Hydrogen Bonded Phenol-Quinolines with Highly Controlled Proton-Transfer Coordinate

Article abstract of DOI:10.1002/ejoc.201600460

A series of polycyclic phenols with intramolecular hydrogen bonds (IMHB) to quinolines was synthesized by Friedl?nder annulation of cycloalkanone-functionalized anisoles with 2-aminobenzaldehyde. The prepared compounds represent the first series of IMHB phenols in which the substitution and conjugation patterns between the phenols and the hydrogen bond acceptors are kept constant, and in which comparable electronic interaction between the two subunits is thus ensured. The distance and relative orientation between the phenolic OH and the quinolone nitrogen atom is controlled by 1,3-cycloalkadienes of different ring sizes to which the phenol and quinoline subunits are formally annulated.¹H δ(OH) chemical shift and X-ray crystal structure characterization support the conclusion that the size and conformational preference of the 1,3-cycloalkadiene rings control the H-bond geometry and strength. As a result, the oxygen to nitrogen distances differ by as much as 0.30 ? across the series.

Full text of DOI:10.1002/ejoc.201600460

DOI: 10.1002/ejoc.201600460
Full Paper
Hydrogen Bonds
Hydrogen Bonded Phenol-Quinolines with Highly Controlled
Proton-Transfer Coordinate
Giovanny A. Parada,[a] Starla D. Glover,[a] Andreas Orthaber,[a] Leif Hammarström,[a] and
Sascha Ott*[a]
Abstract: A series of polycyclic phenols with intramolecular and the quinolone nitrogen atom is controlled by 1,3-cycloalka-
hydrogen bonds (IMHB) to quinolines was synthesized by Fried- dienes of different ring sizes to which the phenol and quinoline
länder annulation of cycloalkanone-functionalized anisoles with subunits are formally annulated. 1H δ(OH) chemical shift and X-
2-aminobenzaldehyde. The prepared compounds represent the ray crystal structure characterization support the conclusion
first series of IMHB phenols in which the substitution and conju- that the size and conformational preference of the 1,3-cyclo-
gation patterns between the phenols and the hydrogen bond alkadiene rings control the H-bond geometry and strength. As
acceptors are kept constant, and in which comparable elec- a result, the oxygen to nitrogen distances differ by as much as
tronic interaction between the two subunits is thus ensured. 0.30 Å across the series.
The distance and relative orientation between the phenolic OH
Introduction
in substantial differences in π-conjugation (different electronic
communication) and ΔpKa's (different substitution pattern) be-
tween the proton donor and acceptor units. Especially the dif-
ferences in π-conjugation impose large variations in resonance
assistance H-bond (RAHB)[13,14] interactions. These differences
make it difficult to clearly dissect the factors that are responsi-
ble for the H-bond strength and to achieve good isolation of
the proton transfer coordinate from other structural and elec-
tronic parameters.
Hydrogen bonds (H-bonds) have been extensively studied for
their role in recognition, assembly and stabilization of biomole-
cules such as DNA pairs and secondary structure of proteins.[1,2]
Their role in enzymatic activity is, however much less under-
stood. Recently, H-bonds have been recognized as a non-cova-
lent interaction able to tune electronic properties or to shape
proton transfer free energy profiles of redox cofactors and ac-
tive sites, thereby altering enzymatic activity.[3–6] Also, proton-
coupled electron transfer (PCET) reactions continue to attract
considerable attention due to their presence in an extensive
variety enzymatic processes.[7] In these reactions, H-bonds facili-
tate the proton wavefunction overlap required for the tunneling
of a proton and an electron in a single kinetic step.[7–9] We have
previously studied rates of PCET as a function of the proton
tunneling distance using intramolecularly H-bonded (IMHB)
tyrosine analogues as synthetic model systems for
tyrosine-161 (TyrZ) H-bonded to His190 in Photosystem II.[10–12]
In these systems, we observed strong dependence of the rates
of PCET as a function of the proton donor–acceptor distance
(dDA). Modulation of dDA was achieved by the presence of a
methylene fragment between an ortho-substituted tyrosine an-
alogue and a covalently attached proton acceptor. While this
design allowed for certain variations of dDA, the methylene spa-
cer led to different conjugation and substitution patterns be-
tween the proton donor and acceptor. This discrepancy resulted
Results and Discussion
Having identified the shortcomings of the previous designs, we
herein report a new series of IMHB phenols where both the H-
bond donor and acceptor have consistent substitution and π-
conjugation patterns, and in which differences in RAHB are thus
minimized. Within this series, the distance between H-bond do-
[a] Department of Chemistry Ångström Laboratories, Uppsala University,
Box 523, 75120 Uppsala, Sweden
E-mail: sascha.ott@kemi.uu.se
http://www.kemi.uu.se/research/molecular-biomimetic/
molecular-inorganic-chemistry/ott-group/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600460.
Scheme 1. a) Structure of the intramolecularly H-bonded phenol-quinolines.
b) Synthesis of 1–3 via Friedländer annulation.
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nor and acceptor (dDA) is controlled by the size and conforma- access to ketone 7 in 95 % yield, followed by methylation to
tional preference of a cycloalkadiene that interconnects the two afford anisole 8 in 66 % yield. Friedländer annulation of anisoles
subunits (Scheme 1). Herein, we report the synthesis and char- 5 and 8 with 2-aminobenzaldehyde in the presence of NH4OAc
acterization of these IMHB phenols, as well as a conformational affords the polycyclic compound 6 and 9 in 95 % yield in both
analysis that allows the rationalization of the observed trends cases. Final deprotection of the phenolic OH proceeds smoothly
in H-bond strength. In addition, we show that halogenation using BBr3 at 65 °C to afford 1 and 2 in 93 % and 95 % yield,
of the phenol presents additional means to alter the H-bond respectively. The raised temperature is necessary in this step as
strength.
Synthetically, it was envisaged that the title compounds
lower temperatures give unsatisfactory yields.
