The proton sponge effect: Substitution of quino[7,8-h]quinoline and the first structurally characterised derivatives

Article abstract of DOI:10.1002/ejoc.201201131

A new route to unsymmetrical derivatives of quino[7,8-h]quinoline was developed. Substitutions at the 2,11-, 4,9- and 6,7-positions of quino[7,8-h]quinoline were also successfully performed. X-ray crystal structure determinations of the resulting products revealed the propensity for derivatives of this molecule to exist in either stabilised keto or imino forms as a result of the formation of a strong intramolecular N-HA...N hydrogen bond. Copyright

Full text of DOI:10.1002/ejoc.201201131

FULL PAPER
DOI: 10.1002/ejoc.201201131
The Proton Sponge Effect: Substitution of Quino[7,8-h]quinoline and the First
Structurally Characterised Derivatives
Karl J. Shaffer,[a] Daniel C. Parr,[a] Marco Wenzel,[a] Gareth J. Rowlands,[a] and
Paul G. Plieger*[a]
Keywords: Nitrogen heterocycles / Proton sponges / Structure elucidation / Nucleophilic substitution
A new route to unsymmetrical derivatives of quino[7,8-h]-
quinoline was developed. Substitutions at the 2,11-, 4,9- and
6,7-positions of quino[7,8-h]quinoline were also successfully
sulting products revealed the propensity for derivatives of
this molecule to exist in either stabilised keto or imino forms
as a result of the formation of a strong intramolecular N–
performed. X-ray crystal structure determinations of the re- H···N hydrogen bond.
istry where heterocyclic compounds similar to quino[7,8-h]-
Introduction
quinoline such as 1,10-phenantholrolene and 2,2Ј-bipyr-
idine are important building blocks. In this study, we were
interested in the extent to which quino[7,8-h]quinoline
could be functionalised, with the eventual aim of enhancing
the photophysical properties of this potentially useful li-
gand. The unusual structural features of quino[7,8-h]quin-
oline molecules make X-ray crystallography a valuable tech-
nique in elucidating the behavior and solid-state forms of
these molecules. We have therefore recorded single-crystal
X-ray structures of as many of the substituted ligands as
possible in both their neutral and protonated forms. We
have previously reported on boron difluoride[5] and CuII[4b]
complexes of quino[7,8-h]quinoline.
Quino[7,8-h]quinoline (Figure 1) is known for its associa-
tion with the class of molecules known as proton sponges.
These are a class of molecules classified according to the
destabilising overlap of the lone pair of electrons on adja-
cent nitrogen atoms within the molecule. This strained ori-
entation is released upon binding of a proton that forms a
strong hydrogen bond between these nitrogen atoms. 1,8-
Bis(dimethylaminonaphthalene) (DMAN),[1] trademarked
by Aldrich as Proton Sponge was the original, and investi-
gations into derivatives of DMAN is now well established
and covered by numerous reviews.[2]
Results and Discussion
2,11-Substitution of Quino[7,8-h]quinoline
Figure 1. Quino[7,8-h]quinoline (I) showing the atom-numbering
Given the rarity of quino[7,8-h]quinoline derivatives in
general, we were interested in developing synthetic proto-
cols for peripheral modification of the ring; ideally we
wanted to be able to alter the substitution at any position.
Our initial studies started with an attempt to form com-
pounds with substitution at the 2,11-positions, which are
situated at either side of the potentially chelating nitrogen
atoms, to see whether this would influence the binding site
of these nitrogen atoms. An attractive route appeared to be
the use of the double Skaup cyclisation with 3-bis(methyl-
thio)acrolein and 1,8-diaminonaphthalene (1), which was
reported to give 2 in 40% yield (Scheme 1).[7]
Despite numerous attempts, we were unable to reproduce
this reaction. The failure was identified to be specific to 1,
as repeating the reported reaction conditions with other
simple anilines gave the expected quinolines. In our hands,
the reported experimental conditions resulted in intractable
scheme.
The synthesis of quino[7,8-h]quinoline was first reported
25 years ago by Zirnstein and Staab.[3] During the interven-
ing quarter century, very few research groups have explored
the coordination ability of this intriguing ligand, with just
a handful of reports on the subject to date.[4,5,6] The ability
to functionalise heterocyclic compounds greatly enhances
their utility, especially in the field of supramolecular chem-
[a] Institute of Fundamental Sciences, Massey University,
Private Bag 11 222, Palmerston North, New Zealand
Fax: +64-6-350-5682
E-mail: P.G.Plieger@massey.ac.nz
Homepage: http://www.massey.ac.nz/massey/learning/
departments/institute-of-fundamental-sciences/
staff/academic/paul-plieger.cfm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201131.
Eur. J. Org. Chem. 2012, 6967–6975
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6967

K. J. Shaffer, D. C. Parr, M. Wenzel, G. J. Rowlands, P. G. Plieger
FULL PAPER
believe that 3 may have been mistakenly characterised as 2
in the original report.
The failure of this route led us to look at the original
synthesis of I (Figure 1) that proceeded via 4.[9] By directly
treating 4 with phosphorus oxychloride, new methyl ester
substituted proton sponge 5 (Scheme 2) was conveniently
formed and fully characterised.
Scheme 1. Attempted double Skraup condensation of 1. Reagents
and conditions: (a) 3,3-bis(methylthio)acrylaldehyde, HOAc, re-
flux, 8 h.
Scheme 2. Synthesis of 2,11-substituted 5. Reagents and condi-
tions: (a) POCl3, 130 °C, 9 min.
The molecular structure of the protonated form of 5 (ob-
tained from the reaction with BF3·OEt2 in the presence of
trace amounts of water) confirmed the ester groups were
retained during the reaction (Figure 3).
Figure 2. Crystal structure of 3 showing the internal H-bond; ellip-
soids are drawn at the 50% probability level.
black tar; however, we were able to isolate and purify a
small quantity of a white compound, which, once charac-
terised, was identified as compound 3; the result of both a
single condensation and acetylation reaction. Subsequent
Figure 3. Crystal structure of the cation [H(5)]+ showing the close
contacts of H(2); ellipsoids are drawn at the 50% probability level.
The asymmetric unit consists of two molecules of 5 and
single-crystal X-ray structure analysis confirmed this as- two tetrafluoroborate anions. The protons on N(2) and
signment (Figure 2). The asymmetric unit of the crystal N(2B) (from the second molecule in the asymmetric unit)
structure of 3 consisted of one molecule of 3 and no solvent were found by way of the Fourier difference map. An im-
molecules (Figure 2). Analysis of the structure revealed that portant distinction between 5 and the crystal structures of
the acetamide group is oriented such that there exists a other protonated proton sponges was that there was no
moderate electrostatic hydrogen bond[8] (located from the auxiliary three-centred hydrogen bonding from anions or
Fourier difference map) between the central nitrogen atoms; solvent to the central proton.[10] The three-centred hydrogen
N(10)–H 1.940(1) Å, N(1)–N(10) 2.639(1) Å, N(1)–H– bond now consisted of an interaction between N(1) and
1
N(10) 138.0(1)°. The H NMR chemical shift for this hy- N(2) and between N(2) and O(113) (Table 1). The methyl
drogen was found at δ = 14.3 ppm, which indicates that this esters appear to shield the proton binding site. In a review
hydrogen bond is also present in solution. As no spectro- chapter on proton sponges,[2a] the authors proposed that
scopic or analytical data was supplied in the original paper four criteria needed to be met for a molecule to be classified
to support the formation of 2, we could not compare it to as a proton sponge and that unsubstituted quino[7,8-h]
the product we isolated. The purification method described quinoline was in violation of the fourth requirement. That
for 2 used silica gel chromatography eluting with a very is, there needed to be the presence of a hydrophobic envi-
nonpolar solvent gradient (hexanes/ethyl acetate, 9:1), and ronment at the nitrogen atoms to account for the low rate
we have not yet synthesised a quino[7,8-h]quinoline com- of proton addition–elimination and to prevent coordination
pound that elutes under these conditions. This led us to of all Lewis acids except the proton. In reality, there is no
6968
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6967–6975

The Proton Sponge Effect: Substitution of Quino[7,8-h]quinoline
Table 1. Important bond lengths and angles associated with the hydrogen bonding of H(2) and H(2B) in [H(5)][BF4].
