Synthesis and Basicity Studies of Quinolino[7,8- h]quinoline Derivatives

Article abstract of DOI:10.1021/acs.joc.0c01428

Quinolino[7,8-h]quinoline is a superbasic compound, with a pKaH in acetonitrile greater than that of 1,8-bis(dimethylaminonaphthalene) (DMAN), although its synthesis and the synthesis of its derivatives can be problematic. The use of halogen derivatives 4,9-dichloroquinolino[7,8-h]quinoline (16) and 4,9-dibromoquinolino[7,8-h]quinoline (17) as precursors has granted the formation of a range of substituted quinolinoquinolines. The basicity and other properties of quinolinoquinolines can be modified by the inclusion of suitable functionalities. The experimentally obtained pKaH values of quinolino[7,8-h]quinoline derivatives show that N4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-diamine (26) is more superbasic than quinolino[7,8-h]quinoline. Computationally derived pKaH values of quinolinoquinolines functionalized with dimethylamino (NMe2), 1,1,3,3-tetramethylguanidino (N-C(NMe2)2) or N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamido (N-P(NMe2)3) groups are significantly greater than those of quinolino[7,8-h]quinoline. Overall, electron-donating functionalities are observed to increase the basicity of the quinolinoquinoline moiety, while the substitution of electron-withdrawing groups lowers the basicity.

Full text of DOI:10.1021/acs.joc.0c01428

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Article
Synthesis and Basicity Studies of Quinolino[7,8-h]quinoline Derivatives
Gareth John Rowlands, Rebecca Severinsen, Jenna K Buchanan, Karl J
Shaffer, Heather Jameson, Nishani Thennakoon, Ivo Leito, Mart Lokov, Agnes
Kütt, Robert Vianello, Ines Despotovi#, Nena Radi#, and Paul G Plieger
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01428 • Publication Date (Web): 30 Jul 2020
Downloaded from pubs.acs.org on August 2, 2020
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Synthesis and Basicity Studies of Quinolino[7,8-h]quinoline
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Derivatives
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Gareth J. Rowlands,[a] Rebecca J. Severinsen,[a] Jenna K. Buchanan,[a] Karl J. Shaffer,[a]
Heather T. Jameson,[a] Nishani Thennakoon,[a] Ivo Leito,[b] Märt Lõkov,[b] Agnes Kütt,[b]
Robert Vianello,[c] Ines Despotović,[c] Nena Radić[c] and Paul G. Plieger*[a]
[a] School of Fundamental Sciences, Massey University, Private Bag 11 222, Palmerston
North, New Zealand
Email: p.g.plieger@massey.ac.nz
[b] Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia
[c] Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
Abstract
Quinolino[7,8-h]quinoline is a superbasic compound, with a pKaH in acetonitrile greater
than that of 1,8-bis(dimethylaminonaphthalene) (DMAN), although its synthesis and the
synthesis of its derivatives can be problematic. The use of halogen derivatives 4,9-
dichloroquinolino[7,8-h]quinoline (16) and 4,9-dibromoquinolino[7,8-h]quinoline (17) as
precursors has granted the formation of a range of substituted quinolinoquinolines. The
basicity and other properties of quinolinoquinolines can be modified by the inclusion of
suitable functionalities. The experimentally obtained pKaH values of quinolino[7,8-
h]quinoline derivatives show that N4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-
diamine (26) is more superbasic than quinolino[7,8-h]quinoline. Computationally derived
pKaH values of quinolinoquinolines functionalised with dimethylamino (NMe2), 1,1,3,3-
tetramethylguanidino (N=C(NMe2)2) or N,N,N′,N′,N′′,N′′-hexamethylphosphorimidic
triamido (N=P(NMe2)3) groups are significantly greater than that of quinolino[7,8-
h]quinoline. Overall, electron-donating functionalities are observed to increase the basicity of
the quinolinoquinoline moiety, while the substitution of electron-withdrawing groups lowers
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the basicity.
Introduction
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The discovery of 1,8-bis(dimethylaminonaphthalene) (DMAN) 1 (Figure 1), the original
Proton Sponge™,1 ignited an intense interest in neutral organic superbases.2-4 The close
proximity of the lone pair of electrons on the proximal nitrogen atoms causes a destabilising
electrostatic interaction that can be alleviated by the coordination of a proton. The neutral
species display helical distortion to ameliorate the lone pair interaction while the protonated
species become planar. This has led to the preparation of a wide range of analogous organic
superbases comprising various nitrogen and/or phosphorus functional groups held in close
proximity.5-7 The unique chemistry of these molecules has seen them used as models for the
study of a variety of theories of bonding and reactivity.8-13
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Figure 1. The structures of DMAN (1), quinolino[7,8-h]quinoline (2), 1,10-phenanthroline (3), 1,10-
phenanthroline coordination (4), quinolino[7,8-h]quinoline coordination (5) and quinolino[7,8-h]quinoline
coordination to boron (6).
One area that has seen less study is the coordination of such compounds to metals.14-18
Only one complex of DMAN 1 itself has been reported.19 The methyl groups cause
unfavourable interactions destabilising metal complexes. It goes without saying that diamines
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are the archetypal bidentate ligand and so there has been interest in using superbasic
compounds as ligands in order to create reactive complexes. At first glance, the
quinolinoquinoline system 2 appears to marry both concepts. The nitrogen lone pairs are
forced together giving the basic properties but, by including the nitrogen in an aromatic
system, the destabilising steric effects of the methyl groups have been removed. Arguably,
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the closest analogue to 2 is 1,10-phenanthroline 3, a ubiquitous ligand in coordination
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chemistry.20,
But, while there are > 45,000 hits in SciFinder for unsubstituted
phenanthroline-metal complexes there are less than 20 for quinolinoquinolines (with any
substitution pattern).22
There are undoubtedly two compelling reasons for this disparity. The first is one of
access. Synthesis of quinolinoquinoline 2 and its derivatives is not simple and there has been
a low supply of these compounds.16, 23-27 The second relates to coordination environment. The
five-membered ring formed on coordination of phenanthroline to a metal 4 can accommodate
a wide range of metals with little distortion to either the ligand or the metal. The same cannot
be said for quinolinoquinolines.28-30 Coordination of a metal results in the formation of six-
membered ring 5 that can only include small metals such as beryllium or boron 6 if there is
not to be significant distortion of either the ligand or the metal.16, 28, 30 The few examples of
metal coordination to quinolinoquinolines suggests that these complexes could be useful
catalyst pre-cursors.15, 17 The high basicity appears to impart a degree of thermal stability
while the out-of-plane complexation (5, M = Pt or Re) should make one coordination site
more accessible for reaction.15 It is clear that there needs to be more study of these
compounds.
