on the nitrogen atoms 

typically increases the thermodynamic stability of complexes formed.74 The type of 

structure achieved by the Wüstefeld group conferred high thermal stability on the 

complexes, with platinum-QQ (fig. 1-27) able to be heated to 380 °C for several days 

without decomposition. Additionally, the out of plane position makes the metal centres 

more reactive and accessible, opening up  the potential for interactions and reactions 

that may otherwise be blocked by the coordinated ligand, such as catalysis.  

 



25 
 

The metal ion positioning for the Wüstefeld QQ complexes is further out of the NCCCN 

plane than observed for the Ga(III) and Al(III) TMPN complexes described on page 6 (fig. 

1-8),  and for a similar TMPN(PtCl2) complex (1.29 Å) crystallised by Wild et al.,75 however 

the high temperature stabilities of these complexes have not been evaluated.   

 

Shaffer et al. synthesised and obtained X-ray crystallographic structures of boron 

difluoride chelates of both quinolino[7,8-h]quinoline (QQ) and the substituted 4,9-

dichloroquinolino[7,8-h]quinoline (Q3).41  The successful formation of these structures, 

with the small coordinated ion, along with the complexes of Wüstefeld et al.,56 makes 

the versatility of QQ ligands in accommodating ions of different sizes apparent. Unlike 

the Pt and Re QQ complexes, the relatively small boron atom fits well to the size of the 

chelation site, sitting only slightly above the mean plane and showing only minor ring 

bowing (fig. 1-28). 
 

 

Figure 1-28: Boron-chelates of 4,9-dichloroQQ (left) and QQ (right). Hydrogen and counter-

ions (BF4
-) omitted for clarity. Images generated in Olex28 using CCDC files PANGES and 

PANGAO with 50% ellipsoids.41   

A variety of bond length and spatial changes accompanied the coordination, including 

reduced distances between the N···N (reflecting both the accommodation of the small 

ion and the reduction in lone pair strain) and C13-C17 (flattening of torsional twist) atom 

pairs, and slight increases in C6-C7 distances (fig. 1-29(right)).  Similar changes can be 

observed with protonation instead of small-ion complexation, while coordination to 

larger metal ions (fig. 1-27) induce increased N···N and decreased C6-C7 distances in a 



26 
 

pincer-like action with a central pivot (fig. 1-29(left)).41 See chapter 5 for more detailed 

discussion of QQ bond length changes occurring upon protonation.  
 

 

Figure 1-29: QQ spatial changes associated with (left) coordination to large metal ions (M) 

such as Pt and Re and (right) protonation or coordination to smaller ions (Y) such as BF2.15  

Copper(II) complexes of 4,9-dichloroquinolino[7,8-h]quinoline (Q3) and pure 

unsubstituted QQ are closer in structure to the Pt and Re complexes, showing some 

bowing of the central aromatic ring structure and the Cu(II) ions residing above the plane 

(fig. 1-30).58  
 

 

Figure 1-30: Cu(II) complexes of 4,9-dichloroquinolino[7,8-h]quinoline (Q3, left) and 

quinolino[7,8-h]quinoline (QQ, right). Hydrogen and counter-ions removed for clarity. Images 

generated in Olex28 using CCDC files NIBSOI and NIBSIC with 50% ellipsoids.58 

 

 



27 
 

1.3.6 - Computational/Theoretical Studies  

A number of computational/theoretical studies that include quinolino[7,8-h]quinolines 

have been published. Bucher published one of the first in 2003.76 This calculated proton 

affinities, pKa values and some geometric parameters for a series of bases containing 

two (e.g. DMAN and QQ), three, and four nitrogen lone pairs to examine how that affects 

the basicity and other parameters. While QQ had a shorter N···N distance, the three to 

four nitrogen bridged bases had far greater basicities (example shown in table 1-1).  

 

Table 1-1: Calculated N···N distances (neutral structures) and pKa (conjugate acids) of QQ (left) 

and coordination compound 623559-12-6 (right). Data published in Bucher et al.76 

 

Some of the proton affinity values calculated in this paper were included in a later study 

(2010) by Bachrach and Wilbanks.77 They investigated a different type of superbase 

which had ‘arms’ containing atoms with electron lone pairs that could bend inwards, 

rather than those that were held in close proximity by a more rigid structure. The DFT 

calculated affinities of several of these were higher than that of QQ and the original 

DMAN proton sponge, indicating other types of compounds may form more effective 

superbase scaffolds than these early proton sponges.77 

 