N–H [Å]
N–X [Å]
N–H–X [°]
N2–H2
1.9500(3)
2.4800(3)
1.9600(3)
2.3900(3)
N2–N1
O113–N1
N1–N2
2.643(3)
2.790(3)
2.646(3)
2.730(3)
N2–H2–N1
135.00(3)
101.00(3)
135.00(3)
103.00(3)
O113–H2
N1–H2B
O31B-H2B
N2–H2–O113
N1–H2B–N1
N2–H2B–O31B
O31B–N1
molecule that matches all the criteria perfectly. The original dicates the presence of the double phenol addition product
proton sponge, 1,8-bis(dimethylamino)naphthalene,[1] has and suggests that this may decompose on workup. To con-
been shown to complex to boron.[11] It would appear that vert 7 back into a dipyridine-type donating ligand, treat-
5 meets the criteria of a proton sponge more effectively in ment with phosphorus oxychloride gave unsymmetrical 8
this case, as the cavity can only support a proton because (Scheme 3b).
of the greater steric influence of the methyl esters. The pre-
viously reported crystal structure of the analogous tetra-
fluoroborate salt of 1,8-bis(dimethylamino)naphthalene
also reveals that there were no significant auxiliary hydro-
gen-bonding interactions.[12] A symmetry-generated tetra-
fluoroborate anion lies above the proton cavity in the crys-
tal structure of [H(5)][BF4], but the short contacts exceed
what would be considered weak hydrogen bonding. For a
molecule based on quino[7,8-h]quinoline, 5 replicates this
shielding of the proton well. To the best of our knowledge,
5 is currently the only confirmed quino[7,8-h]quinoline de-
rivative with 2,11-substitution, and the ester groups offer
great potential for elaboration and also fine-tuning of the
binding site.
Scheme 3. Nucleophilic substitution of 6 with oxygen donors. Rea-
gents and conditions: (a) tBuC6H4OH, KOH, 150 °C, 4 h;
(b) POCl3, 120 °C, 9 min; (c) NaOMe, MeOH reflux, 2 h.
4,9-Substitution of Quino[7,8-h]quinoline
The known compound 4,9-dichloroquino[7,8-h]quinoline
(6) was synthesised by a modification[5] of the original prep-
We subsequently found that both of the chlorides could
aration by Staab and co-workers.[3] We discovered that it be substituted by sodium methoxide leading to the isolation
was possible to simultaneously improve the yield and de- of disubstituted quino[7,8-h]quinoline 9 (Scheme 3c). The
crease the reaction time of the critical de-esterification step success of this reaction supports the theory that the hydrox-
by employing hydrothermal conditions.[5] Our modification ide anion is directly responsible for the formation of 7. The
gave us a reliable and large-scale route to 6. The 4,9-substi- 4,9-substitution patterns of 7 and 9 were confirmed by elu-
tuted chlorides present an opportunity to further function- cidation of their X-ray crystal structures.
alise the ring system. Initially, we were interested in elabo-
Attempts to crystallise 7 in the presence of copper per-
rating the rings by nucleophilic aromatic substitution, as chlorate by vapour diffusion of diethyl ether in acetonitrile
this would give us a route to selectively functionalise the resulted in the isolation of protonated 7 as the perchlorate
rings.[13] The very properties that make 6 intriguing also salt and no metal complex (Figure 4). CHN analysis of the
hamper its usability; purification by standard techniques is bulk crystallised material suggested the formulation
highly problematic, and so reactions were optimised to pro- [H(7)][ClO4]; however, upon analysis of a single crystal suit-
duce high-yielding reactions with simple workup pro- able for X-ray determination, the asymmetric unit was
cedures. We first investigated the substitution of the 4,9- found to consist of two molecules of 7 and only one per-
chlorides on 6 with oxygen-donor nucleophiles (Scheme 3). chlorate. The charge was balanced by a central proton (lo-
Direct substitution of the chlorides with phenol unexpec- cated by the difference Fourier map) that formed a bridge
tedly led to nearly quantitative conversion to 7 (Scheme 3a). between the two molecules of 7 (Figure 4). Both carbonyl
The preference for 7 over the quinoline-4-ol tautomer is groups associated with this bridging hydrogen were elon-
easy to understand: the high basicity of the proton sponge gated to a partial double bond length of 1.300(3) Å. The
analogues favours protonation of the nitrogen atoms with difference map placed the proton as a formal bond to
concomitant formation of the keto form of the heterocycle. O(9A) with a strong hydrogen bond[8] to O(9) [O(9A)–
What is less explicable is the formation of either tautomer H(9AA) 1.610(2) Å, O(9A)–O(9) 2.444(2) Å] and an
from 6 in the first place. The most logical explanation is the O(9A9–H(9AA)–O(9) angle of 175.00(2)°. Although this
direct substitution of the chloride by a hydroxide anion un- single crystal was a minor product compared to the bulk
der the harsh conditions followed by tautomerism. Interest- material, it allowed identification of the structural features
ingly, mass spectrometric analysis of the crude material in- of 7 to reinforce the NMR and MS structural assignments.
Eur. J. Org. Chem. 2012, 6967–6975
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6969

K. J. Shaffer, D. C. Parr, M. Wenzel, G. J. Rowlands, P. G. Plieger
FULL PAPER
The bulk material of formula [H(7)][ClO4] most likely had with p-toluidine to form 11a could be achieved as a melt in
all O(9) positions protonated with the charge balanced by neat p-toluidine. Purification proved to be more compli-
a perchlorate anion.
cated than that of 10 (Scheme 4b), but purification was
eventually achieved by silica gel column chromatography
whereby compound 11a was slowly eluted (CH2Cl2/MeOH/
NEt3, 8:8:1 gradient).
Figure 4. Crystal structure depicting the hydrogen-bond dimer
[H(7)2]ClO4 showing the bridging proton, H(9AA), between O(9)
and O(9A); ellipsoids are drawn at the 50% probability level.
A heated DMSO solution of 9 followed by slow cooling
gave single crystals of 9. The asymmetric unit consists of
three molecules of the neutral form of 9; one molecule is
shown in Figure 5. The three molecules of 9 in the asym-
metric unit have N(1)–C(17)–C(13)–N(2) torsion angles of
13.73(49), 8.83(49) and 8.13(50)°, which are smaller than
the angles found in the neutral form of 6 with a 20.02(9)°
torsional twist.[5] This significant difference in the torsional
angle of these neutral forms of this ligand can be attributed
to the weak hydrogen bonding that is present in both crystal
structures. In 9, weak hydrogen bonds between the nitrogen
atoms of one molecule and the hydrogen atoms in the 2,11-
positions or on the methoxy groups of an adjacent molecule
exist, which aid in reducing the lone pair–lone pair interac-
tion between the two nitrogen atoms. This arrangement of
molecules is not possible in 6 where instead the lone elec-
tron pairs on the heteroatoms are orientated towards the
chloroform solvent molecules.[5]
Scheme 4. Nucleophilic substitution of 6 with nitrogen donors.
Reagents and conditions: (a) p-toluidine, toluene, reflux, 4 h; (b) p-
toluidine, 150 °C, 4 h or (c) methyl anthranilate, 120 °C, 2 h.