Given that there is clearly an opportunity to exploit this understudied system we wanted
to develop chemistry that would allow access to a range of substituted quinolinoquinolines.
This would permit us to pursue our interests in the coordination of small metals,31 catalysis,32,
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33 supramolecular chemistry,34-36 and the synthesis of unusual heterocycles.37-39
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This paper outlines the current state of syntheses of substituted quinolinoquinolines.16, 17,
23-26 As the basicity of these compounds influences their synthesis and complexation, a study
of the basicity of these compounds as determined by pKaH values would be highly
informative, thus an investigation of both computationally derived and experimentally
obtained pKaH values has been undertaken and are provided.
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Results and Discussion
Naming and numbering
Quinolino[7,8-h]quinoline is a fused ring system, considered to be two quinoline
heterocyclic ring systems fused together. While prior publications have used the prefix quino-
for the quinoline ring system,15-17, 23-26, 40, 41 we have adopted the quinolino- nomenclature due
to updated IUPAC recommendations no longer listing quino- as an accepted contracted
prefix.42 The naming of this compound is based on the numbering of the parent and
substituent quinoline molecules (Figure 2a).43-45 Fusion occurs at the face, or two-atom bond,
labelled h on the parent quinoline. The numbers 7 and 8 designate the fused atoms of the
attached quinoline substituent. To number the atoms of quinolino[7,8-h]quinoline, the
molecular structure is oriented so that the greatest number of rings are located in the upper
right quandrant and the heteroatoms are assigned the lowest possible position numbers.
Numbering then begins on the most counterclockwise atom of the top right ring, and
proceeds in a clockwise direction around the molecule (Figure 2b). Bridgehead carbon atoms
are not formally numbered, and are instead given the number of the preceding non-fused
carbon atom followed by a letter (starting with “a” for an adjacent carbon atom).43-45
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Figure 2. (a) Determination of the nomenclature of quinolino[7,8-h]quinoline and (b) the atom numbering
scheme.
Synthesis of the quinolinoquinoline core
The synthesis of quinolinoquinolines of the type 7 is not trivial as revealed by the
checkered history of these compounds. There have been a number of reported syntheses46
that have not stood up to scrutiny.40
Figure 3. Structure of quinolino[7,8-h]quinoline derivatives.
It is widely accepted that the first synthesis of these quinolinoquinolines (8 R1 = R3 = H;
R2 = Cl; and 2 R1 = R2 = R3 = H) was by Staab and co-workers.25, 26 The chloro derivative
was first coordinated to a metal, platinum and rhenium, some 15 years later.15 There was no
mention of these compounds in the synthetic literature until a new route to 2-
(methylthio)quinolines (9 R1 = SCH3, R2 = R3 = H) was reported in 200447 and an
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improvement on the cyclisation step of the original synthesis was detailed in 2007.48 The
former route looked attractive as the sulfide group presents a handle for modification.49-56
Unfortunately, we have been unable to repeat this chemistry and suspect that the reaction
halted after a single cyclisation and acetylation.24
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With all this in mind, the goal of our research was to access larger quantities of
quinolinoquinolines that contained a handle for subsequent functionalisation. This would
enable us to study their coordination properties, tune their basicity as well as alter undesirable
physical properties such as their low solubility. In order to elaborate the basic
quinolinoquinoline core we required suitable functionality. The previous syntheses of such
ortho-fused quinolines delivers ester groups at the 2,11 positions and ketones at the 4,9
positions (12; Scheme 1). This seemed ideal for our purposes.
Synthesis of ortho-fused quinoline 12 was achieved following the original Honda
procedure (Scheme 1).41 Mixing 1,8-diaminonapthalene 10 with two equivalents of dimethyl
acetylenedicarboxylate in ethanol furnishes the difumarate 11 as a yellow precipitate that,
after a simple wash, can be used in the cyclisation step. Addition of 11 to biphenyl ether at
250 °C followed by stirring for 20 minutes resulted in the expected product of aromatic
electrophilic substitution. Again, purification was simplified by the relative insolubility of the
product, filtration and washing give the product with sufficient purity to obtain
microanalytical data and 1H NMR in deuterated TFA.
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Scheme 1. Synthesis of the chloroquinoline 13.
Functionalisation of the quinolinoquinoline core
Functionalisation of the pyridinone-like tetracycle 12 was problematic due to its poor
solubility. Two transformations have proven high yielding. The first was
aromatisation/dehydration by treatment with phosphorus oxychloride to give the
chloroquinoline 13. A protonated version of this compound was fully characterised including
X-ray crystallographic data.24 It shows the expected planar arrangement with an internal
hydrogen bond between the ester carbonyl and the proton. So far, all attempts to derivatise
this molecule by either reducing the esters or substituting the chlorine atoms have met with
failure. Even so, to the best of our knowledge this remains the only 2,11-disubstituted
quinolinoquinoline that is capable of more than bidentate coordination, and as such shows
potential for future study.
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The second transformation involves hydrolysis and decarboxylation to give the ortho-
fused quinolinone (Scheme 2). When we started this research, this step represented the
bottleneck for the synthesis of quinolinoquinolines: the reported procedure involved
hydrolysis followed by a high temperature (370 °C) and low-pressure decarboxylation (10-5
torr) performed in a sublimation apparatus. We have developed a two-step, ‘one-pot’ reaction
based on chemistry by Strauss and Trainor57 that permits this transformation to be achieved
far more readily. Heating a mixture of diester 12 and sodium acetate in water to 250 °C for 1
hour in a microwave reactor gives 15 of sufficient purity that it can be purified after the
subsequent aromatisation reaction (Scheme 2).16 While reaction in a microwave is
convenient, we found it easier to scale the reaction by performing it under conventional
heating in a Teflon-lined stainless steel sealed vessel over a period of 12 - 16 hours.16
Chlorination with phosphorus oxychloride delivered the ortho-fused quinolinoquinoline 16 in
good yield for the two steps. Alternatively, the bromide 17 could be formed by treatment with
phosphorus oxybromide. This compound is more reactive than the chloride. Initial attempts
to hydrolyse 17 in aqueous dimethylamine gave the substituted and hydrolysed
dimethylamino quinolinone 18 (Scheme 3). In the absence of dimethylamine, 17 readily
undergoes a single hydrolysis to give the non-symmetric quinolinone 19. Calculations show
that keto-19 as drawn is 16.4 kcal mol-1 more stable than enol-19.