In the following year, Horbatenko and Vyboishchikov published a study on 

intramolecular N-H···N hydrogen bonds in eight proton sponges, including QQ, through 

a variety of functionals and computational methods – this research indicated that the 

centrally bound proton in protonated QQ was largely delocalised.78 

 

 

 
 

N···N distance (pm) 274 343 

pKAH 19.2 26.0 



28 
 

1.3.7 - Patents – Organic Electronic Devices  

More than one patent has also been published with molecules containing the QQ core 

that look at their use in electronic devices, including one in 2010 by Shibata et al. 

investigating organic white luminescent devices,79 and another in 2011 by Stoessel et al. 

which focussed more on coordination compounds for electronic devices.80 Other 

patents involving QQ have included the topics of battery electrolytes.81 As these patents 

have not yet translated into other publications, further details of compounds involved 

will not be discussed. 

 

1.4 -  Beryllium Coordination 

 

Figure 1-31: Crystal structure of (Be(PhC(O)O)2)12 obtained by Müller and Buchner as an 

example of an existing beryllium complex.82 Image generated in Olex28 from the CCDC file 

YEZQAY. 

With the proven proton sponge and chelation abilities of QQ, it was theorised that QQ 

derivatives could be effective and selective chelators of beryllium metal ions (Be(II)). The 

small QQ chelation site should allow for coordination of Be(II), the smallest and hardest 

metal ion, without much distortion - similar to B(III) (fig. 1-28). 

 

Research into the interactions, chemistry, and coordination of beryllium compounds 

(fig. 1-31)  is an ongoing and developing field. Beryllium is an exceptionally useful metal 

with a wide range of applications based on its unique properties. This metal element has 



29 
 

a relatively low density (1.8 g/cm3) and high boiling point (2970 °C).83 It can be used to 

improve the electrical and thermal conductivity of copper and nickel in the form of an 

alloy, can impart high elasticity and be incorporated into windows for X-ray tubes as 

beryllium is transparent to X-rays. 

 

Beryllium has long been considered the most toxic non-radioactive element,84 and is 

both a carcinogen and the cause of the potentially-fatal chronic beryllium disease 

(CBD).85-86 It should be noted, however, that the acute toxicity of Be2+ ions (LD50) is lower 

than that of other known toxic ions such as Cd2+ and Ba2+.87 There is also approximately 

35 mg of beryllium present in the human body, although it has no known biological 

role.88  

 

Theoretical modelling has provided significant insight into the prediction of structures 

and properties of beryllium metal-ligand complexes, allowing for ligand design towards 

the most effective chelators.85 

 

1.5 -  Coordination cages 

 

Figure 1-32: Molecular mechanics representation of a potential QQ cage structure. 

Quinolino[7,8-h]quinoline derivatives have potential as building blocks for multinuclear 

organometallic structures (e.g. fig. 1-32). The compounds have: scope in the size of 

metals that could be bound; a range of existing substituents, and the angles of some 



30 
 

side groups that are responsive to changes in protonation and/or metal binding states. 

These factors could be the basis of stimuli-responsive coordination cages.37  

 

1.6 -  Summary 

Quinolino[7,8-h]quinoline is a unique heterocyclic compound with tunable proton 

sponge properties. However, research involving derivatives of this structure has been 

limited - by difficult core syntheses and synthetic obstacles that are partially 

consequences of some of the properties that make it a research interest, including 

strong basicities and non-symmetric compound formation. With proven metal-

coordination, and the ability to functionalise the heterocycle, some of these obstacles 

can be turned into opportunities, and the development of QQ synthesis and chemistry 

is a research avenue with high potential. 

 

1.7 -  Proposed Aims 

The main objectives of this thesis are as follows: 

 

 Synthesise a range of new derivatives based on the quinolino[7,8-h]quinoline core 

structure, and develop knowledge of their synthetic behaviour and general chemistry. 

 

 Gain insight into the structural changes involved in the protonation and/or 

coordination of these derivatives. 

 

 Analyse the superbasic properties and trends of QQ derivatives in collaboration with 

international research groups. 

 

 Explore the use of QQ derivatives in forming coordination complexes with small Be(II) 

ions, based on their proton sponge properties, also involving international 

collaboration. 

 

 Coordination of QQ derivatives with metal ions of different sizes, including in the 

formation of supramolecular structures. 

 

 

 



31 
 

Chapter 2 -  Synthesis of New Derivatives 

This section will focus mainly on the synthesis of symmetrical and non-symmetrical 

compounds based on the quinolino[7,8-h]quinoline (QQ) core structure. QQ derivatives 

have high pKa values and flexible coordination properties and have received little 

attention, making them desirable targets to explore further. Refer to Chapter 1 

(introduction) for further information. 