HRMS and NMR spectroscopy confirmed the presence
of 11a as did the measurement of several different X-ray
crystal structures (Figures 6 and 7). Finally, we were inter-
ested in constructing a substituted derivative of 6 with ex-
tended conjugation capable of enhanced fluorescence, and
so we prepared compound 11b (Scheme 4c). The methyl es-
ter group on the aromatic ring on this molecule allows H-
bonding back to the secondary amines or imines depending
on the tautomeric form and both help to enhance the rigid-
ity and maintain the planarity of the whole system. The
combination of which may provide a pathway to electron
delocalisation across the molecule. Molecules 11a and 11b
were sparingly soluble in hot [D6]DMSO and their 1H
NMR spectra showed highly deshielded protons at δ =
16.41 and 15.69 ppm, respectively; the large downfield
shifts are typical for highly deshielded protons located be-
tween the ring nitrogen atoms. This NMR evidence offers
Figure 5. Crystal structure of 9 showing the atom labels, ellipsoids
are drawn at the 50% probability level.
Next, we investigated the substitution of the chlorides on further confirmation that these molecules adopt a partial
6 with nitrogen-donor nucleophiles (Scheme 4). The substi- imino tautomeric form in their neutral state and that one
tution of the 4,9-chlorides on 6 with anilines was attempted; of the protons is located between the two ring nitrogen
p-toluidine was used to test the reaction methodology, as it atoms rather than localised on the aniline substituent. A
was hoped that the methyl group would provide improved crystal structure of 11a was obtained by cooling a solution
solubility. Addition of a single toluidine unit was achieved at 4 °C in CH2Cl2/MeOH overnight. The asymmetric unit
by heating
a fourfold excess to reflux in toluene (Figure 6) revealed that, upon crystallisation, 11a exists in
(Scheme 4a). The insolubility of product 10 allowed for the partial tautomer form with a hydrogen atom located on
simple purification: the reagents were simply heated to- the ring N(2) nitrogen atom rather than on the imino N(91)
gether and the product was filtered off to remove the excess nitrogen atom (the hydrogen was located by the Fourier dif-
amounts of the starting materials. We established the loca- ference map). The C(9)–N(91) bond length at 1.311(2) Å
1
tion of the proton by H NMR spectroscopy, as 10 was has significant double-bond character relative to C(4)–
sparingly soluble in hot [D6]DMSO and a peak at δ = N(41) 1.367(2) Å. This arrangement appears to be further
14.62 ppm confirmed the highly deshielded position typical stabilised by one methanol solvent molecule. The methanol
for protons bound to proton sponges.[1,3b,14] Disubstitution solvent interacts with a moderate electrostatic hydrogen
6970
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6967–6975

The Proton Sponge Effect: Substitution of Quino[7,8-h]quinoline
bond[8] with O(21)–H(21) 0.820(2) Å, N(91)–H(21)
1.950(2) Å, O(21)–N(91) 2.753(2) Å and an O(21)–H(21)–
N(91) angle of 167.00(2)°. There are several instances where
simple quinolines showed similar tautomerism after nucleo-
philic aromatic substitution of an aniline.[15] In these pa-
pers, the tautomerism was reversible; however, as a result
of the basicity of 10, 11a and 11b, the thermodynamic equi-
librium sits firmly in favour of one of the two aniline groups
present adopting the imino form, as evidenced in both the
solution and solid-state studies.
Figure 7. Crystal structure of [H(11a)][BF4]; ellipsoids are drawn at
the 50% probability level.
of 11a, the neutral form of 11b (Figure 8c) is also not fluo-
rescent. Although no crystals were grown, it is reasonable
to assume that protonation occurs at the same position for
molecule 11b. The crystal structures of [H(11a)][BF4] and
neutral 11a both show that the substituted anilines are ro-
tated away from the plane of the heterocyclic ring. Al-
though no crystal structure was obtained, the hydrogen
bonding present between the secondary amines and the
methyl esters of [H(11b)][BF4] may align the aniline substit-
uents with the central heterocycle. The optimised geome-
tries of both [H(11a)][BF4] and [H(11b)][BF4] were calcu-
lated at the B3LYP/6-311++g(2d,p) level (Supporting Infor-
mation). The angles between the aniline substituents and
the heterocyclic ring for [H(11a)][BF4] were 67.57 and
71.37°, which were reduced to 43.90 and 41.20° for
[H(11b)][BF4] suggesting that this is in fact the case.
Figure 6. Crystal structure of 11a; ellipsoids are drawn at the 50%
probability level.
Further protonation of these molecules is possible. This
results in the equilibrium being driven back towards the
secondary amine form. The evidence for this comes from
both NMR spectroscopy and X-ray studies on the proton-
ated form of 11a, which was synthesised by treating 11a
with BF3·OEt2 in the presence of trace amounts of water.
Upon crystallisation, a compound with the formula
1
[H(11a)]BF4 was obtained. Analysis of the H NMR spec-
trum of this tetrafluoroborate salt revealed chemical shifts
corresponding to the central NH proton at δ = 18.79 ppm
and two secondary amine proton signals at δ = 10.11 ppm.
1
Notably, the H NMR shift corresponding to the central
NH proton is now further downfield than that of the simi-
larly positioned proton in the neutral form of 11a (δ
=16.41 ppm). Crystals of [H(11a)]BF4 were formed by vap-
our diffusion of diethyl ether into a methanolic solution
containing the salt. The asymmetric unit consists of one
molecule of protonated 11a and one tetrafluoroborate
anion (Figure 7). The hydrogen atoms on N(4) and N(9)
and the proton on N(1) were located by the Fourier differ-
ence map. As expected, the C(4)–N(4) [1.354(4) Å] and
C(9)–N(9) [1.374(4) Å] bond lengths are no longer signifi-
cantly different and both are significantly longer than those
found for C(9)–N(91) in the neutral form of 11a (Figure 6),
that is, the molecule is no longer in the tautomeric imino
Figure 8. Compounds (a) 11a, (b) [H(11a)][BF4], (c) 11b and
(d) [H(11b)][BF4] viewed in the dark under a longwave 385-nm UV
lamp.
Analysis of the molecular orbitals involved in the π–π*
form. The tetrafluoroborate anion interacts with a moder- transitions for [H(11a)][BF4] and [H(11b)][BF4] provide
ately strong hydrogen bond to the secondary amine N4[8] more evidence for these empirical observations (Supporting
[F(4)–H(4A) 2.080(3) Å, N(4)–F(4) 2.869(3) Å] and an Information, Figure S1). The weak fluorescence observed
N(4)–H(4A)–F(4) angle of 152.00(3)°.
for [H(11a)][BF4] appears to be due to partial intramolecu-
The enhanced fluorescence of the protonated form of 11b lar charge transfer from one aniline substituent back into
over that of 11a is best illustrated by Figure 8. The neutral the heterocyclic ring. In contrast, the strong fluorescence
imino form of 11a is not fluorescent (Figure 8a). Upon pro- observed for [H(11b)][BF4] appears to be due to an increase
tonation, the imino form is converted into the secondary in the delocalisation of the intramolecular charge over two
amine tautomer, and in the process the rigidity of the core thirds of the molecule (Supporting Information, Figure S2).
quino[7,8-h]quinoline ring system is enhanced, which leads The strong fluorescence of [H(11b)][BF4] must, therefore,
to a mild fluorescent response (Figure 8b). As in the case arise from both an increase in the structural rigidity and
Eur. J. Org. Chem. 2012, 6967–6975
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6971

K. J. Shaffer, D. C. Parr, M. Wenzel, G. J. Rowlands, P. G. Plieger
FULL PAPER
the electron delocalisation across the molecule and shows tive examples. Some progress in the preparation of func-
that with careful choice of substituent, quino[7,8-h]quinol- tionalised quino[7,8-h]quinolines derivatives has been ob-
ine may show utility as a fluorescence-active compound.
served. Preliminary results with Pd0 coupling reactions
show promise and will be reported at a later date.