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Scheme 2. Synthesis of halogen derivatives 16 and 17.
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Scheme 3. Synthesis of quinolinones 18 and 19.
The previous synthesis of 16 suggested that the intermediate is the ortho-fused
quinolinone 14.25 While we have not fully characterised this molecule, infrared spectroscopy
would suggest that the tautomer, 15, predominates.16 In addition, our calculations at the
B3LYP/6–31+G(d,p) level show that 15 is by 12.0 kcal mol-1 more stable than 14, and by
17.6 kcal mol-1 than a potential 4,9-dihydroxy tautomer, thus confirming the experiments.
This tautomer maximises aromaticity and minimises structural distortions. The ortho-fused
quinolinone forces two hydrogen atoms into close proximity and arrangement that can only
be accommodated if the molecule adopts a helical twist. Based on computational modelling,
the torsional angle for this helical twist in 14 is 22.0°. Tautomerisation leads to a planar
structure and would be in keeping with subsequent results.
Interestingly, Staab and co-workers26 reported that the dechlorinated derivative 2 is
planar in the solid state. This is unusual for molecules with a ‘proton sponge’-like structure,
where the lone pair interactions distort the core to give a helical twist to the molecule. After
inspection of the data, it is almost certain that hydrogen bonding between 2 and a bridging
water molecule alleviates unfavourable interactions. X-ray crystallographic analysis of
crystals of 16 grown under anhydrous conditions reveal this molecule to have the expected
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distortion in the solid state of 20.02(9)° (Figure 4a).16 Protonation of 16 stops the
unfavourable lone pair interactions and gives a planar species (Figure 4b). This is confirmed
by our computational analysis, which shows that in 16 the helical torsional twist is 21.1°,
indicating a non-planarity. Upon protonation, in 16H+ the same dihedral angle assumes 0.0°,
thus clearly indicating the planarisation.
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Figure 4. X-ray crystal structures of the neutral (a) and protonated (b) forms of 16. Chloroform solvent
molecules for (a) and the tetrafluoroborate counter ion for (b) have been removed for clarity, ellipsoids are
drawn at the 50% probability level.16
Nucleophilic substitution of halogen appended derivatives
We first investigated the substitution of the chlorides in the hope that this would improve
the limited solubility of 16 as well as allowing the basicity to be tuned. Indeed, our
calculations shows that the gas-phase proton affinity of the parent 2 is reduced from 255.4 to
251.0 kcal mol–1 when two chlorine atoms are introduced as in 16. Yet, when the latter
substituted by the electron-donating group, such as dimethylamino moiety, the resulting
proton affinity increases to 269.0 kcal mol–1 (see later). Formation of aromatic ethers and
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amines was attempted used the methodology of Schmittel.58 Reaction of 16 with 4-tert-
butylphenol and KOH furnishes the non-symmetric monoether 20 in which one of the
chlorides has been hydrolysed to give the quinolinone tautomer (Scheme 4). Subsequent
reaction with phosphorus oxychloride yields the monochloride 21.24 The more nucleophilic
toluidine does not require external base and furnishes either the mono-imine 22 or the
product of double displacement 23 depending on whether the reaction is performed in toluene
or a melt formed from neat toluidine at 150 °C. A similar reaction delivered the highly
fluorescent ester derivative 24.24 In each case, addition results in the formation of a tautomer
in which the disfavoured lone pair interactions are ameliorated by protonation.
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Scheme 4. Nucleophilic substitution of 16 with oxygen and nitrogen donors.
Similar chemistry permits the synthesis of alkyl ethers and amines as well. With a strong
nucleophile, such as sodium methoxide, the dichloro-derivative 16 was used but for the less
nucleophilic amine the more reactive dibromide 17 was required (Scheme 5).
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Scheme 5. Synthesis of 25 and 26 by nucleophilic substitution.
We were also interested in making a water soluble quinolinoquinoline by substituting the
chloride groups of 16 with sulfonic acid moieties via reaction with sodium sulfite. While the
mass spectrum of the reaction mixture showed some di-substitution of the chloride groups,
the only stable product formed over a range of reaction conditions was the monosulfonate 27
(Scheme 6). NMR analysis confirmed the formation of 27 rather than the phenol tautomer.
This was supported by our calculations, which showed 27 is 15.3 kcal mol-1 more stable than
the phenol tautomer.
Scheme 6. Synthesis of the monosulfonate quinolinone 27.
Palladium-catalyzed cross-coupling reactions
Formation of the dibromide 17 opened the door for palladium-catalyzed cross-coupling
reactions as a route to functionalise the quinolinoquinoline core. Our initial attempts utilised
4-pyridineboronic acid pinacol ester as the coupling partner. Under typical Suzuki-Miyaura
reaction conditions using Pd(PPh3)4 as the pre-catalyst, Cs2CO3 as base and a mixture of 1,4-
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dioxane and water as solvent, the monopyridine derivative 28 could be isolated in 96% yield
(Scheme 7). X-ray crystallographic analysis of 28 confirms the quinolinone tautomer is
formed (Figure S1). The water was included in the mistaken belief that it would increase the
rate of reaction either by affecting hydrolysis of the boron ester, or promoting formation of
either the boronate or oxo-palladium species.59 With hindsight, it is clear that the addition of
water leads to hydrolysis of one bromide to form the hydrogen bond-stabilised quinolinone.
The second, activated, bromide then participates in the cross-coupling reaction.
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Scheme 7. Synthesis of 3-pyridine and 4-pyridine functionalised quinolinoquinolines via palladium-
catalyzed cross-coupling reactions.
Performing the reaction under anhydrous conditions with dry DMF as solvent led to the
desired dipyridine 29. For the 4-pyridine derivative, moderate conversion was observed (~
60%) along with formation of a small quantity of the mono-pyridine derivative 28.