The analogous ketone en route to compound 3 was made
would become accessible from the condensation of cycloalkan- available through a four-step sequence starting from 3-
one-functionalized anisoles with 2-aminobenzaldehyde via bromoanisole (Scheme 2). Lithium–halogen exchange, followed
Friedländer annulation (Scheme 1). This methodology guaran- by alkylation using 1,4-dibromobutane gave rise to 10 in 64 %
tees complete control over the regiochemistry of the formed yield. Subsequently, the aliphatic bromide 10 was converted to
quinoline relative to the phenol as the orientation of the former its Grignard reagent which was further reacted with dry CO2 to
is determined by the position of the ketone in the cycloalkane afford 11 in 78 % yield. In order to direct the subsequent cycli-
rings during the annulation step.
zation to the ortho-position of the anisole, the para-position
first had to be blocked by converting it to the bromide. Hence,
anisole 11 was treated with bromine to afford 12 in 96 % yield.
The subsequent cyclization of 12 using polyphosphoric acid
(PPA) results in the formation of the key anisole 13 as envis-
aged, and in 99 % yield. Compound 13 has previously been
reported,[17] but the synthetic sequence reported herein is
shorter and proceeds generally in high yields. Friedländer annu-
lation of 13 proceeds as usual with 2-aminobenzaldehyde in
the presence of NH4OAc to afford polycyclic 14 in 47 % yield.
Palladium-catalyzed reductive hydro-dehalogenation of 14
(81 %), followed by hydroxyl cleavage using BBr3 gives rise to 3
in 90 % yield (Scheme 2, c).
As outlined in Scheme 2, the ketone intermediates that are
needed for the Friedländer annulation en route to 1 and 2 are
readily available in two steps from suitable bicyclic starting ma-
terials, while a more complex sequence had to be devised for
the preparation of 3. The synthesis of 1 starts with a rearrange-
ment of 4-chromanone with AlCl3 to afford indanone 4[15,16] in
60 % yield. For the subsequent annulation step, it is imperative
to protect the phenolic OH which can be done in good yield
by treatment with KOH and MeI. The ketone that is required
for the preparation of 2 can be prepared by hydrogenation of
naphthalene-1,8-diol over palladium on charcoal which gives
Halogenated derivatives of 1 and 2 were prepared to illus-
trate that the electronics, and thus the H-bond strength can be
further tuned by functionalizations of the phenols. At the same
time, halogenated derivatives provide valuable synthetic han-
dles that would allow for future covalent attachment of other
functional groups, for example photoactive units for light-in-
duced intramolecular electron transfer reactions. As starting
point, we explored the para-bromination and iodination of 1
and 2 (Scheme 3). 4-Bromoanisole analogues of 1 and 2 (1-Br
and 2-Br) were obtained by reacting anisoles 6 and 9 with NBS
and HBF4·Et2O in acetonitrile at room temperature.[18] Subse-
quent methoxy deprotection as usual affords 1-Br and 2-Br in
55 % and 59 % overall yields in two steps. 4-Iodophenol ana-
logues of 1 and 2 (1-I and 2-I) were obtained by reacting 1 and
2 in a sealed vial with NIS and HBF4·Et2O in acetonitrile at
100 °C for 5 min under microwave irradiation.[19,20] This proce-
Scheme 2. Synthesis of the intramolecularly H-bonded phenol-quinolines 1–
3 (a–c, respectively).
Scheme 3. Synthesis of halogenated derivatives of phenols 1 and 2.
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dure afforded 1-I and 2-I in 45 % and 24 % yield, respectively.
Significant structural variations of the H-bond geometry
In case of the iodination of 1, another by-product, 1-2I, which across the series were observed in the solid-state structures of
features a second iodide in the ortho-position could be isolated. the compounds. Of all synthesized anisoles and phenols de-
1
scribed herein, single crystals suitable for X-ray crystallographic
analysis could be obtained for compounds 1, 2, 3, 14, 1-2I and
2-Br. ORTEP views at 50 % probability are presented in Figure 1.
The series of IMHB phenols shows significant variations in
The H-NMR spectra of 1–3 show signal patterns in the aro-
matic region consistent with those expected for [2,3]-substi-
tuted phenols and [2,3]-substituted quinolines. In general, cor-
responding aromatic protons within the series show similar
chemical shifts. The methylene, 1,2-ethylene and 1,3-propylene the proton donor–acceptor distance dDA (ΔdON = 0.30 Å). In the
fragments of 1, 2 and 3, respectively, can be identified at lower series 1–3, 1 exhibits the largest dON = 2.8487(5) Å distance,[24]
frequencies. Importantly, the 1H-NMR chemical shift of the followed by 3 with dON = 2.666(1) Å, and finally 2 which features
phenolic proton in 1–3 is observed at above 9 ppm, confirming the shortest dON = 2.567(2) Å. The resulting trend of the proton
the expectation of intramolecular H-bonding between the donor–acceptor distance dDA is thus 1 > 3 > 2. The empirical
phenol and the quinoline. The 1H δ(OH) chemical shift spans correlation between dDA and the H-bond strength[24,25] allows
circa Δδ = 5 ppm over the series following the trend 1 (δ = us to establish the trend 1 < 3 < 2 within the series, i.e. the
1
9.86 ppm) < 3 (δ = 11.75 ppm) < 2 (δ = 14.69 ppm) in CD2Cl2. same order as deduced from the H δ(OH) chemical shifts. Al-
1
The empirical correlation between H δ(OH) chemical shift and though only neutron diffraction allows the accurate assignment
the H-bond strength[21–23] allows us to establish the trend 1 < of crystallographic proton positions, the phenolic protons were
3 < 2 for the H-bond strength within the series. Notably, this located in the electron density maps and their positions were
trend does not simply reflect the ring size of the 1,3-cycloalka- allowed to refine freely. The O–H distance (dON) varies according
diene between the phenol and the quinolone, pointing towards to the following trend: 1 (1.03 Å) < 3 (0.913 Å) < 2 (0.942 Å)
additional factors that determine the H-bond strength. The which is also in agreement with the established H-bond
presence of halide substituents at the phenol moiety of 1–2 strengths. The N···H distance (dN–H) follows the complementary
has a small, but detectable effect on the H-bond strength as trend: 2 (1.733 Å) < 3 (1.874 Å) < 1a (1.97 Å). The O–H···N angle
1
seen for example in the H-NMR spectrum of 2-Br where the (α) for 1, 2 and 3 shows significantly distortions from linearity
phenolic OH resonates at δ = 15.10 ppm compared to that of and does not follow any specific trend: 142.03°, 145.24° and
2 at δ = 14.69 ppm.