6,7-Substitution of Quino[7,8-h]quinoline
Experimental Section
To access the 6,7-positions of quino[7,8-h]quinoline, we
found that nitration of 6 in fuming HNO3/H2SO4 gave se-
lective electrophilic substitution of two NO2 groups
(Scheme 5). The mass spectra revealed the chlorides had re-
mained intact and that the NO2 groups had replaced two
hydrogen atoms somewhere on the ring.
General Procedures: Unless otherwise stated, all reagents and sol-
vents were purchased from commercial sources and used without
further purification. NMR spectra were collected with Bruker Av-
ance 400 and 500 MHz spectrometers. All chemical shifts are re-
ported relative to residual solvent (1H, 13C). Microanalyses were
performed at the Campbell Microanalytical Laboratory at the Uni-
versity of Otago. Electrospray mass spectra were recorded with a
Mircomass ZMD spectrometer run in the positive ion mode. High-
resolution mass spectra were recorded with a microTOF-Q mass
spectrometer operating at a nominal voltage of 3500 V. This service
was provided by The University of Auckland. IR spectra were re-
corded with a Bruker Alpha-P diamond anvil system. Single-crystal
X-ray data were collected at reduced temperature with a Rigaku
Spider diffractometer equipped with a copper rotating anode X-
ray source and a curved image plate detector. The crystals were
mounted in an inert oil, transferred into the cold gas stream of the
detector and irradiated with graphite monochromated Cu-Kα (k =
1.54178 Å) X-rays. The data was collected by the Crystal Clear
program (v.1.4.0) and processed with FS-PROCESS to apply the
Lorentz and polarisation corrections to the diffraction spots (inte-
grated 3 dimensionally). The structures were solved by direct meth-
ods by using SHELXS-97 and refined by using the SHELXL-97
Scheme 5. Electrophilic substitution of 6 with nitrogen donors.
Reagents and conditions (a) HNO3, H2SO4, 120 °C, 2 min.
Not unsurprisingly, the compound showed poor solubil-
1
ity in all solvents; however, a H NMR spectrum recorded
in hot [D6]DMSO of a protonated form of 12 revealed that
the product possesses C2 symmetry, and this allowed assign-
ment of the protons in the 2,3- and 10,11-positions on the
ring, leaving the 5,6- and 7,8-positions as likely points of
NO2 substitution. In the absence of a crystal structure, it program.[19] Absorption correction was carried out empirically. Hy-
drogen atoms were calculated at their ideal positions unless other-
wise stated.
is only possible to speculate exactly which positions were
substituted; however, nitration reactions under similar con-
ditions of a related proton sponge led to substitution at the
para-positions to the nitrogen, as confirmed by X-ray crys-
tal structure determination.[16] In addition, quinolines un-
dergo nitration at the 6-position;[17] therefore, on the basis
of this additional evidence, we propose that the substitution
of 12 is more likely to have occurred at the 6- and 7-posi-
Computational: Density functional theory (DFT) calculations were
carried out by using the Gaussian09 package of programs.[20]
Becke’s three-parameter hybrid exchange correlation function con-
taining the non-local gradient correction of Lee, Yang and Parr
(B3LYP),[21] in conjunction with the 6-311G++(2d,p) basis set were
used to obtain the optimised geometries.
tions. Reduction of the nitro groups to amines may provide N-[2-(Methylthio)benzo[h]quinolin-10-yl]acetamide (3): A mixture of
3,3-bis(methylthio)acrylaldehyde (0.300 g, 2.00 mmol) and
1
additional sites for further functionalisation; for example,
DMAN was grafted onto silica for use as a base catalyst for
the Knoevenagel condensation between benzaldehyde and
different active methylene compounds as well as for the
Claisen–Schmidt condensation of benzaldehyde and 2-hy-
droxyacetophenone to chalcones and flavanones.[18]
(0.174 g, 1.10 mmol) in glacial acetic acid (30 mL) was heated un-
der reflux for 8 h. The excess amount of acetic acid was removed
in vacuo, and the residue was quenched with a saturated NaHCO3
solution. The residue was extracted with CH2Cl2 (200 mL), and the
organic layer was washed with water (2ϫ 200 mL), filtered and
dried with MgSO4. Purification by silica gel column chromatog-
raphy (hexanes/EtOAc, 9:1) gave 3 as a pale brown solid, which
1
darkened upon storing. Rf = 0.21 (hexanes/EtOAc, 2:1). H NMR
Conclusions
(500 MHz, CDCl3): δ = 2.43 (s, 3 H, COCH3), 2.69 (s, 3 H, SCH3),
3
7.33 (d, J5,6 = 8.5 Hz, 1 H, 6-H), 7.51–7.68 (m, 4 H, 3,7,8,9-H),
This report outlines the first successful syntheses of 2,11-
and 6,7-substituted quino[7,8-h]quinoline derivatives that
have shown, despite poor solubility and poor elution behav-
iour of the quino[7,8-h]quinoline moiety, that it is possible
to substitute and purify this molecule in positions other
than the 4,9-positions. We have also shown that direct sub-
stitution at the 4,9-positions is possible with a number of
derivatives that were successfully formed and characterised.
The propensity for the molecule to tautomerise, as evi-
denced by X-ray crystallography, was explored and ulti-
3
3
8.05 (d, J5,6 = 8.5 Hz, 1 H, 5-H), 9.02 (d, J3,4 = 7.9 Hz, 1 H, 4-
H), 14.3 (s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.7
(t), 25.9 (t), 116.6 (q), 117.0 (s), 118.0 (s), 122.8 (s), 124.3 (q), 124.8
(s), 128.1 (s), 129.0 (s), 135.4 (q), 136.9 (s), 139.2 (q), 147.3 (q),
158.0 (q), 169.4 (q) ppm.
Crystal Data for 3: C16H14N2OS, colourless block, dimensions
¯
0.55ϫ0.34ϫ0.33 mm, triclinic, space group P1, a = 7.2715(2) Å,
b = 9.8011(2) Å, c = 10.4908(2) Å, α = 106.4320(10)°, β =
99.5190(10)°, γ = 106.4390(10)°, U = 662.88(3) Å3, μ = 0.240 mm–1,
Z = 2, Dc = 1.415 gcm–3, F(000) = 296, T = 173(2) K. A total of
mately provides a pathway to unsymmetrical mixed deriva- 7336 reflections were collected by using a Bruker SMART four
6972
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6967–6975

The Proton Sponge Effect: Substitution of Quino[7,8-h]quinoline
3
3
circle diffractometer in the range 2.31 Ͻ 2θ Ͻ 66.50°. A semiempir-
ical absorption correction (SADABS-2004/1) was applied. The
2603 independent reflections were used to solve the structure by
direct methods (SHELXS-97), which resulted in the location of all
non-hydrogen atoms. All non-hydrogen atoms were made aniso-
tropic and the refinement (SHELXL-97) of 181 parameters con-
verged to R1 = 0.0310 [for 2603 reflections having I Ͼ 4σ (I)], wR2
= 0.0854 and goodness of fit 1.090 (for all 2603 F2 data). Peak/hole
0.335/–0.244 eÅ–3.