Purification was problematic with the only success being achieved with fractional
crystallisation, which gave a disappointing 26% of the pure material.
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Figure 5. X-ray crystal structure of 29; ellipsoids are drawn at the 50% probability level.
The structure of the compound 29 was confirmed by X-ray crystallography (Figure 5).
This shows the expected helical twist in the quinolinoquinoline core, as the nitrogen lone
pairs minimise interaction. The helical torsional twist is significantly greater at 24.19(12)°
than that observed in the dichloro derivative 16 (20.02(9)°). This is in excellent agreement
with the calculated helical torsional twist of 23.3°. The pyridyl side groups are each twisted at
63.29° angles to the mean central plane and sit almost perpendicularly with respect to each
other (83.01°). The divergent angle of these pyridine groups will prevent coordination to the
same metal ion.
Similarly, it is possible to prepare the di-3-pyridine derivative 30 utilising the anhydrous
coupling conditions. Fractional crystallisation results in a yield of 30%.
The monopyridine quinolinone 28 can be primed for a second coupling reaction by
bromination. This would allow the preparation of non-symmetric quinolinoquinolines.
Simply re-subjecting this compound to the standard bromination conditions gave the desired
quinolinoquinoline 31 in 54% yield (Scheme 8).
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Scheme 8. Synthesis of the non-symmetric quinolinoquinoline 31.
Electrophilic aromatic substitution reactions
Having investigated substitution at the 2,11- and 4,9-positions, we were also interested in
functionalisation of the 6,7-positions of the core. One of the simplest methods is electrophilic
aromatic substitutions such as nitration. Such chemistry would install a nitrogen atom into the
molecule that might permit further functionalisation at a later stage. Addition of dichloride 16
to a pre-heated mixture of fuming nitric acid and concentrated sulfuric acid for just 2 minutes
gave the dinitro compound 32 in 35% yield (Scheme 9). All data suggests formation of this
isomer but, not unexpectedly, this derivative shows limited solubility and characterisation has
been challenging. Mass spectroscopy confirms this composition.
Scheme 9. Synthesis of the dinitro quinolinoquinoline 32 and subsequent hydrolysis.
Eventually, we were able to grow crystals suitable for X-ray crystallographic analysis
(Figure S3). These indicated hydrolysis of one of the chloro substituents occurred during
recrystallisation. As expected, once hydrolysis occurs, the planar hydrogen bond stabilised
quinolinone tautomer 33 is formed. Due to this compound being the unsought hydrolysis
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product, no further characterisation was attempted.
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The work above presents the most comprehensive study of ortho-fused quinoline proton
sponge analogues to date. We have shown that a functionalised core can be readily accessed
in synthetically useful quantities. The halogenated derivatives, 16 and 17, act as good
precursors to a range of new compounds. This will permit the basicity of this system to be
fine-tuned as well as the development of new and useful materials.
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Throughout the synthetic studies the propensity for these compounds to undergo
hydrolysis and form a hydrogen bond-stabilised ortho-fused quinoline quinolinone system
has plagued efficient transformations. We suspect that the basic nature of these proton sponge
analogues leads to protonation of the nitrogen and activation of one of the halogen atoms. To
gain more insight into the basicity of this core, experimental and computational studies were
undertaken on a number of the derivatives.
Experimental basicity studies
The methodology and experimental set up for the quinolinoquinoline derivatives in
acetonitrile was essentially the same as in previous publications.60, 61, The terminology pKaH
has been used to express the basicity of each base, rather than pKa, to clearly express that it
refers to the protonation of a base (or deprotonation of the protonated base).2 The determined
pKaH values for quinolino[7,8-h]quinoline and its derivatives are given in Table 1. A
superbase has occasionally been defined as a base with pKaH value of the conjugate acid
greater than that of the proton sponge DMAN.2 The pKaH of DMAN in acetonitrile is 18.63.62
Based on this definition, two of the compounds for which pKaH was measured had values
consistent with that of a superbase. The assigned pKaH for quinolino[7,8-h]quinoline was
19.60,62 greater than that of DMAN in acetonitrile. The diamine derivative 26 had a higher
pKaH of 23.97, suggesting an even greater ability to act as a superbase. The increased basicity
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of 26 compared to quinolino[7,8-h]quinoline is likely due to the activating diethylamino
groups which increase electron delocalisation and help to stabilise the positive charge of the
conjugate acid.
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Compounds 16 and 17 both had experimentally determined pKaH values slightly less than
that of DMAN, while the pKaH values of 13, 15 and 20 were significantly lower. Therefore
these five quinolino[7,8-h]quinoline derivatives cannot be classified as superbases. The
quinolinoquinoline derivatives 13, 16 and 17 contain deactivating groups which would
destabilise the conjugate acid by withdrawing electron density from the aromatic system. The
–CO2CH3 group in 13 is a stronger deactivating group than the halogens in 16 and 17,
accounting for its lower basicity. The reduced basicity in 15 and 20 can be attributed to the
increased stability of the neutral base due to prototropic tautomerism, involving the proton
transfer from an –OH group to the pyridine nitrogen.
We also investigated the effect of the angle of the helical torsional twist on the pKaH of
quinolino[7,8-h]quinoline derivatives. Computational analysis reveals the most basic
derivative, 26, has a change in torsional angle from 29.1° to 5.0° upon protonation.
However, 13 has a similar calculated helical torsional twist is 28.4° in the neutral base and
6.0° in the protonated form and yet has a significantly lower basicity. Both 15 and 20 are
planar structures due to the prototropic tautomerisation, and yet they record higher pKaH
values in comparison to 13. The neutral bases of 2, 16 and 17 have torsional angles of 17.3°,
21.1° and 19.0°, which do not correlate with the respective pKaH values. Looking at all
factors, it appears the size of the helical torsional twist of the neutral base does not affect the
basicity of quinolino[7,8-h]quinoline derivatives. Instead the basicity is heavily dependent on
the presence of electron withdrawing or electron donating groups.
Table 1. Experimentally determined pKaH in acetonitrile and calculated proton affinities (PA), gas-phase
basicities (GB) and pKaH in acetonitrile for quinolinoquinoline derivatives.