142.72°, respectively.
Figure 1. ORTEP views at 50 % probability of 1, 2, 3, 1-2I, 2-Br and 14, front and side-on views. b) Selected crystallographic parameters. c) Relevant structural
parameters of the IMHB: proton donor–acceptor distance (dON), dihedral angle between the proton-donor acceptor subunits (θ) and O–H···N angle (α).
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The observed trend in H-bond strength 1 < 3 < 2 is analyzed gen and nitrogen, the absence of the H-bond, and the steric
on the basis of the conformational preference of the rings that demand of the methyl group.
connect the phenol and quinolone subunits, and how this pref-
erence impacts the spatial orientation of the two units relative
to each other (Figure 2). In the case of 1, the small internal
angles of the 1,3-cyclopentadiene ring enforce the in-plane sep-
aration of the phenol and the quinoline which results in the
longest dDA of the series. The sp2 carbons of the 1,3-diene ring
feature internal angles of circa 109° that are considerably
smaller than unstrained sp2 carbon atoms (120°). A similar but
smaller angular strain is also observed for the sp3 methylene
carbon (103°) compared to an un-strained sp3 carbon (109°). On
the other hand, the planarity of the 1,3-cyclopentadiene indu-
ces co-planarity between the phenol and the quinoline (θ =
2.8°). In the case of 2, the unstrained internal angles of the 1,3-
cyclohexadiene ring (ca. 119° on the 1,3-diene carbon atoms
and ca. 110° in the methylene groups) promote the closest dis-
tance between the phenol and the quinoline, resulting in the
shortest dDA of the series. The 1,3-cyclohexadiene adopts its
typical twisted conformation with staggered protons in the 1,2-
ethylene fragment. This conformation results in a small dihedral
angle between the phenol and the quinoline of θ = 13.0°. In
the case of 3, the intermediate dDA between that of 1 and 2
results from the twist boat conformation adopted by the 1,3-
cycloheptadiene ring which results in a significantly larger dihe-
dral angle between the phenol and the quinoline of θ = 36.4°.
Thus, in case of 3, the relatively long dDA does not originate
from in-plane separation of the phenol and quinoline that is
responsible for the dDA differences in 1 vs. 2, but from the dihe-
dral angle and the out-of-plane separation of the two aromatic
subunits due to the twisted boat conformation of the 1,3-cyclo-
heptadiene ring. It is worth noting that 3 appears to have a
small energy barrier for the interconversion between its two
twist boat conformers since the enantiotopic protons of the
1,3-propylene fragment are indistinguishable on the 1H-NMR
timescale at 298 K, as opposed to the situation in anisoles 14
and 15 (Figure S3, S14 and S15). The solid-state structure of 14
reveals a significantly larger dihedral angle between the anisole
and the quinoline (60.5°, Figure 1), which is attributed to the
electrostatic repulsion of the valence free electron pairs of oxy-
The effect of halogenation of the phenol ring on the H-bond
strength can also be observed in the solid-state structures. No-
tably, 2-Br shows smaller dON and θ compared to 2, consistent
with a decrease of the pKa of the bromo-substituted phenol
compared to that of the parent IMHB phenol 2. With 2-Br being
a stronger acid than 2, the H-bond strength in 2-Br is increased,
a finding that is consistent with the observations in the 1H
δ(OH) chemical shifts.
Conclusions
The series of IMHB phenols 1–3 could be readily synthesized
by the Friedländer annulation of suitable cycloalkanone-func-
tionalized anisoles with 2-aminobenzaldehyde. The design of
the compounds is unique in the sense that 1–3 represent the
first series of IMHB phenols with differing H-bond strengths,
but identical substitution and conjugation patterns. As a result,
differences on the influence of cooperative effects such as reso-
nance assisted hydrogen bonding (RAHB) on the H-bond
strength are minimized.[13,14] The size and the conformational
preference of the central 1,3-cycloalkadiene in 1–3 controls the
spatial separation of the phenol and the quinoline, and there-
fore the exhibited trend in H-bond strength. Owing to these
unique features, we believe that IMHB phenols 1–3 are highly
suitable systems for proton-coupled electron transfer studies.
Experimental Section
General: NMR spectra were recorded at ambient temperature on a
JEOL Eclipse + 400 MHz spectrometer (operating at 399.8 MHz) or
Varian Mercury Plus 300 MHz spectrometer (operating at
300.03 MHz) at 293 K. Chemical shifts are given in ppm and refer-
enced internally to the residual solvent signal. Column chromatog-
raphy was performed on Merck silica gel SI-60 Å (35–70 or 0.063–
0.200 mm), or pre-packaged 50–100 g silica columns FLASH col-
umns on a HPFC Biotage SP4 system (Biotage). Microwave heating
was performed in seal-vials using an InitiatorTM single mode micro-
wave cavity at 2450 MHz (Biotage). High-resolution mass spectrom-
etry (HRMS) were performed using
a high-resolution and
FTMS+pNSI mass spectrometer (orbitrapXL), using a MicroTOF spec-
trometer with ESI core at University of Münster. HPLC-MS data were
obtained on a Dionex Ultimate 3000 system on a Phenomenex
Gemini C18 column (150 × 4.6 mm, 5 μ) coupled to Thermo LCQ
Deca XP with electrospray ionization (ESI). Solvents used for HPLC:
0.05 % HCO2H in H2O and 0.05 % HCO2H in CH3CN.
7-Hydroxyindanone (4):[15,16,27] A round bottle flask loaded with
5.0 g (37.8 mmol) of 4-chromanone and 10.0 g (97.5 mmol) of anhy-
drous powder AlCl3 was heated at 180 °C for 20 min and then at
200 °C for 30 min. The reaction mixture was cooled down to room
temperature and HCl 37 % was added. The resulting slurry was ex-
tracted with dichloromethane, dried with anhydrous MgSO4. The
solvent was evaporated and the residue chromatographed on silica
gel with n-hexane/ethyl acetate (4:1), yield 3.35 g, 60 %. 1H NMR
(400 MHz, 298 K, CDCl3): δ = 9.07 (s, 1 H), 7.47 (dd, J = 8.2, 7.5 Hz,
1 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.76 (d, J = 8.2 Hz, 1 H), 3.18–3.05 (m,
2 H), 2.77–2.65 (m, 2 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ =
210.19, 157.58, 155.34, 137.70, 122.76, 117.51, 113.52, 36.06, 25.94
Figure 2. Internal angles and conformation of the 1,3-cycloalkadienes rings
in 1, 2, and 3.