C(CH3)3], 6.84 (d, J10,11 = 6.2 Hz, 1 H, 11-H), 6.87 (d, J2,3 =
3
5.4 Hz, 1 H, 3-H), 7.21 (d, J2,3 = 8.6 Hz, 2 H, 2-PhH), 7.56 (d,
3J2,3 = 8.6 Hz, 2 H, 3-PhH), 7.78 (d, 3J5,6 = 8.7 Hz, 1 H, 6-H), 7.93
3
3
(d, J10,11 = 6.2 Hz, 1 H, 10-H), 8.09 (d, J7,8 = 6.2 Hz, 1 H, 7-H),
3
3
8.50 (d, J7,8 = 6.2 Hz, 1 H, 8-H), 8.62 (d, J5,6 = 8.7 Hz, 1 H, 5-
H), 8.80 (d, 3J2,3 = 5.4 Hz, 1 H, 2-H); 16.30 (s, 1 H, NH) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 31.5 (t), 34.6 (q), 105.4 (s), 111.1
(s), 115.0 (q), 116.7 (q), 119.5 (q), 120.6 (s), 122 (s), 124.1 (s), 125.6
(s), 126.1 (q), 127.4 (s), 127.7 (s), 137.0 (q), 138.4 (s), 140.4 (q),
148.5 (q), 148.7 (s), 149.3 (q), 151.4 (s), 162.8 (s) ppm. IR: ν =
˜
Dimethyl 4,9-Dichloroquinolino[7,8-h]quinoline-2,11-dicarboxylate
(5): Phosphorus oxychloride (1.25 mL, 13.5 mmol) was added to 4
(0.394 g, 1.06 mmol), and the reaction mixture was stirred at
130 °C for 9 min. The reaction mixture was poured into ice–water
(200 mL), basified with 6 m KOH (20 mL) and extracted with
CH2Cl2 (200 mL). The organic layer was filtered and dried with
2957, 1615, 1583, 1527, 1505, 1492, 1432, 1422, 1386, 1275, 1216,
1198, 1184, 855, 827 cm–1. LRMS: m/z = 395.55 [M]+. C26H22N2O2
(394.47): calcd. C 79.16, H 5.62, N 7.10; found C 79.68, H 5.99, N
6.36. The product was recrystallised by vapour diffusion of diethyl
ether into a MeCN solution containing 7 with an equimolar quan-
tity of copper perchlorate. C26H22N2O2·HClO4 (494.93): calcd. C
63.10, H 4.68, N 5.66; found C 63.00, H 4.60, N 5.70.
1
MgSO4 to give 5 (0.315 g, 72%). H NMR (500 MHz, CDCl3): δ
3
= 4.19 (s, 6 H, COCH3), 8.20 (d, J5,6 = 8.9 Hz, 2 H, 6,7-H), 8.55
3
(s, 2 H, 3,10-H), 8.60 (d, J5,6 = 8.8 Hz, 2 H, 5,8-H) ppm. 13C
Crystal Data for 7: C52H45N4ClO4, colourless needle, dimensions
NMR (125 MHz, CDCl3): δ = 53.3 (t), 122.5 (s), 125.0 (s), 127.1
(q), 127.9 (q), 130.9 (s), 136.9 (q), 144.0 (q), 147.8 (q), 148.1 (q),
165.2 (q) ppm. LRMS: m/z = 415.02 [M]+. C20H12Cl2N2O4·0.5H2O
(423.02): calcd. C 56.62, H 3.09, N 6.60; found C 56.73, H 3.08, N
6.60.
0.5ϫ0.1ϫ0.05 mm, monoclinic, space group P21/c,
a
=
16.964(3) Å, b = 10.938(2) Å, c = 24.162(5) Å, α = 90.00°, β =
101.65(3)°, γ = 90.00°, U = 4391.2(15) Å3, μ = 1.282 mm–1, Z = 4,
Dc = 1.345 gcm–3, F(000) = 1864, T = 100(2) K. A total of 17488
reflections were collected by using a Rigaku MM007 rotating an-
ode in the range 6.65 Ͻ 2θ Ͻ 144.18°. A semiempirical absorption
correction (ABSCOR; Higashi, 1995) was applied. The 10421 inde-
pendent reflections were used to solve the structure by direct meth-
ods (SHELXS-97), which resulted in the location of all non-hydro-
gen atoms. All non-hydrogen atoms were made anisotropic and the
[H(5)][BF4]: BF3·OEt2 (0.121 mL, 0.964 mmol) was added to 5
(0.100 g, 0.241 mmol) in dry CH2Cl2 (5 mL) under an atmosphere
of Ar, and the mixture was stirred at room temperature for 8 h.
The reaction mixture was diluted with CH2Cl2, and the solvent was
separated from deposited [H(5)][BF4] and dried under vacuum. The
product was then set up for crystallisation by vapour diffusion of
diethyl ether into a MeCN solution containing [H(5)][BF4]. Brown
crystals suitable for X-ray crystallography were obtained after 1 d.
1H NMR (500 MHz, CD3CN): δ = 4.23 (s, 6 H, COCH3), 8.43 (d,
3J5,6 = 9.1 Hz, 2 H, 6,7-H), 8.64 (d, J = 9.1 Hz, 2 H, 5,8-H), 8.68
(s, 2 H, 3,10-H), 19.14 (s, 1 H, NH) ppm. 13C NMR (125 MHz,
CD3CN): δ = 55.5 (t), 117.3 (q), 125.2 (s), 128.1 (s), 129.7 (q), 133.7
(s), 140.2 (q), 143.4 (q), 145.4 (q), 152.3 (q), 162.1 (q) ppm. LRMS:
refinement (SHELXL-97) of 587 parameters converged to R1
=
0.0643 [for 8316 reflections having I Ͼ 4σ (I)], wR2 = 0.1569 and
goodness of fit 1.050 (for all 8316 F2 data). Peak/hole 0.403/
–0.426 eÅ–3.
4-(4-tert-butylphenoxy)-9-chloroquinolino[7,8-h]quinoline (8): Phos-
phorus oxychloride (1.00 mL, 10.7 mmol) was added to 7 (0.258 g,
0.655 mmol), and the reaction mixture was stirred at 120 °C for
9 min under an atmosphere of Ar. The reaction mixture was poured
into water (200 mL) and basified with 6 m KOH (20 mL) and ex-
tracted with CH2Cl2 (200 mL). A small portion of decolourising
carbon was added, and the organic layer was dried with MgSO4
and filtered to give 8 (0.264 g, 98%). 1H NMR (500 MHz, CDCl3):
–
m/z = 415.53 [M]+. C20H13N2O4Cl2H+·BF4 (503.04): calcd. C
47.75, H 2.60, N 5.57; found C 47.78, H 2.33, N 5.64.
Crystal Data for [H(5)][BF4]: C20H13N2O2Cl2BF4, yellow prism, di-
mensions 0.2ϫ0.15ϫ0.1 mm, triclinic, space group P21/c, a =
3
δ = 1.42 [s, 9 H, C(CH3)3], 7.25 (d, J2,3 = 8.7 Hz, 2 H, 2-PhH),
11.0327(2) Å,
113.4460(10)°,
b
β
=
=
13.5997(2) Å,
99.4340(10)°,
c
γ
=
=
15.1206(3) Å,
97.8210(10)°,
α
U
=
=
3
3
7.30 (d, J2,3 = 6.5 Hz, 1 H, 3-H), 7.64 (d, J2,3 = 8.7 Hz, 3-PhH),
3
3
2001.82(7) Å3, μ = 3.573 mm–1, Z = 4, Dc = 1.669 gcm–3, F(000) =
1016, T = 100(2) K. A total of 10378 reflections were collected by
using a Rigaku MM007 rotating anode in the range 6.58 Ͻ 2θ Ͻ
144.00°. A semiempirical absorption correction (ABSCOR; Higa-
shi, 1995) was applied. The 5797 independent reflections were used
to solve the structure by direct methods (SHELXS-97), which re-
sulted in the location of all non-hydrogen atoms. All non-hydrogen
atoms were made anisotropic and the refinement (SHELXL-97) of
596 parameters converged to R1 = 0.0406 [for 5280 reflections hav-
ing I Ͼ 4σ (I)], wR2 = 0.1095 and goodness of fit 1.080 (for all
5280 F2 data). Peak/hole 0.336/–0.391 eÅ–3.
8.00 (d, J10,11 = 4.9 Hz, 1 H, 10-H), 8.32 (d, J7,8 = 9.0 Hz, 1 H,
3
3
7-H), 8.40 (d, J5,6 = 8.9 Hz, 1 H, 6-H), 8.70 (d, J5,6 = 8.9 Hz, 1
H, 5-H), 8.83 (d, 3J7,8 = 9.0 Hz, 1 H, 8-H), 9.44 (d, 3J10,11 = 4.9 Hz,
1 H, 11-H), 9.61 (d, J2,3 = 6.5 Hz, 1 H, 2-H) ppm. 13C NMR
3
(125 MHz, CDCl3): δ = 31.1 (t), 34.6 (q), 105.7 (s), 116.6 (q), 120.0
(s), 120.1 (q), 122.6 (s), 123.6 (s), 126.0 (q), 126.7 (q), 127.1 (s),
127.9 (s), 128.8 (s), 129.8 (s), 137.6 (q), 140.0 (q), 145.0 (q), 146.5
(s), 146.6 (q), 149.8 (q), 150.0 (s), 151.1 (q) ppm. IR: ν = 2957,
˜
1595, 1496, 1475, 1417, 1262, 1218, 1205, 842 cm–1. HRMS (ESI+):
calcd. for C26H21N2OCl [M + H]+ 413.1415; found 413.1415.