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Structure Functionality
Experimental
Calculated
pKaH
PA
GB
pKaH
(kcal mol-1)
(kcal mol-1)
2
R1 = R2 = R3 = H
19.60
255.4
248.8
246.8
240.8
19.6
9.9
13
R1 = CO2CH3, R2 = 9.24
Cl, R3 = H
15a
16
R1 = R3 = H, R2 =
OH
12.21
17.64
17.58
12.10
242.9
251.0
250.8
245.4
235.0
243.0
242.2
237.2
12.4
17.3
17.2
12.5
R1 = R3 = H, R2 =
Cl
17
R1 = R3 = H, R2 =
Br
20b
R1 = R3 = H, R2-1
= 4-tBu-PhO, R2-2
= OH
26
32
I
R1 = R3 = H, R2 =
NEt2
23.97
269.5
236.4
259.8
281.4
260.8
228.3
251.6
272.6
23.0
12.1
20.3
29.9
R1 = H, R2 = Cl, R3
= NO2
R1 = NMe2, R2 =
R3 = H
II
R1 = N=C(NMe2)2,
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R2 = R3 = H
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8
III
IV
V
R1 = N=P(NMe2)3,
R2 = R3 = H
286.6
269.0
279.3
290.6
262.8
271.7
275.9
273.8
298.1
303.3
280.7
261.4
273.3
283.2
254.9
264.9
269.3
266.4
290.6
295.8
31.4
23.6
26.0
29.6
20.8
22.5
23.0
24.2
33.1
35.5
9
R1 = R3 = H, R2 =
NMe2
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R1 = R3 = H, R2 =
N=C(NMe2)2
VI
VII
VIII
IX
X
R1 = R3 = H, R2 =
N=P(NMe2)3
R1 = R2 = H, R3 =
NMe2
R1 = R2 = H, R3 =
N=C(NMe2)2
R1 = R2 = H, R3 =
N=P(NMe2)3
R1 = R2 = R3 =
NMe2
XI
XII
R1 = R2 = R3 =
N=C(NMe2)2
R1 = R2 = R3 =
N=P(NMe2)3
a Neutral base exists as the quinolinone tautomer 15 in Scheme 2.
b Neutral base exists as the quinolinone tautomer 19 in Scheme 4.
Computational basicity studies
Next, we investigated the basicities of other quinolino[7,8-h]quinoline derivatives yet to
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be synthesised and compared those with some of the systems reported here. By
functionalising with electron donating dimethylamino (NMe2), 1,1,3,3-
2
7
8
9
tetramethylguanidino (N=C(NMe2)2), or N,N,N′,N′,N′′,N′′-hexamethylphosphorimidic
triamido (N=P(NMe2)3) groups we hoped to further improve the basicity of the
quinolino[7,8-h]quinoline motif. Structures with these functionalities at the X, Y and/or Z
positions were modelled computationally and their gas-phase proton affinities (PAs), gas-
phase basicities (GBs) and pKaH in acetonitrile calculated (Table 1).
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Monoprotonation of the parent 2 to give the cation [2-H]+ has an associated PA of 255.4 kcal
mol-1. This makes it a stronger base than DMAN (PA = 245.8 kcal mol-1),60 and justifies the
choice of the quinolino[7,8-h]quinoline core in the design of highly potent organic
superbases. In the conjugate acid, the attached proton is placed on one of the nitrogen atoms
with d(N–H) = 1.056 Å, and hydrogen-bonded to another pyridine nitrogen with d(N∙∙∙∙∙N) =
2.613 Å, d(NH∙∙∙∙∙N) = 1.704 Å and the N–H∙∙∙∙∙N angle of 141.2°. Such asymmetry of the
protonation fragment is seen in all other studied bases, and is in line with earlier reports on
similar systems.13, 63 However, calculations at the B3LYP/6–31+G(d,p) level show that the
transition state for the proton transfer from one pyridine nitrogen to another lies only 0.7 kcal
mol-1 above the asymmetric [2-H]+, which features a single negative frequency of 1163i cm–1
corresponding to the N–H∙∙∙∙∙N ↔ N∙∙∙∙∙H–N vibration, resulting in a symmetrical structure
with d(N∙∙∙∙∙N) = 2.477 Å, both d(NH∙∙∙∙∙N) = 1.286 Å and the N–H∙∙∙∙∙N angle of 149.0°.
Such a small barrier allows a spontaneous proton shuttle in solution and likely in the solid
state, as it was observed earlier in related derivatives.64, 65 Each of the quinolino[7,8-
h]quinoline derivatives had greater PAs and GBs than 2, which can be attributed to the added
functionalities acting as activating groups, donating electron density to the aromatic system
and further stabilising the conjugate acid formed. Interestingly, both halogeno derivatives 16
and 17 are stronger bases than their hydroxyl analogue 15. This is brought about as a result of
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the prototropic tautomerism in the latter, involving the proton transfer from one of the –OH
groups to the pyridine nitrogen, which stabilised the neutral base and reduces the resulting
basicity. This effect is equally seen in both the gas-phase (around 8 kcal mol-1) and
acetonitrile solution (around 5 pKaH units). Nevertheless, attachment of further electron-
withdrawing substituents, as in 32, significantly reduces the basicity, as two nitro groups at
positions 6 and 7 lower both the proton affinity and pKaH value by 14.6 kcal mol-1 and 5.2
units, respectively. Substitution of one of the –OH groups with the 4-tBu-PhO substituent, as
in 20, reduces the magnitude of this effect and improves the basicity in the gas-phase, yet
without a significant effect in the solution. Disubstituted derivatives confirm an already
observed trend in which systems with the phosphazeno groups surpass the basicity of those
with guanidino and dimethylamino moieties,7 being fully in line with the electron-donating
ability of those substituents. This is evident in all of the corresponding triads, namely I–III,
IV–VI and VII–IX. Interestingly, the largest basicity-amplifying effect is observed when
substituents are placed at the para-position to the quinolinoquinoline nitrogen. We attribute
this to the fact that at the ortho-position, despite being closer to the protonation centre, the
attached groups cause steric interference which reduces their optimal effect. When placed at
positions 6 and 7, the effect is diminished due to the further distance from the protonation
site. Accordingly, the greatest proton affinity of 290.6 kcal mol-1 was calculated for I, which
also had the greatest gas-phase basicity and pKaH of disubstituted compounds. In
hexasubstituted systems, the phosphazene derivative XII again dominates with the gas-phase
proton affinity exceeding the hyperbasicity limit of 300 kcal mol-1,66 reaching PA = 303.3
kcal mol-1 and pKaH = 35.5, being the strongest superbase investigated here.