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ppm. HRMS (ESI): Calcd. for C9H8O2Na 171.0422, found 171.0418
+ 1/19 diethyl ether] C 81.81, H 4.72, N 5.96; found C 81.79, H 4.92,
N 6.00.
m/z [M + Na+].
7-Methoxyindanone (5):[16,28] A round bottle flask loaded with
0.5096 g (9.08 mmol) of finely ground KOH and 10 mL of DMSO
was heated gently until a homogeneous solution was achieved.
Upon cooling to room temperature, 1.0055 g (6.789 mmol) of 4
were added and the mixture was stirred for 10 min. The mixture
was cooled to 5 °C in an ice/water bath and 2.4 mL (7.4 mmol) of
MeI were added dropwise. The ice/water bath was removed and
the mixture was stirred for 30 min. After this, the mixture was
poured into water and extracted with dichloromethane. The organic
layer was extracted with brine, dried with anhydrous MgSO4 and
concentrated under vacuum. The residue was chromatographed on
silica gel eluted with dichloromethane, yield 0.8960 g, 81 %. 1H NMR
(400 MHz, 298 K, CDCl3): δ = δ = 7.49 (dd, J = 8.2, 8.0 Hz, 1 H), 6.99
(d, J = 8.0 Hz, 1 H), 6.76 (d, J = 8.2 Hz, 1 H), 3.93 (s, 3 H), 3.13–3.00
(m, 2 H), 2.72–2.58 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
8-Hydroxytetralone (7):[30] As follows: An autoclave reactor was
loaded with 2.5 g (15.6 mmol) Naphthalene-1,8-diol, 130 mg of
Palladium/charcoal activated 10 wt.-% and 2.5 mL of ethanol
(99.5 %). The reactor was sealed and three cycles of nitrogen fol-
lowed by hydrogen were performed. The reactor was then pressur-
ized at 4 atm of hydrogen and heated at 60 °C for 48 h. Upon
cooling and depressurization the reaction mixture was filter on a
celite plug and washed with ethanol (99.5 %). The solvent was re-
moved under vacuum leaving a black oil residue. The oil was dis-
solved in n-hexane and further filtered on a short silica plug. The
solvent was removed under vacuum affording a clear oil. The oil
gradually turns dark on the bench over several weeks, yield 2.4 g,
1
95 %. H NMR (400 MHz, 298 K, CDCl3): δ = 12.42 (s, 1 H), 7.36 (dd,
J = 8.4, 7.8 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 7.8 Hz, 1
H), 2.93 (dd, J = 6.8 Hz, 2 H), 2.69 (dd, J = 6.30 Hz, 2 H), 2.10 (q, 2
204.86, 158.06, 136.48, 125.28, 118.53, 108.87, 55.83, 36.86, 25.63 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ = 205.28, 163.02,
ppm. HRMS (ESI): Calcd. for C10H10O2Na 185.0578, found 185.0574
145.59, 136.38, 118.91, 117.17, 115.64, 39.06, 29.88, 22.99 ppm.
HRMS (ESI): Calcd for C10H10O2Na 185.0573 found 185.0577 m/z [M
+ Na+].
m/z [M + Na+].
4-Methoxy-11H-indeno[1,2-b]quinoline (6):[29] A carefully dried
three neck flask equipped with condenser was loaded with 3.6 g
(47 mmol) of ammonium acetate (dried with P2O5), 0.76 g
(4.7 mmol) of 5, 0.85 g (7.0 mmol) of 2-aminobenzaldehyde and
26 mL of ethanol (99.5 %). The mixture was stirred for 5 d at room
temperature under a nitrogen atmosphere, and then heated at
80 °C for 30 min. The solvent was evaporated under vacuum and
the residue was washed with dichloromethane. The dichloro-
methane solution was concentrated under vacuum and further
chromatographed on silica gel with n-hexane/ethyl acetate (2:1),
yield 1.1 g, 95 %. 1H NMR (300 MHz, 298 K, CDCl3): δ = 8.27 ppm
(d, J = 8.4 Hz, 1 H); 8.14 (s, 1 H); 7.79 (dd, J = 8.1, 1.2 Hz, 1 H), 7.67
(ddd, J = 8.1, 6.9, 1.5 Hz; 1 H); 7.48 (ddd, J = 8.1, 6.9, 1.2 Hz; 1 H);
7.44 (dd, J = 8.4, 8.1 Hz; 1 H); 7.21 (dd, J = 8.1, 1.5 Hz; 1 H); 7.00 (d,
J = 8.1 Hz; 1 H); 4.14 (s, 3 H), 4.04 (s, 2 H) ppm. 13C NMR (100 MHz,
298 K, CDCl3): δ = 161.28, 157.53, 147.88, 134.60, 132.01, 131.60,
131.33, 130.11, 129.68, 129.07, 127.59, 126.66, 126.18, 117.90,
109.74, 56.36, 34.48 ppm. HRMS (ESI): Calcd for C17H13NOH
248.1075 found 248.1076 m/z [M + H+].
8-Methoxytetralone (8):[31] The title compound was synthesized
similarly to 5. Chromatographic purification was done with silica gel
eluted with n-hexane/ethyl acetate (9:1), yield 0.889 g, 66 %. 1H
NMR (400 MHz, 298 K, CDCl3): δ = 7.37 (t, J = 8.0 Hz, 1 H), 6.86–
6.78 (m, 2 H), 3.9 (s, 3 H) 2.91 (t, J = 8.0 Hz, 2 H), 2.62 (t, J = 8.0 Hz,
2 H), 2.09–2.00 (m, 2 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ =
197.77, 160.59, 147.37, 134.16, 122.45, 120.96, 110.17, 56.20, 41.18,
31.06, 23.09 ppm. HRMS (ESI): Calcd for C11H12O2Na 199.0735 found
199.0738 m/z [M + Na+].