4,9-Dimethoxyquino[7,8-h]quinoline (9): Sodium methoxide
(0.072 g, 1.338 mmol) was added to 6 (0.050 g, 0.167 mmol) in
MeOH (10 mL), and the mixture was heated at reflux for 2 h under
9-(4-tert-Butylphenoxy)quinolino[7,8-h]quinolin-4(1H)-one (7):
A
mixture of 4-tert-butylphenol (7.72 g, 51.2 mmol), potassium hy-
droxide (0.460 g, 9.35 mmol) and 6 (0.200 g, 0.668 mmol) was an atmosphere of Ar. The reaction mixture was diluted with
stirred at 150 °C for 4 h. The reaction mixture was diluted with
CH2Cl2 (200 mL) and washed with 7 m HCl (10 mL) in water
(200 mL) then basified with 6 m KOH (10 mL). The organic layer
was dried with MgSO4 and filtered. The product was purified by
silica gel column chromatography (CH2Cl2/MeOH, 95:5) to give 2
(0.258 g, 98%). 1H NMR (500 MHz, CDCl3): δ = 1.42 [s, 9 H,
CH2Cl2 (100 mL) and MeOH (10 mL), and the solution was then
washed with 2 m KOH (10 mL) in water (100 mL). The organic
layer was dried with MgSO4, filtered and concentrated to give 9
(0.048 g, 100%). The product was recrystallised by heating to dis-
1
solution in hot DMSO then slowly cooling. H NMR (500 MHz,
MeOD): δ = 3.35 (s, 6 H, OCH3), 7.20 (d, 3J2,3 = 5.0 Hz, 2 H, 3,10-
Eur. J. Org. Chem. 2012, 6967–6975
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6973

K. J. Shaffer, D. C. Parr, M. Wenzel, G. J. Rowlands, P. G. Plieger
FULL PAPER
3
3
H), 7.90 (d, J5,6 = 8.7 Hz, 2 H, 6,7-H), 8.35 (d, J5,6 = 8.7 Hz, 2
2920, 1594, 1560, 1512, 1457, 1421, 1388, 1326, 822, 800 cm–1.
HRMS (ESI+): calcd. for C30H24N4 [M + H]+ 441.2074; found
3
H, 5,8-H), 8.99 (d, J2,3 = 5.0 Hz, 2 H, 2,11-H) ppm. 13C NMR
(125 MHz, MeOD): δ = 50.0 (t), 102.9 (s), 121.7 (q), 123.1 (s), 125.7 441.2068 .
(q), 128.2 (s), 137.9 (q), 148.4 (q), 151.6 (s), 164.4 (q) ppm. IR: ν
˜
Crystal Data for 11a: C31H28N4O, yellow chip, dimensions
0.4ϫ0.15ϫ0.15 mm, orthorhombic, space group P212121, a =
7.8131(16) Å, b = 14.208(3) Å, c = 22.211(4) Å, α = 90.00°, β =
90.00°, γ = 90.00°, U = 2465.6(9) Å3, μ = 0.617 mm–1, Z = 4, Dc =
1.273 gcm–3, F(000) = 1000, T = 100(2) K. A total of 9733 reflec-
tions were collected by using a Rigaku MM007 rotating anode in
the range 6.54 Ͻ 2θ Ͻ 143.80°. A semiempirical absorption correc-
tion (ABSCOR; Higashi, 1995) was applied. The 4104 independent
reflections were used to solve the structure by direct methods
(SHELXS-97), which resulted in the location of all non-hydrogen
atoms. All non-hydrogen atoms were made anisotropic and the re-
= 3322, 1600, 1519, 1443, 1416, 1281, 1129, 1007, 837, 811 cm–1.
HRMS (ESI+): calcd. for C18H14N2O2 [M + H]+ 291.1128; found
291.1128.
Crystal Data for 9: C18H14N2O2, colourless chip, dimensions
0.6ϫ0.05ϫ0.05 mm, monoclinic, space group P21/c,
a =
6.9964(14) Å, b = 12.597(3) Å, c = 46.260(9) Å, α = 90.00°, β =
94.19(3)°, γ = 90.00°, U = 4066.3(14) Å3, μ = 0.762 mm–1, Z = 12,
Dc = 1.423 gcm–3, F(000) = 1824, T = 123(2) K. A total of 7370
reflections were collected by using a Rigaku MM007 rotating an-
ode in the range 6.70 Ͻ 2θ Ͻ 143.20°. A semiempirical absorption
correction (ABSCOR; Higashi, 1995) was applied. The 6224 inde-
pendent reflections were used to solve the structure by direct meth-
ods (SHELXS-97), which resulted in the location of all non-hydro-
gen atoms. All non-hydrogen atoms were made anisotropic and the
finement (SHELXL-97) of 329 parameters converged to R1
=
0.0392 [for 3788 reflections having I Ͼ 4σ (I)], wR2 = 0.1030 and
goodness of fit 1.066 (for all 3788 F2 data). Peak/hole 0.178/
–0.271 eÅ–3.
refinement (SHELXL-97) of 601 parameters converged to R1
=
[H(11a)][BF4]: BF3·OEt2 (0.484 mL, 3.856 mmol) was added to 11a
(0.100 g, 0.227 mmol) in dry CH2Cl2 (5 mL) under an atmosphere
of Ar, and the mixture was stirred at room temperature for 10 min.
The reaction mixture was diluted with diethyl ether, and the solvent
was separated from deposited [H(11a)][BF4], which was dried under
vacuum. The product was then set up for crystallisation by vapour
diffusion of diethyl ether into a MeOH solution containing
[H(11a)][BF4]. Yellow crystals suitable for X-ray crystallography
were obtained after 1 d. 1H NMR (500 MHz, [D6]DMSO): δ = 2.40
0.0940 [for 1963 reflections having I Ͼ 4σ (I)], wR2 = 0.1984 and
goodness of fit 0.828 (for all 1963 F2 data). Peak/hole 0.299/
–0.487 eÅ–3.