 

The formation of QQ derivatives involved difficult syntheses, working with small 

quantities and low yields. Additional challenges, as described throughout this chapter, 

included problematic QQ purification. Side reactions commonly resulted in compounds 

with similar physical properties to the desired products, such as similar solubilities and 

polarities (similar Rf values in column chromatography conditions). It was found that 

fractional recrystallisation in solvents such as DCE often gave the purest products. 

 

2.1 -  Overview 

The reaction scheme in figure 2-1 presents a summary of the pathways developed and 

optimised to produce a variety of quinolino[7,8-h]quinoline based compounds. Some 

early-stage reactions have been employed in a similar manner to those previously 

published, while others, particularly the later steps, have been designed for purpose or 

heavily modified and combined from multiple sources. 

 

 

 

 

 

 

 

 



32 

 

 

Figure 2-1: Summarised QQ reaction scheme.  

As discussed in chapter 1, the keto-enol tautomer of quinolino[7,8-h]quinoline-4,9-

(1H,12H)-dione (Q2) presented in figure 2-1 is the most stable form for this compound11 

- although the NMR spectra shows a symmetric compound, it is collected in strong acid 

(TFA-d) (fig. 2-2). Halogen substitution of Q2 gives the dihalide products 4,9-

dichloroquinolino[7,8-h]quinoline (Q3) and 4,9-dibromoquinolino[7,8-h]quinoline (Q4) 

that provide the main entry points to the new 4,9- functionalisations. 

 

 

 

 

 



33 

 

 

Figure 2-2: 1H NMR of Q2 in d-trifluoroacetic acid (TFA-d) showing four aromatic proton 

signals, indicative of a symmetrical QQ structure ((a), with trifluoroacetate anion).  

Although some QQ derivatives with functional groups at positions other than 4 and 9 

have been made previously (see chapter 1), these proved difficult to modify and were 

not the focus for this project. NMR spectra corresponding to the syntheses described in 

this chapter can be found in appendix C. 

 

2.2 -  Symmetrical QQ derivatives 

2.2.1 - Challenges 

A common obstacle ubiquitous in QQ synthesis, particularly of symmetrical di-

substituted compounds at the 4 and 9 positions, is competition between the desired 

transformation and other reactions that act to cleave halide substituents in these 

positions; the most common of which is hydrolysis, causing reversion back to the 

relatively inactive oxo groups. This process is energetically favourable as it allows for 

keto-enol tautomerism and subsequent protonation of one central nitrogen atom – this 

    2
.0

1
 

                    2
.0

5
 

                                                              2
.0

2
 

                                                                                                                         2
.0

0
 

9
.3

1
 

9
.3

0
  

          9
.1

6
 

9
.1

4
 

                                                  8
.6

9
 

8
.6

7
 

                                                                                                              7
.9

0
 

7
.8

8
 

T
F

A
 

ppm 

9.0                                                                                                                                                                                                                                                                                                   8.5                                                                                                                                                                                                                                                                                                  8.0 

11                                                                                                                                                                                                              10                                                                                                                                                                                                                    9                                                                                                                                                                                                                       8                                                                                                                                                                                                                        7                                                                                                                                                                                                                        6 

 

a) 



34 

 

is driven by the relief of nitrogen lone pair  lone pair destabilisation energy/torsional 

strain. See Chapter 1 (intro) for further information.  

 

This phenomenon led to competing, alternative pathway issues throughout the project 

and was found to be mediated/accelerated by the presence of water (see 2.2.1.1 for 

more detail). Reactions designed to produce doubly R-substituted QQs regularly 

resulted in mixtures of the desired product and some singly R-substituted products, at 

various ratios. In the majority of results, these single ‘R’ side products featured one of 

the 4 or 9 positioned halide ‘active sites’ having been substituted with the desired R 

group, while the other underwent hydrolysis, with the oxo tautomeric group in the place 

of the secondary halide which prevented the subsequent R substitution from taking 

place. In some syntheses, the problem could sometimes be mitigated by using reactants 

in relative excess, freshly distilling solvents/reactants just prior to use, and/or by running 

the reaction in a dry argon atmosphere. In select situations, where the substitution 

reaction was less favourable, halide cleavage/hydrolysis occurred under reaction 

conditions without substitution, resulting in mono-halide QQ species – this was later 

supported experimentally by the synthesis of Q9. 