1-Methoxy-5,6-dihydrobenzo[c]acridine (9):[29] The title com-
pound was synthesized similarly to 6. Chromatographic purification
was done with silica gel eluted with n-hexane/ethyl acetate (2:1),
yield 0.317 g, 60 %. 1H NMR (400 MHz, 298 K, CDCl3): δ = 8.21 (d,
J = 8.0, 1.1 Hz, 1 H), 7.94 (s, 1 H), 7.74 (dd, J = 8.1, 1.0 Hz, 1 H), 7.65
(ddd, J = 8.0, 6.9, 1.1 Hz, 1 H), 7.45 (ddd, J = 8.1, 6.9, 1.0 Hz, 1 H),
7.32 (dd, J = 8.3, 7.4 Hz, 1 H), 7.01 (d, J = 8.3 Hz, 1 H), 6.92 (d, J =
7.4 Hz, 1 H), 4.01 (s, 3 H), 3.01 (dd, J = 8.2, 4.8 Hz, 2 H), 2.90 (dd,
J = 8.4, 4.7 Hz, 2 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ =
158.93, 153.11, 146.99, 143.26, 133.62, 132.58, 130.88, 129.36,
128.94, 127.37, 126.87, 126.62, 123.62, 120.61, 111.93, 56.73, 30.07,
29.76 ppm. HRMS (ESI): Calcd for C18H15NOH 262.1232 found
262.1225 m/z [M + H+].
11H-Indeno[1,2-b]quinolin-4-ol (1): A carefully dried three neck
flask equipped with condenser was loaded with 0.420 g (1.72 mmol)
of 6 and 20 mL of CHCl3. The mixture was cooled 5 °C in an ice/
water bath and 6.9 mL of BBr3 (1
M in dichloromethane) were added
dropwise. The ice/water bath was removed and the mixture was
heated at 65 °C overnight. Upon cooling to room temperature,
20 mL of saturated aqueous solution of NaHCO3 were slowly added.
The organic phase was separated and further extracted with di-
chloromethane and brine. The organic extract was dried with anhy-
drous MgSO4 and concentrated under vacuum for further chroma-
tography on silica gel eluted with n-hexane/ethyl acetate (9:1), yield
0.371 g, 93 %. Slow evaporation of a Et2O solution of the compound
afforded off-white needles. Different attempts to obtain crystals for
5,6-Dihydrobenzo[c]acridin-1-ol (2): The title compound was syn-
thesized similarly to 1, yield 0.200 g, 95 %. Slow evaporation of a
Et2O solution of the compound afforded crystals suitable for X-ray
1
crystallography. H NMR (400 MHz, 298 K, CD2Cl2): δ = 14.69 ppm
(s, 1 H); 8.01 (s, 1 H), 8.00 (dd, J = 8.0,1.2 Hz, 1 H); 7.79 (dd, J = 8.0,
1.2 Hz, 1 H), 7.68 (ddd, J = 8.0, 7.2, 1.2 Hz; 1 H); 7.53 (ddd, J = 8.0,
7.2, 1.2 Hz; 1 H); 7.25 (dd, J = 8.0, 7.6 Hz; 1 H); 6.88 (d, J = 8.0 Hz; 1
H); 6.76 (d, J = 8.0 Hz; 1 H); 3.14 (m, 2 H); 3.02 (m, 2 H) ppm. 13C
NMR (100 MHz, 298 K, CD2Cl2): δ = 160.86, 156.11, 144.53, 140.90,
134.84, 132.01, 130.99, 129.77, 127.56, 127.54, 127.48, 126.80,
118.67, 116.98, 116.14, 28.80, 28.74 ppm. MS (ESI): Calcd for
C17H13NOH 248.11 a.u, found 248.27 m/z [M + H+]. HRMS (ESI): Calcd
for C17H13NOH 248.1075 found 248.1073 m/z [M + H+]. [C17H13NO
+ 1/12 diethyl ether] C 82.13, H 5.50, N 5.53, found C 82.08, H 5.49,
N 5.51.
1
X-ray crystallography were unsuccessful. H NMR (400 MHz, 298 K,
CD2Cl2): δ = 9.86 ppm (s, 1 H); 8.21 (s, 1 H), 8.09 (dd, J = 8.3,1.2 Hz,
1 H); 7.87 (dd, J = 8.0, 1.2 Hz, 1 H), 7.71 (ddd, J = 8.3, 7.0, 1.2 Hz; 1
H); 7.54 (ddd, J = 8.0, 7.0, 1.2 Hz; 1 H); 7.39 (dd, J = 8.0, 7.6 Hz; 1
H); 7.15 (d, J = 7.6 Hz; 1 H); 6.93 (d, J = 8.0 Hz; 1 H); 4.06 (s, 2 H)
ppm. 13C NMR (100 MHz, 298 K, CD2Cl2): δ = 163.25 ppm, 156.08,
147.13, 146.21, 134.57, 132.30, 131.65, 129.48, 128.51, 128.36,
127.39, 126.01, 125.11, 117.03, 113.73, 34.63 ppm. MS (ESI): Calcd
1-(4-Bromobutyl)-3-methoxybenzene (10):[17] A carefully dried
g (10.7 mmol) of 3-
bromoanisole and 50 mL of dry THF was cooled to –78 °C in an
for C16H11NOH 234.09 found 234.45 m/z [M + H+]. HRMS (ESI): Calcd three neck flask loaded with 2.00
for C16H11NOH 234.0919 found 234.0920 m/z [M + H+]. [C16H11NO
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acetone/dry ice slurry under nitrogen atmosphere. To this mixture
4.3 mL of nBuLi 2.5 in hexane were added dropwise over 20 min.
stir bar was loaded with 10 g of P2O5 and 4.5 mL of H3PO4 85 % wt
in H2O. The mixture was stirred and heated in an oil bath at 170 °C
for 1 h. The temperature was decreased to 50 °C and 0.342 g
(1.19 mmol) of 12 were added. The heating was continued over-
night. The mixture was poured into ice (ca. 250 mL) and then ex-
tracted with ethyl acetate. The ethyl acetate was further extracted
with aqueous NaHCO3(dil). The ethyl acetate extract was then dried
with anhydrous MgSO4 and concentrated under vacuum, yield
0.317 g, 99 % yield. 1H NMR (400 MHz, 298 K, CDCl3): δ = 7.52 (d,
J = 8.9 Hz, 1 H), 6.71 (d, J = 8.9 Hz, 1 H), 3.78 (s, 3 H), 2.90 (t, J =
6.3 Hz, 2 H), 2.62–2.56 (m, 2 H), 1.80–1.69 (m, 4 H) ppm. 13C NMR
(100 MHz, 298 K, CDCl3): δ = 206.62, 155.15, 137.86, 134.84, 130.60,
114.42, 111.67, 56.17, 41.72, 30.88, 23.73, 21.97 ppm. HRMS (ESI):
Calcd. for C12H13BrO2Na 290.9991, found 290.9985 m/z [M + Na+].