(E)-N-[9-Chloroquinolino[7,8-h]quinolin-4(1H)-ylidene]-4-methylani-
line (10): A solution of p-toluidine (0.143 g, 1.338 mmol) and 6
(0.100 g, 0.334 mmol) was heated at reflux for 4 h in toluene
(20 mL). The precipitate of crude 10 was filtered and dissolved in
CH2Cl2 (200 mL) and MeOH (20 mL) and then washed with water
(200 mL) and 6 m KOH (20 mL). The organic layer was dried with
MgSO4 and filtered. Compound 10 was precipitated from hot
DMSO by addition of EtOAc and filtered (0.099 g, 80%). 1H NMR
3
(s, 6 H, CH3), 7.06 (d, J5,8 = 6.3 Hz, 2 H, 6,7-H), 7.38 (m, 8 H,
3
3
2,3-PhH), 8.26 (d, J2,3 = 9.1 Hz, 2 H, 3,10-H), 8.72 (d, J5,6
=
3
6.3 Hz, 2 H, 5,8-H), 8.78 (d, J2,3 = 9.1 Hz, 2 H, 2,11-H), 10.11 (s,
2 H, NH), 18.79 (s, 1 H, NH) ppm. 13C NMR (125 MHz, [D6]-
DMSO): δ = 21.1 (t), 102.8 (s), 116.5 (q), 116.7 (q), 123.6 (s), 125.3
(s), 126.6 (s), 130.8 (s), 136.1 (q), 136.3 (q), 136.8 (q), 143.6 (q),
145.7 (s), 153.0 (q) ppm. HRMS (ESI+): calcd. for C30H24N4 [M
+ H]+ 441.2074; found 441.2068.
3
(500 MHz, CDCl3, MeOD): δ = 2.37 (s, 3 H, CH3), 6.97 (d, J5,6
3
= 7.0 Hz, 2 H, 6-H), 7.28 (m, 4 H, 2,3-PhH), 7.84 (d, J10,11
=
5.0 Hz, 2 H, 10-H), 8.09 (d, 3J7,8 = 9.0 Hz, 2 H. 7-H), 8.12 (d, 3J2,3
3
= 9.0 Hz, 2 H, 3-H), 8.40 (d, J2,3 = 9.0 Hz, 2 H, 2-H), 8.57 (d,
3
3J5,6 = 7.0 Hz, 2 H, 5-H), 8.68 (d, J7,8 = 9.0 Hz, 2 H, 8-H), 9.03
(d, 3J10,11 = 5.0 Hz, 2 H, 11-H); (in [D6]DMSO) 14.62 (s, 1 H, NH)
ppm. 13C NMR (125 MHz, CDCl3, MeOD): δ = 20.0 (t), 101.3 (s),
115.7 (q), 115.9 (q), 122.3 (s), 122.6 (s), 124.7 (s), 125.3 (s), 125.4
(s), 127.3 (q), 128.6 (s), 130.1 (s), 133.6 (q), 136.7 (q), 137.7 (q),
138.3 (q), 140.6 (s), 144.1 (q), 146.5 (q), 148.1 (s), 155.2 (q) ppm.
Crystal Data for [H(11a)][BF4]: C30H25N4BF4, yellow rod, dimen-
sions 0.8ϫ0.3ϫ0.05 mm, monoclinic, space group P21/c, a =
16.076(3) Å, b = 17.296(4) Å, c = 9.1906(18) Å, α = 90.00°, β =
97.00(3)°, γ = 90.00°, U = 2536.3(9) Å3, μ = 0.858 mm–1, Z = 4,
Dc = 1.384 gcm–3, F(000) = 1096, T = 123(2) K. A total of 8257
reflections were collected by using a Rigaku MM007 rotating an-
ode in the range 6.52 Ͻ 2θ Ͻ 143.40°. A semi-empirical absorption
correction (ABSCOR; Higashi, 1995) was applied. The 4242 inde-
pendent reflections were used to solve the structure by direct meth-
ods (SHELXS-97), which resulted in the location of all non-hydro-
gen atoms. All non-hydrogen atoms were made anisotropic and the
IR: ν = 2999, 1627, 1596, 1552, 1515, 1496, 1475, 1426, 1398, 1365,
˜
1346, 1220, 1180, 1148, 845, 825 cm–1. LRMS: m/z = 370.72 [M +
H]+. Elemental analysis was measured for the tetrafluoroborate
salt. C23H17ClN3·BF4·0.75H2O (471.17): calcd. C 58.63, H 3.96, N
8.92; found C 58.59, H 3.68, N 8.82.
(E)-N-p-Tolyl-9-(p-tolylimino)-9,12-dihydroquinolino[7,8-h]quinolin-
4-amine (11a): A solution of p-toluidine (2.75 g, 25.6 mmol) and 6
(0.100 g, 0.334 mmol) was stirred at 150 °C for 4 h. The reaction
mixture was diluted with CH2Cl2 (200 mL) and washed with water
(200 mL) and 6 m KOH (20 mL). The organic layer was dried with
MgSO4 and filtered. The product was purified by silica gel column
refinement (SHELXL-97) of 355 parameters converged to R1
=
0.0660 [for 2736 reflections having I Ͼ 4σ (I)], wR2 = 0.1710 and
goodness of fit 1.085 (for all 2736 F2 data). Peak/hole 0.425/
–0.371 eÅ–3.
(E)-Methyl 2-[9-(o-Tolylamino)quinolino[7,8-h]quinolin-4(1H)-ylid-
chromatography (CH2Cl2/MeOH, 90:10; CH2Cl2/MeOH, 50:50; eneamino]benzoate (11b):
A mixture of methyl anthranilate
CH2Cl2/MeOH/NEt3, 47:47:6) to give 11a (0.136 g, 92%). The
(6.65 mL, 51.4 mmol) and 6 (0.200 g, 0.668 mmol) was stirred at
120 °C for 2 h. The reaction mixture was diluted with CH2Cl2
(200 mL) and washed with water (200 mL) and 6 m KOH (20 mL).
The organic layer was dried with MgSO4 and filtered. The product
product was recrystallised by cooling to 4 °C in CH2Cl2/MeOH
1
overnight. H NMR (500 MHz, CDCl3, [D6]DMSO): δ = 2.33 (s,
3
3
6 H, CH3), 6.66 (d, J5,6 = 6.4 Hz, 2 H, 6,7-H), 7.12 (d, J2,3
=
3
7.9 Hz, 4 H, 2-PhH), 7.23 (d, J2,3 = 7.9 Hz, 4 H, 3-PhH), 7.95 (d, was purified by silica gel column chromatography (CH2Cl2/MeOH,
3J2,3 = 8.8 Hz, 2 H, 3,10-H), 8.25 (d, J2,6 = 6.4 Hz, 2 H, 5,8-H), 90:10; CH2Cl2/MeOH, 50:50; CH2Cl2/MeOH/NEt3, 47:47:6) to
3
8.61 (d, J2,3 = 8.8 Hz, 2 H, 2,11-H), 16.41 (s, 1 H, NH) ppm. 13C give 11b (0.093 g, 26%). 1H NMR (500 MHz, CDCl3, MeOD): δ
3
3
NMR (125 MHz, CDCl3, [D6]DMSO): δ = 20.6 (t), 101.8 (s), 116.2 = 3.97 (s, 6 H, COCH3), 7.17 (t, J5,6 = 7.6 Hz, 2 H, 6-PhH), 7.57
3
(q), 118.3 (q), 123.1 (s), 123.2 (q), 124.7 (s), 130.0 (s), 133.0 (s), (m, 4 H, 4,5-PhH), 7.68 (d, J3,4 = 8.0 Hz, 2 H, 3-PhH), 7.99 (d,
135.8 (q), 141.4 (q), 142.6 (q), 143.4 (q), 152.2 (s) ppm. IR: ν = 3J5,6 = 8.8 Hz, 2 H, 6,7-H), 8.04 (d, J2,3 = 7.9 Hz, 2 H, 3,10-H),
3
˜
6974
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6967–6975

The Proton Sponge Effect: Substitution of Quino[7,8-h]quinoline
3
Chem. Int. Ed. 2001, 40, 3182–3184; b) K. J. Shaffer, M. Wen-
zel, P. G. Plieger, Polyhedron 2012; DOI: 10.1016/
j.poly.2012.05.001.