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The calculated pKaH for quinolino[7,8-h]quinoline (2) (19.6) is in excellent agreement
with the literature value of 19.60,62 which holds for all other systems where this comparison
is available (Table 1). This confirms the validity of the employed computational methodology
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Conclusions
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This work provides an as current comprehensive study of the synthesis of quinolino[7,8-
h]quinoline and its derivatives. The functionalised core can be synthesised in appreciable
quantities, with the halogen derivatives 16 and 17 acting as precursors for a range of new
compounds. The tendency for quinolinoquinoline compounds to hydrolyse and form
hydrogen bond stabilised quinolinone tautomers has been problematic throughout the
synthetic studies. A number of new quinolino[7,8-h]quinoline derivatives have been
presented, which has allowed for the investigation into the basicity of these compounds.
Quinolino[7,8-h]quinoline is already appreciably basic, surpassing both the gas-phase
and acetonitrile solution basicities of DMAN, which makes it a superbasic system in both
phases. The synthesised quinolinoquinoline 26 presented an even greater basicity than
quinolino[7,8-h]quinoline, with the electron-donating diethylamino groups thought to
destabilise the conjugate acid. Computational studies show that careful substitution of the
quinolino[7,8-h]quinoline skeleton allows fine tuning of the resulting basicity, with electron-
accepting groups reducing the basicity parameters. Electron-donating moieties increase the
resulting basicity and this effect is highest when these are introduced at positions 4 and 9,
para to the quinolinoquinoline nitrogen. Several modelled compounds had calculated pKaH
values greater than any experimentally determined for a quinolino[7,8-h]quinoline derivative,
showing the potential for increased superbasicity of these compounds.
Experimental section
General Procedures: Unless otherwise stated, all reagents and solvents were purchased
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from commercial sources and used without purification. The heat source for all syntheses was
a temperature-controlled oil bath, with paraffin oil for temperatures less than 100 °C and
silicone oil for temperatures greater than 100 °C. NMR spectra were collected on Bruker
Avance 500 and 700 MHz spectrometers. All chemical shifts are reported relative to residual
solvent (1H, 13C). Microanalyses were performed at the Campbell Microanalytical Laboratory
at the University of Otago. High resolution mass spectra were recorded on either a
micrOTOF-Q mass spectrometer, operating at a nominal voltage of 3500 V, or a Thermo
Scientific Q-Exactive Focus Hybrid Quadrupole-Orbitrap mass spectrometer. IR and UV-Vis
spectra were recorded with a Nicolet 5700 FT-IR and a UV-1800 Shimadzu
spectrophotometer respectively.
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Synthesis of 4,9-dibromoquinolino[7,8-h]quinoline (17): Phosphorus oxybromide
(2.97 g, 10.4 mmol) was added to 14 (0.520 g, 2.08 mmol) and the reaction was stirred at 200
°C for 30 min under an atmosphere of Ar. The reaction mixture was diluted with CH2Cl2
(200 mL) and MeOH (20 mL) and basified with 6M KOH (20 mL) in water (200 mL). A
small portion of decolourising carbon was added and the organic layer was filtered and dried
with MgSO4 to give 17 (0.533 g, 66%). 1H NMR (500 MHz, CDCl3): δ = 9.18 (brd, J = 4.7,
13
2H), 8.51 (d, J = 8.9, 2H), 8.09 (d, J = 8.9, 2H), 7.94 (d, J = 4.7, 2H) ppm. C{1H} NMR
(125 MHz, CDCl3): δ = 149.8, 148.2, 136.4, 134.4, 129.0, 128.8, 127.8, 126.1, 125.5 ppm.
79
HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C16H9N2 Br81Br 388.9107; Found 388.9102.
Synthesis
of
9-(dimethylamino)quinolino[7,8-h]quinoline-4(1H)-one
(18):
Dimethylamine solution (40% aq., 15 mL) was added to 17 (57 mg, 0.148 mmol) and heated
under reflux for 24 - 48 h. Water (150 mL) was added and the residue was extracted with
CH2Cl2 (150 mL). The organic layer was washed with water (2 x 100 mL), dried with
MgSO4, filtered, and dried in vacuo to give 18 (26 mg, 60%). 1H NMR (500 MHz, CDCl3): δ
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= 16.15 (s, 1H; NH), 8.68 (d, J = 5.4 Hz, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 9.0 Hz,
1H), 7.90 (dd, J = 6.5, 6.5 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 6.97 (d,
J = 5.4 Hz, 1H), 6.51 (d, J = 6.6 Hz, 1H), 3.11 (s, 6H; CH3) ppm. 13C{1H} NMR (125 MHz,
CDCl3): δ = 178.3, 158.5, 148.9, 147.2, 144.1, 140.7, 137.4, 136.2, 125.8, 125.6, 124.6,
123.1, 120.5, 117.6, 111.5, 108.1, 44.1 ppm. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for
C18H16N3O 290.1288; Found 290.1278.
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Synthesis of 9-bromoquinolino[7,8-h]quinoline-4(1H)-one (19): A 2:3 MeOH:H2O (5
mL) was added to 17 (6 mg, 0.0155 mmol) and heated under reflux for ~14 h. The solvent
was removed in vacuo then the precipitate dissolved in a solution of 24:1 CHCl3:MeOH (25
mL). The solution was washed with water (3 x 30 mL), dried with MgSO4, filtered, and dried
1
in vacuo to give 19 (4 mg, 80%). H NMR (500 MHz, CDCl3): δ = 15.49 (s, 1H; NH), 8.85
(d, J = 4.9 Hz, 1H), 8.77 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 9.1 Hz, 1H), 8.08 (d, J = 9.1 Hz
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1H), 8.01 – 7.98 (m, 2H), 7.86 (d, J = 8.6 Hz, 1H), 6.61 (d, J = 7.3 Hz, 1H) ppm. C{1H}
NMR (125 MHz, CDCl3): δ = 178.4, 176.1, 148.3, 146.8, 146.4, 140.3, 137.8, 137.1, 130.4,
127.2, 126.5, 125.6, 123.5, 112.1, 108.1 ppm. HRMS (ESI/TOF) m/z: = [M + H]+ Calcd for
C16H10N2O81Br 326.9951; Found 326.9975.