M
The formed slurry was stirred at –78 °C for 1 h. A second carefully
dried three neck flask was loaded with 5.11 mL (42.8 mmol) of 1,4-
dibromobutane and 20 mL of dry THF at room temperature under
nitrogen atmosphere. The slurry of the aryllithium at –78 °C was
transferred dropwise through a cannula into the solution of 1,4-
dibromobutane vigorously stirred at room temperature. The transfer
was performed over 1 h. Upon completion of the transference, the
reaction was stirred overnight at room temperature under nitrogen
atmosphere. After this, the solvent was evaporated under vacuum
and the residue was extracted with dichloromethane and brine. The
organic extract was dried with anhydrous MgSO4 and concentrated
under vacuum for further flash chromatography on a HPFC system
with a silica gel cartridge eluted with a gradient n-hexane 100 % to
n-hexane/ethyl acetate (95:5), yield 1.66 g, 64 %. 1H NMR (400 MHz,
298 K, CDCl3): δ = 7.20 (t, J = 7.8 Hz, 1 H), 6.81–6.70 (m, 3 H), 3.80
(s, 3 H), 3.42 (t, J = 6.7 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 1.94–1.84
(m, 2 H), 1.82–1.72 (m, 2 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3):
δ = 159.74, 143.51, 129.42, 120.89, 114.30, 111.18, 55.23, 35.07,
33.72, 32.29, 29.77 ppm. HRMS (ESI): Calcd. for C11H15BrOAg
350.93399, found 350.93410 m/z [M + Ag+].
5-(3-Methoxyphenyl)pentanoic Acid (11):[17] A carefully dried
three neck flask equipped with condenser and an addition funnel
was loaded with 416 mg of Mg turnings and a iodine crystal under
a nitrogen atmosphere. The flask was gently heated with a heat-
gun until dark red fumes of iodine appeared. The flask was cooled
down to room temperature. The addition funnel was loaded with
0.700 g (2.89 mmol) of 10 and 10 mL of dry diethyl ether. Few
drops of the solution of 10 were added to the activated Mg and
gentle heating was applied. The heating was stopped and the rest
of the solution of 10 was added dropwise over 30 min. The reaction
was then stirred for 30 min at room temperature and then heated
at 35 °C for 20 min. A round bottle flask loaded with dry ice was
connected to P2O5 trap which in turn was connected to a cannula.
This setup was then used to bubble the mixture of the alkyl Gri-
gnard with dry CO2(g) through the cannula. The mixture was bub-
bled with dry CO2(g) for 10 min and then cooled to 5 °C in an ice/
water bath. An aqueous solution of HCl 20 % v/v was slowly added.
The mixture was extracted with diethyl ether when the hydrogen
evolution from the oxidation of the excess Mg ceased. The ethereal
solution was separated and further extracted with NaOH 10 % wt/
v (3 × 15 mL). The aqueous solution was separated and HCl 37 %
was added until pH = 2. This solution was extracted with diethyl
ether. The diethyl ether solution was separated, dried with anhy-
drous MgSO4 and concentrated under vacuum, yield 0.473 g, 78 %.
1H NMR (400 MHz, 298 K, CDCl3): δ = 7.20 (t, J = 8.0 Hz, 1 H), 6.80–
6.70 (m, 3 H), 3.80 (s, 3 H), 2.62 (t, J = 6.8 Hz, 2 H), 2.38 (t, J = 6.7 Hz,
2 H), 1.74–1.64 (m, 4 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ =
179.58, 159.72, 143.73, 129.37, 120.90, 114.25, 111.15, 55.22, 35.64,
33.89, 30.72, 24.35 ppm. HRMS (ESI): Calcd. for C12H15O3 207.1021,
found 207.1027 m/z [M – H]–.
4-Bromo-1-methoxy-6,7-dihydro-5H-benzo[6,7]cyclohepta-
[1,2-b]quinoline (14): A carefully dried three neck flask equipped
with condenser was loaded with 1.00 g (12.9 mmol) of ammonium
acetate (dried with P2O5), 0.317 g (1.12 mmol) of 13, 0.247 g
(2.04 mmol) of 2-aminobenzaldehyde and 12 mL of ethanol
(99.5 %). The mixture was stirred for 5 days at room temperature
under nitrogen atmosphere, and then heated at 80 °C for 8 h. The
solvent was removed under vacuum and the residue was washed
with dichloromethane. The dichloromethane solution was concen-
trated under vacuum and further chromatographed on silica gel
with n-hexane/ethyl acetate (9:1), yield 0.188 g, 47 %. 1H NMR
(400 MHz, 298 K, CD2Cl2): δ = 8.07 (dd, J = 8.4, 1.5 Hz, 1 H), 7.99 (s,
1 H), 7.84 (dd, J = 8.1, 1.1 Hz, 1 H), 7.69 (ddd, J = 8.4, 6.9, 1.5 Hz, 1
H), 7.61 (d, J = 8.9 Hz, 1 H), 7.55 (ddd, J = 8.1, 6.9, 1.1 Hz, 1 H), 6.90
(d, J = 8.9 Hz, 1 H), 3.77 (s, 3 H), 3.21–3.09 (m, 1 H), 2.78 (dd, J =
13.3, 6.2 Hz, 1 H), 2.44 (td, J = 12.6, 6.9 Hz, 1 H), 2.19–1.94 (m, 3 H)
ppm. 13C NMR (100 MHz, 298 K, CD2Cl2): δ = 156.79, 156.38, 146.80,
139.28, 134.03, 133.74, 133.39, 129.71, 129.31, 128.66, 127.81,
127.05, 126.47, 114.31, 112.37, 56.39, 30.00, 29.75, 29.57 ppm. HRMS
(ESI): Calcd for C19H16BrNOH 354.0488 found 354.0484 m/z [M +
H+].