8.28 (d, J5,6 = 8.8 Hz, 2 H, 5,8-H) 8.89 (m, 2 H, 2,11-H); (in
[D6]DMSO) 15.69 (s, 1 H, NH) ppm. 13C NMR (125 MHz, CDCl3,
MeOD): δ = 52.5 (t), 104.4 (s), 116.2 (q), 118.1 (q), 118.2 (q), 119.5
(s), 121.8 (s), 123.5 (s), 127.3 (s), 131.9 (s), 134.3 (s), 136.1 (q),
[5]
[6]
K. J. Shaffer, T. M. McLean, M. R. Waterland, M. Wenzel,
P. G. Plieger, Inorg. Chim. Acta 2012, 380, 278–283.
a) T. Kurata, K. Ishidai (Konica Minolta Holdings, Inc.),
patent JP2012014973A, Japan, 2012, 22pp; b) K. Shibata (Fuji-
film Corporation), patent JP2010135689A, Japan, 2010, 51pp;
c) P. Stoessel, H. Mayer, W. C. Kaska (Merck Patent GmbH),
patent WO2011116857A1, Germany, 2011, 68pp; d) H.-U.
Wuestefeld, W. C. Kaska, G. D. Stucky, F. Schueth, B. Krebs
(Studiengesellschaft Kohle Mbh), patent WO2002059134A1,
Germany, 2002, 26 pp.
K. Panda, I. Siddiqui, P. K. Mahata, H. Ila, H. Junjappa, Syn-
lett 2004, 449–452.
T. Steiner, Angew. Chem. 2002, 114, 50–80; Angew. Chem. Int.
Ed. 2002, 41, 48–76.
141.4 (q), 143.1 (q), 145.5 (s), 149.3 (q), 168.5 (q) ppm. IR: ν =
˜
3243, 1585, 1552, 1527, 1491, 1452, 1416, 1390, 1321, 1252, 1082,
738 cm–1. HRMS (ESI+): calcd. for C32H24N4O8 [M + H]+
529.1870; found 529.1866.
4,9-Dichloro-6,7-dinitroquinolino[7,8-h]quinoline (12): To a mixture
of fuming nitric acid (1 mL) and concentrated sulfuric acid (1 mL)
heated briefly to initiate NO2 generation was added 6 (0.050 g),
and the reaction mixture was stirred for 2 min at 120 °C. The mix-
ture was poured onto ice. The mixture was diluted with CH2Cl2
(100 mL) and MeOH (10 mL) and washed with 6 m KOH (20 mL).
The organic layer was dried with MgSO4, filtered, and concentrated
to give 12 (0.023 g, 35%). 1H NMR (500 MHz, 70 °C, [D6]DMSO):
[7]
[8]
[9]
K. Honda, H. Nakanishi, A. Yabe, Bull. Chem. Soc. Jpn. 1983,
56, 2338–2340.
G. A. Jeffrey, Crystallogr. Rev. 2003, 9, 135–176.
J. S. Hartman, J. A. W. Shoemaker, Polyhedron 2000, 19, 165–
176.
3
3
δ = 6.52 (d, J2,3 = 7.4 Hz, 1 H, 3-H), 8.34 (d, J5,6 = 5.0 Hz, 1 H,
10-H), 8.37 (dd, J1,2 = 5.2 Hz, J2,3 = 7.4 Hz, 1 H, 2-H), 9.09 (s,
3
3
[10]
[11]
3
1 H, 8-H), 9.15 (s, 1 H, 5-H), 9.31 (d, J10,11 = 5.0 Hz, 1 H, 11-H),
15.59 (d, J1,2 = 5.2 Hz, 1 H, NH) ppm. 13C NMR (125 MHz,
3
[12]
[13]
K. Wozniak, T. M. Krygowski, B. Kariuki, W. Jones, E. Grech,
J. Mol. Struct. 1990, 240, 111–118.
M. Schmittel, H. Ammon, Eur. J. Org. Chem. 1998, 785–792.
70 °C, [D6]DMSO): δ = 111.1 (q), 113.4 (s), 120.1 (q), 121.3 (q),
123.7 (q), 123.8 (q), 124.9 (s), 125.1 (s), 126.3 (s), 140.5 (q), 141.8
(s), 142.8 (q), 145.3 (q), 145.6 (q), 148.3 (q), 152.8 (s) ppm. HRMS
(ESI+): calcd. for C16H6Cl2N4O4 [M + H]+ 388.9839; found
388.9832.
[14] a) V. Raab, J. Kipke, R. M. Gschwind, J. Sundermeyer, Chem.
Eur. J. 2002, 8, 1682–1693; b) V. Raab, K. Harms, J. Sun-
dermeyer, B. Kovacevic, Z. B. Maksic, J. Org. Chem. 2003, 68,
8790–8797; c) V. Raab, E. Gauchenova, A. Merkoulov, K.
Harms, J. Sundermeyer, B. Kovacevic, Z. B. Maksic, J. Am.
Chem. Soc. 2005, 127, 15738–15743.
[15] a) A. A. Avetisyan, I. L. Aleksanyan, L. P. Ambartsumyan,
Russ. J. Org. Chem. 2008, 44, 723–727; b) M. Manoj, K. J. R.
Prasad, Z. Naturforsch. B 2009, 64, 851–857.
[16] T. Barth, C. Krieger, F. A. Neugebauer, H. A. Staab, Angew.
Chem. Int. Ed. Engl. 1991, 30, 1028–1030.
[17] V. G. Pawar, M. L. Sos, H. B. Rode, M. Rabiller, S. Heynck,
O. W. A. L. van, R. K. Thomas, D. Rauh, J. Med. Chem. 2010,
53, 2892–2901.
CCDC-893097 (for 3), -893098 (for [H(5)][BF4]), -893099 (for
11a), -893100 (for 7), -893101 (for [H(11a)][BF4]) and -893102 (for
9) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectra for compounds 3, 5,
H(5)BF4, 7, 8, 9, 10, 11a, H(11a)BF4, 11b and 12; molecular orbital
plots for compounds H(11a)BF4 and H(11b)BF4.
[18] A. Corma, S. Iborra, I. Rodriguez, F. Sanchez, J. Catal. 2002,
211, 208–215.
[19] G. M. Sheldrick, SHELXTL Programs for Crystal Structure
Analysis, University of Göttingen, Germany, 1998.
Acknowledgments
[20] , M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-
gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Starov-
erov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Ad-
amo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Mar-
tin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
Revision C.02, Gaussian, Inc., Wallingford, CT, 2009.
[21] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
Received: August 20, 2012
K. J. S. would like to thank the New Zealand Tertiary Education
Commission for a Top Achiever Doctorial Scholarship.
[1] R. W. Alder, P. S. Bowman, W. R. S. Steele, D. R. Winterman,
Chem. Commun. (London) 1968, 723–724.
[2] a) A. F. Pozharskii, V. A. Ozeryanskii, The Chemistry of Ani-
lines, part 1, Wiley, Chichester, UK, 2007, vol. 2, pp. 931–1139;
b) A. L. Llamas-Saiz, C. Foces-Foces, J. Elguero, J. Mol.
Struct. 1994, 328, 297–323; c) K. Nagasawa, Superbases for
Organic Synthesis: Guanidines, Amidines, Phosphazenes and Re-
lated Organocatalysts, Wiley, Chichester, UK, 2009, pp. 251–
271; d) A. F. Pozharskii, V. A. Ozeryanskii, E. A. Filatova,
Chem. Heterocycl. Compd. 2012, 48, 200–219.
[3] a) C. Krieger, I. Newsom, M. A. Zirnstein, H. A. Staab, Angew.
Chem. 1989, 101, 72–73; Angew. Chem. Int. Ed. Engl. 1989, 28,
86–88; b) M. A. Zirnstein, H. A. Staab, Angew. Chem. 1987,
99, 460–462.
[4] a) H.-U. Wüstefeld, W. C. Kaska, F. Schuth, G. D. Stucky, X.
Bu, B. Krebs, Angew. Chem. 2001, 113, 3280–3282; Angew.
Published Online: October 30, 2012
Eur. J. Org. Chem. 2012, 6967–6975
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6975