Synthesis of N4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-diamine (26):
Excess neat diethylamine (20 mL) was added to 17 (100 mg, 0.258 mmol) and heated under
reflux for 48 – 72 h. Water (50 mL) was added and the residue was extracted with CH2Cl2
(100 mL). The organic layer was washed with water (3 x 100 mL), dried with MgSO4,
filtered and dried in vacuo to give 26 (86 mg, 90%). 1H NMR (500 MHz, CDCl3): δ = 19.42
(s, 1H; NH), 9.22 (dd, J = 3.0, 6.2 Hz, 2H), 8.23 (d, J = 9.1 Hz, 2H), 7.98 (d, J = 9.1 Hz, 2H),
7.30 (d, J = 6.2 Hz, 2H), 3.68 (q, J = 7.1 Hz, 8H; CH2CH3), 1.38 (t, J = 7.1 Hz, 12H;
13
CH2CH3) ppm. C{1H} NMR (125 MHz, CDCl3): δ = 158.6, 144.5, 144.4, 135.9, 125.6,
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125.3, 119.8, 117.1, 108.9, 47.2, 12.4 ppm. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for
C24N4H29 373.2387; Found 373.2385.
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Synthesis of 9-oxo-9,12-dihydroquinolino[7,8-h]quinoline-4-sulfonic acid (27):
Sodium sulfite (0.084 g, 6.667 mmol) and 16 (0.050 g, 0.167 mmol) in water (10 mL) was
refluxed for 4 h. The solvent was removed and the crude reaction mixture was dissolved in
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DMSO and filtered then precipitated with EtOAc to give 27 (0.093 g, 26%). H NMR (500
MHz, DMSO-d6) δ = 15.47 (d, J = 4.2 Hz, 1H; NH), 9.20 (d, J = 4.6 Hz, 1H), 9.03 (d, J = 9.2
Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.30 (dd, J = 6.7, 6.7 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H),
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8.13 (d, J = 4.6 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 6.34 (d, J = 7.1 Hz, 1H) C{1H} NMR
(125 MHz, DMSO-d6) δ = 176.5, 152.9, 148.2, 147.2, 139.6, 139.6, 135.8, 127.9, 127.4,
125.2, 124.4, 123.2, 123.1, 118.9, 116.7, 110.6 ppm. HRMS (ESI/TOF) m/z: [M - H]- Calcd
for C16H9N2O4S 325.0283; Found 325.0289.
Synthesis of 9-(pyridin-4-yl)quinolino[7,8-h]quinoline-4(1H)-one (28): A 1,4-dioxane
: water solution (3:2, 20 mL) was added to a mixture of 17 (100 mg, 0.258 mmol), 4-pyridine
boronic acid pinacol ester (211 mg, 1.03 mmol), caesium carbonate (420 mg, 1.29 mmol) and
the Pd(PPh3)4 catalyst (15 mg, 0.013 mmol) and stirred at 80 °C for 16 h under an
atmosphere of Ar. Water (50 mL) was added and the residue extracted with CHCl3. The
aqueous layer was washed with CHCl3 (2 x 25 mL) and the combined organic layers were
dried with MgSO4, filtered and dried in vacuo to give 28 (80 mg, 96%). Purification by
column chromatography was achieved by passing the crude compound through activated
Alumina (neutral) with 2% MeOH in DCM (with a few drops of Et3N). 1H NMR (700 MHz,
DMSO-d6): δ = 15.46 (d, J = 5.1 Hz, 1H; NH), 9.29 (d, J = 4.6 Hz, 1H; ), 8.84 (dd, J = 1.4,
4.6 Hz, 2H), 8.50 (d, J = 8.5 Hz, 1H), 8.33 – 8.31 (m, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.98 –
7.95 (m, 2H), 7.87 (d, J = 4.6 Hz, 1H), 7.68 (dd, J = 1.4, 4.6 Hz, 2H), 6.36 (dd, J = 1.4, 7.4
13
Hz, 1H) ppm. C{1H} NMR (176 MHz, CDCl3): δ = 150.5, 148.4, 147.5, 146.9, 145.2,
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140.3, 140.2, 140.1, 136.6, 129.9, 126.1, 125.5, 125.2, 125.0, 124.8, 123.7, 122.4, 117.5,
111.5 ppm. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for C21H14N3O 324.1131; Found
324.1131. C21H13N3O·1.5H2O: calculated C 71.92, H 4.61, N 11.99; found C 72.23, H 4.33,
N 12.03. IR (KBr disk): = 3433, 1627, 1614, 1571, 1525, 1504, 1188, 831 cm-1.
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휈
Synthesis of 4,9-di(pyridin-4-yl)quinolino[7,8-h]quinoline (29): Dry DMF (20 mL)
was added to a mixture of 17 (100 mg, 0.258 mmol), 4-pyridine pinacol ester (211 mg, 1.03
mmol), caesium carbonate (420 mg, 1.29 mmol) and the Pd(PPh3)4 catalyst (30 mg, 0.026
mmol) and stirred at 80 °C for 21 h. Water (50 mL) was added and the residue extracted with
CHCl3. The organic layer was washed with water (3 x 50 mL), dried with MgSO4, filtered
and dried in vacuo. The product was purified by recrystallisation from hot CH2Cl2 to give 29
(26 mg, 26%). Crystals suitable for X-ray crystallography were grown by slow evaporation of
29 in a 1:1:1 DCM:MeOH:CHCl3 solvent mixture. 1H NMR (700 MHz, CDCl3) δ = 9.46 (d,
J = 4.2 Hz, 2H; 2,11-H), 8.84 (dd, J = 1.6, 4.3 Hz, 4H; 2-Py-H), 7.99 (d, J = 8.8 Hz, 2H; 5,8-
H), 7.94 (d, J = 8.8 Hz, 2H; 6,7-H), 7.54 (d, J = 4.3 Hz, 2H; 3,10-H), 7.51 (dd, J = 1.6, 4.3
Hz, 4H; 3-Py-H) ppm. 13C{1H} NMR (176 MHz, CDCl3): δ = 150.2 (C2-Py, C2’-Py), 149.8
(C2, C11), 147.9 (C12a, C12c), 146.5 (C4, C9), 145.6 (C4-Py, C4’-Py), 135.5 (C4a, C8a),
128.1 (C6, C7), 126.9 (C12b), 125.7 (C5, C8), 125.6 (C6a), 124.6 (C3-Py, C3’-Py), 121.0
(C3, C10) ppm. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for C26H17N4 385.1448; Found
385.1447. C26H16N4·0.8CH2Cl2: calculated C 71.35, H 3.93, N 12.43; found C 71.35, H 3.79,
N 12.76. UV-Vis (CHCl3) λmax (ɛ / L mol-1 cm-1): 278 (58200), 359 (5820), 377 (6970) nm.