1-Methoxy-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quin-
oline (15): A carefully dried three bottle neck reactor was loaded
with 0.188 g (0.531 mmol) of 14, 7 mg of palladium/charcoal acti-
vated 10 wt.-%, 10 mL of ethanol (99.5 %) and 3 mL of ethyl acetate.
The mixture was placed under a hydrogen atmosphere by 3 cycles
of subtle vacuum followed by hydrogen. After a hydrogen atmos-
phere was set, 400 mL of triethylamine were added to the mixture
which was then left with stirring at room temperature overnight.
After this, the mixture was filtered through Celite, the solvent was
removed under vacuum and the residue extracted with dichloro-
methane and water. The dichloromethane solution was separated
and dried with anhydrous MgSO4 and further concentrated under
1
vacuum, yield 0.119 g, 81 %. H NMR (400 MHz, 298 K, CD2Cl2): δ =
8.06 (dd, J = 8.4, 1.2 Hz, 1 H), 7.97 (s, 1 H), 7.81 (dd, J = 8.1, 1.5 Hz,
1 H), 7.66 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.52 (ddd, J = 8.1, 6.9,
1.2 Hz, 1 H), 7.35 (dd, J = 8.2, 7.6 Hz, 1 H), 6.99 (d, J = 8.2 Hz, 1 H),
6.88 (d, J = 7.5 Hz, 1 H), 3.78 (s, 3 H), 2.78–2.69 (m, 1 H), 2.62–2.53
(m, 1 H), 2.53–2.45 (m, 1 H), 2.29–2.19 (m, 1 H), 2.10–2.01 (m, 2 H)
ppm. 13C NMR (100 MHz, 298 K, CD2Cl2): δ = 158.00, 157.39, 147.31,
141.28, 134.33, 134.18, 130.17, 129.67, 128.80, 128.33, 128.01,
127.36, 126.51, 121.07, 111.14, 56.62, 31.62, 31.00, 30.35 ppm. HRMS
(ESI): Calcd for C19H17NOH 276.1383 found 276.1382 m/z [M + H+].
5-(2-Bromo-5-methoxyphenyl)pentanoic Acid (12): The title
compound was synthesized according to a literature procedure.[17]
Yield 0.620 g, 96 % yield. 1H NMR (400 MHz, 298 K, CDCl3): δ = 7.40
(d, J = 8.7 Hz, 1 H), 6.76 (d, J = 3.0 Hz, 1 H), 6.62 (dd, J = 8.7, 3.0 Hz,
1 H), 3.78 (s, 3 H), 2.71 (t, J = 8.0 Hz, 2 H), 2.41 (t, J = 8.0 Hz, 2 H),
1.79–1.61 (m, 4 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ =
178.76, 159.01, 142.34, 133.34, 116.07, 114.95, 113.19, 55.50, 36.03,
33.71, 29.28, 24.38 ppm. HRMS (ESI): Calcd. for C12H14BrO3 285.0132,
found 285.0132 m/z [M – H]–.
6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-1-ol
(3):
The title compound was synthesized similarly to 1, yield 0.0473 g,
90 %. Slow evaporation of a Et2O solution of the compound af-
forded crystals suitable for X-ray crystallography. 1H NMR (400 MHz,
298 K, CD2Cl2): δ = 11.75 (s, 1 H), 8.11 (s, 1 H), 8.04 (dd, J = 8.5,
1-Bromo-4-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-
one (13):[17] A round bottle flask equipped with a large magnetic
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1.5 Hz, 1 H), 7.85 (dd, J = 8.1, 1.1 Hz, 1 H), 7.71 (ddd, J = 8.4, 6.9,
1.5 Hz, 1 H), 7.56 (ddd, J = 8.1, 6.9, 1.2 Hz, 1 H), 7.26 (dd, J = 8.2,
7.4 Hz, 1 H), 6.94 (dd, J = 8.2, 1.1 Hz, 1 H), 6.83 (dd, J = 7.4, 1.1 Hz,
1 H), 2.68 (t, J = 7.1 Hz, 2 H), 2.57 (t, J = 7.1 Hz, 2 H), 2.29 (p, J =
(d, J = 8.5 Hz, 1 H), 3.83 (s, 2 H) ppm. 13C NMR (100 MHz, 298 K,
CDCl3): δ = 162.56, 155.92, 149.49, 146.69, 140.22, 132.78, 131.46,
129.38, 128.26, 128.20, 127.04, 126.06, 126.01, 116.61, 80.62, 39.24
ppm. HRMS (ESI): Calcd for C16H10NOIH 359.9880 found 359.9875
7.1 Hz, 2 H) ppm. 13C NMR (100 MHz, 298 K, CD2Cl2): δ = 159.57, m/z [M + H]+. Trace amounts of the by-product1,3-diiodo-11H-in-
156.83, 144.92, 141.10, 136.69, 134.53, 130.66, 129.39, 127.89,
deno[1,2-b]quinolin-4-ol (1–2I) were also isolated after the chromat-
127.29, 127.09, 126.73, 122.44, 120.38, 115.05, 32.43, 31.82, 30.99 ographic separation for which crystals suitable for X-ray diffraction
ppm. MS (ESI): Calcd for C18H15NOH 262.12 found [M + H+] = 262.21
m/z. HRMS (ESI): Calcd for C18H15NOH 262.11226 found 262.1223
m/z [M + H+]. [C18H15NO + 1/13ethyl acetate] C 82.02 %, H 5.87, N
5.22, found C 82.05, H 5.90, N 5.15.
were obtained. ESI-MS also confirmed the identity of the by-product
Calcd for C16H9NOI2H 485.06 found 486.24 m/z [M + H]+.