 

2.2.1.1 -  Synthesis of 9-bromoquinolino[7,8-h]quinoline-4(1H)-one (Q9) 

With mounting evidence arising from the synthesis of QQ derivatives supporting the 

notion that the presence of water accelerates halide hydrolysis, experiments were 

performed involving 4,9-dibromoquinolino[7,8-h]quinoline (Q4) and water in the 

absence of other reagents.  

 

 

Figure 2-3: Synthesis of Q9 from Q4. 

Heating Q4 to reflux overnight in a solution of 40% MeOH (included for solubility) in H2O 

resulted in partial hydrolysis, with close to 100% conversion to 9-bromoquinolino[7,8-



35 
 

h]quinoline-4(1H)-one (Q9), confirming the role of water in this common QQ 

phenomenon. 

 

NMR analysis showed the expected loss of symmetry, with the number of aromatic 

signals corresponding to core QQ hydrogen atoms doubling from four to eight each with 

appropriate 1H integrations, concurrent with the appearance of the central nitrogen 

proton signal (fig. C-10). Matching J-coupling values and 2D correlation NMR 

spectroscopy (1H COSY and 1H/13C HMBC, fig. C-12) allowed for the identification of spin 

coupled protons and aided in 13C assignments, and a 1H/13C HMBC assisted in 13C 

assignments (fig. C-12). Some ambiguity remains on the assignment of spin-coupled 

pairs of proton signals therefore the final assignments are tentative. Identification was 

further supported by high-resolution mass spectrometry, with a close match between 

the observed parent ion peak at 326.9975 m/z, a close match to the calculated [M+H]+  

value calculated for Q9 (326.9951).   

 

The proposed hydroxyl-substitution-tautomerisation mechanism of this reaction is 

shown in figure 2-4. Calculations supported this, showing that of the keto and enol forms 

of Q9, the enol was less stable by 16.4 kcal mol-1. The hydrolysis only occurs once as 

there is no further reduction of strain to be gained by the addition of a second oxygen.11  
 



36 
 

 

Figure 2-4: Proposed mechanism for partial hydroxyl substitution and tautomerisation from 

4,9-dibromoQQ. 

With a Q9 yield of ~60% (that may be improvable upon further optimisation), this 

reaction presents a fresh entrance point for asymmetric synthesis and the creation of 

new QQ derivatives, such as a mixed pyridin-4-yl- and pyridin-3-yl- substituted 

compound. 

 

2.2.2 - Suzuki-Miyaura Coupling 

The Suzuki-Miyaura coupling reaction has become a cornerstone of organic chemistry 

for the formation of new carbon-carbon bonds since its development in 1979.89-90 It is a 

palladium(0) catalysed reaction between an organic halide compound (usually aryl or 

vinyl) and an organoboronic acid derivative that results in the formation of a carbon-

carbon bond, with the foundation reaction typically requiring the two coupling partner 

reactants described, a Pd(0) catalyst (or Pd(II) pre-catalyst), a base (e.g. K2CO3) and 

solvent.89 This method can be applied to a wide variety of reactants and be mediated by 

altering catalysts, co-catalysts and solvents, making it an ideal candidate for use in 



37 
 

quinolino[7,8-h]quinoline chemistry. A generalised Suzuki-Miyaura coupling mechanism 

is shown in figure 2-5.91 
 

 

Figure 2-5: Generalised Suzuki-Miyaura coupling mechanism showing the oxo-Pd pathway. 

Boronate pathway transmetalation proceeds by the reaction of ‘2’ directly with the boronate 

species without formation of ‘3’.  

Water is a common addition in Suzuki-Miyaura cross-coupling reactions, and initial 

hypotheses suggested its inclusion in QQ chemistry would be beneficial – for facilitation 

of the formation of an oxo-Pd (fig. 2-5,3) or boronate species, base-solubility, or 

acceleration of boronic ester hydrolysis.11, 92 However, it was discovered that the 

inclusion of water severely hinders the formation of doubly-substituted QQ derivatives. 

As described in 2.2.1, an aqueous-based solvent system accelerates the hydrolysis of 

one halide from the starting material over the formation of a disubstituted compound – 

because of this, a switch to dry solvents (usually DMF on the basis of solubility) was 

made when di-substitution was the goal. With side products of similar properties, 

purification was problematic, and yields could not be optimised. 
 

 

R1-X 

 

M+(-OR) 
base 

M+X- 
 

 
R2-BY2-OR- 

 

 

R2-BY2
 

 

 
RO-BY2-OR- 

 

 
R2-R1 

 



38 
 

 

Figure 2-6: Possible Suzuki-Miyaura coupling pathways for the formation of mono- a