IR (FT): = 3033, 1596, 1580, 1413, 1067, 871, 830, 775, 704 cm-1.
휈
Synthesis of 4,9-di(pyridin-3-yl)quinolino[7,8-h]quinoline (30): Dry DMF (25 mL)
was added to a mixture of 17 (100 mg, 0.258 mmol), 3-pyridine boronic acid pinacol ester
(211 mg, 1.03 mmol), caesium carbonate (420 mg, 1.29 mmol), (t-Bu)3PHBF4 (8 mg, 0.026
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mmol) and Pd2(dba)3 (24 mg, 0.026 mmol). The suspension was stirred at 100°C for 20 h
under an atmosphere of Ar. Water (50 mL) was added and the reaction mixture was basified
with 6M KOH (40 mL) and extracted with CHCl3. The organic layer was washed with water
(3 x 50 mL), dried with MgSO4, filtered and dried in vacuo. The product was purified by
recrystallisation from hot DCE to give 30 (30 mg, 30%). 1H NMR (500 MHz, DMSO-d6): δ =
9.63 (d, J = 5.0 Hz, 2H; 2,11-H), 8.95 (br s, 2H; 2-Py-H), 8.90 (d, J = 4.0 Hz, 2H; 6-Py-H),
8.52 (d, J = 9.0 Hz, 2H; 5,8-H), 8.32 (d, J = 9.0 Hz, 2H; 6,7-H), 8.29 (d, J = 5.0 Hz, 2H;
3,10-H), 8.23 (d, J = 7.6 Hz, 2H; 4-Py-H), 7.79 – 7.76 (m, 2H; 5-Py-H) ppm. 13C{1H} NMR
(125 MHz, DMSO-d6): δ = 150.9 (C6-Py, C6’-Py), 150.2 (C2-Py, C2’-Py), 147.8 (C2, C11),
144.1 (C12a, C12c), 138.1 (C4-Py, C4’-Py), 136.5 (C3-Py, C3’-Py), 136.3 (C4, C9), 134.0
(C4a, C8a), 133.0 (C6a), 129.8 (C5, C8), 127.3 (C6, C7), 126.4 (C12b), 124.4 (C5-Py, C5’-
Py), 124.0 (C3, C10) ppm. HRMS (ESI/TOF) m/z: [M + H]+ Calcd for C26H17N4 385.1448;
Found 385.1482.
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Synthesis of 4-bromo-9-(pyridin-4-yl)quinolino[7,8-h]quinoline (31): Phosphorous
oxybromide (266 mg, 0.928 mmol) was added to 28 (100 mg, 0.309 mmol) and stirred at 200
°C for 30 min under at atmosphere of Ar. A MeOH : CH2Cl2 solution (1:10, 33 mL) was
added, the reaction mixture sonicated and then basified with 6M KOH (10 mL). Water (50
mL) was added to the reaction mixture and the organic layer collected. The aqueous layer
was washed with MeOH : CH2Cl2 (1:10, 66 mL) and the combined organic layers were dried
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with MgSO4, filtered, and dried in vacuo to give 31 (65 mg, 54%). H NMR (700 MHz,
DMSO-d6): δ = 19.78 (s, 1H; NH), 9.67 (d, J = 4.3 Hz, 1H), 9.33 (d, J = 5.2 Hz 1H), 8.97 (s,
2H), 8.72 – 8.70 (m 1H), 8.66 – 8.65 (m, 1H), 8.62 (d, J = 5.2 Hz, 1H) 8.59 (dd, J = 1.2, 9.0
Hz, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.33 – 8.31 (m, 1H), 7.83 (s, 2H) ppm. 13C{1H} NMR (176
MHz, DMSO-d6) δ = 152.1, 149.6, 147.9, 146.1, 143.6, 141.0, 139.0, 137.0, 130.7, 130.5,
129.2, 128.9, 127.8, 127.4, 127.3, 126.0, 124.7, 123.8, 116.2. HRMS (ESI/Orbitrap) m/z: [M
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+ H]+ Calcd for C21H1379BrN3 386.0287; Found 386.0280.
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Experimental determination of pKaH values: A Perkin Elmer Lambda 40 or Agilent
Cary 60 UV-Vis spectrophotometer connected with optical fibre cables to an external cell
compartment inside a MBraun Unilab glovebox filled with argon (5.0 purity) was used for all
UV-Vis spectrophotometric titrations. This setup ensured that moisture and oxygen contents
during titrations were always under 10 ppm.
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Triflic acid (Aldrich, 99+ %) and tert-butylimino-tris(pyrrolidino)phosphorane (Fluka,
≥97 %) were used to prepare acidic and basic titrant solutions. The concentrations of the
titrant solutions were in the range of 1 – 5∙10-3 mol L-1 and the concentrations of the
quinolinoquinoline derivatives and reference compounds were in the range of 1 – 14∙10-5 mol
L-1. Acetonitrile (Romil 190 SpS far UV/gradient quality) was used as solvent after drying
with molecular sieves (3 Å) for at least 12 hours, which lowered the water content to a range
of 2 – 6 ppm.
The determination of pKaH values was based on the measurement of differences in the
basicities of two bases. The first one was a quinolinoquinoline derivative and the second one
a reference base with a previously known pKaH values.62 Both compound solutions were
titrated individually and as a mixture in order to obtain the spectra of neutral and fully
protonated as well as some partially protonated forms. The spectrophotometric data was used
to calculate the dissociation levels (see equation 1) of conjugate acids of both bases in all
mixtures formed during the titration. Using the dissociation levels (α) the differences in pKaH
values (∆pKaH) of the quinolinoquinoline and the reference base can be calculated according
to equation 2.
[ ]
B
훼 = [ ] +
+
[
BH
]
B
(1)
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