4-Iodo-5,6-dihydrobenzo[c]acridin-1-ol (2-I): The title compound
was synthesized similarly to (1-I). Chromatographic purification
done on a flash HPFC system with a 10 g SNAP silica gel cartridge
eluted with a gradient n-pentane/ethyl acetate (100:0) to 95:5, yield
1-Bromo-11H-indeno[1,2-b]quinolin-4-ol (1-Br): A microwave vial
was loaded with 203.2 mg (0.822 mmol) of 6, 148.0 mg
(0.831 mmol) of N-bromosuccinimide and 15 mL of acetonitrile
(dried with CaH2). The vial was sealed and bubbled with nitrogen
for 10 min. The vial was cooled to –20 °C and 120.0 μL (0.88 mmol)
of HBF4·Et2O were added affording a homogeneous solution. The
cooling bath was removed and the mixture was warmed up to
room temp. The reaction was monitored by LC-MS. Stirring was
continued for 24 h. 5 mL of saturated aqueous solution of NaHCO3
were added. The mixture was extracted with (5 mL × 3) of dichloro-
methane. The dichloromethane solution was separated, dried with
anhydrous MgSO4 and concentrated under vacuum. The residue
was chromatographed on silica gel eluted with n-hexane/ethyl acet-
ate (3:1). The fractions containing the mono-brominated intermedi-
ates were collected and further methoxy deprotection was per-
formed similarly to 1. Chromatographic purification was done on
silica gel eluted with n-hexane/ethyl acetate (9:1), yield 140.6 mg,
1
68.5 mg, 24 %. H NMR (400 MHz, 298 K, CDCl3): δ = 15.31 (s, 1 H),
7.98 (s, 1 H), 7.98 (dd, J = 8.0, 1.4 Hz, 1 H), 7.75 (dd, J = 8.1, 0.9 Hz,
1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.67 (ddd, J = 8.5, 7.0, 1.4 Hz, 1 H),
7.51 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 6.74 (d, J = 8.8 Hz, 1 H), 3.10 (s,
4 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ = 161.20, 155.05,
143.97, 141.94, 141.76, 134.69, 129.96, 129.76, 127.38, 127.33,
127.14, 126.90, 118.80, 118.29, 86.65, 29.84, 28.25 ppm. HRMS (ESI):
Calcd for (C17H12NOI)H 374.0036 found 374.0024 m/z [M + H]+.
CCDC 1455651 (for 1), 1455654 (for 2), 1455649 (for 3), 1455652
(for 1-2I), 1455653 (for 2-Br), and 1455650 (for 14) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
1
Acknowledgments
55 % overall yields in two steps. H NMR (400 MHz, 298 K, CD2Cl2):
δ = 8.27 (s, 1 H), 8.10 (dd, J = 8.4, 1.4 Hz, 1 H), 7.89 (dd, J = 8.2,
1.0 Hz, 1 H), 7.74 (ddd, J = 8.4, 7.0, 1.4 Hz, 1 H), 7.56 (ddd, J = 8.0,
7.1, 1.0 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H),
4.01 (s, 2 H) ppm. 13C NMR (100 MHz, 298 K, CD2Cl2): δ = 162.81,
155.48, 147.29, 145.84, 134.77, 133.68, 132.29, 129.96, 128.78,
128.62, 127.68, 126.74, 126.59, 116.52, 109.68, 36.35 ppm. HRMS
(ESI): Calcd for C16H10BrNO 312.0019 found 312.0044 m/z [M + H+].
This work was supported by the Swedish Research Council, the
Swedish Energy Agency and the Knut and Alice Wallenberg
Foundation.
Keywords: Hydrogen bonds · Donor–acceptor distance ·
Conjugation · Nitrogen heterocycles · Phenols
4-Bromo-5,6-dihydrobenzo[c]acridin-1-ol (2-Br): The title com-
pound was synthesized similarly to 1-Br, yield 294.0 mg, 59 % over-
all yields in two steps. H NMR (400 MHz, 298 K, CD2Cl2): δ = 15.10
[1] G. A. Jeffrey, W. Saenger, Hydrogen Bonding in Biological Structures,
Springer-Verlag, Berlin/Heidelberg, Germany, 1991.
1
(s, 1 H), 8.06 (s, 1 H), 8.01 (dd, J = 8.3, 1.4 Hz, 1 H), 7.82 (dd, J = 8.2,
1.0 Hz, 1 H), 7.71 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.55 (ddd, J = 8.1,
7.0, 1.1 Hz, 1 H), 7.48 (d, J = 8.8 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H),
3.16 (s, 4 H) ppm. 13C NMR (100 MHz, 298 K, CD2Cl2): δ = 160.65,
155.52, 144.49, 139.42, 135.77, 135.26, 130.65, 130.20, 127.95,
127.71, 127.69, 127.37, 118.72, 118.22, 112.41, 28.70, 28.29 ppm.
HRMS (ESI): Calcd for C17H12BrNO 326.0175 found 326.0198 m/z [M
+ H+].
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1-Iodo-11H-indeno[1,2-b]quinolin-4-ol (1-I): A microwave vial
was loaded with 100.2 mg (0.430 mmol) of 1, 193.6 mg
(0.860 mmol) of N-Iodosuccinimide and 15 mL of acetonitrile (dried
with CaH2). The vial was sealed and 235.0 μL (1.7 mmol) of
HBF4·Et2O were added affording a homogeneous solution. The mix-
ture was heated at 100 °C for 5 min using microwave irradiation.
Upon cooling to room temperature, 5 mL of saturated aqueous
solution of NaHCO3 were added. The mixture was extracted with
(5 mL × 3) of dichloromethane. The dichloromethane solution was
separated, dried with anhydrous MgSO4 and concentrated under
vacuum. The residue was chromatographed on silica gel eluted with
n-pentane/ethyl acetate (2:1), yield 70.0 mg, 45 % 1H NMR
(400 MHz, 298 K, CDCl3): δ = 8.14 (s, 1 H), 8.05 (dd, J = 8.4, 1.4 Hz,
1 H), 7.80 (dd, J = 8.2, 1.0 Hz, 1 H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1
H), 7.63 (d, J = 8.5 Hz, 1 H), 7.51 (ddd, J = 8.2, 7.0, 1.1 Hz, 1 H), 6.76
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Received: April 12, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Hydrogen Bonds
G. A. Parada, S. D. Glover,
A. Orthaber, L. Hammarström,
S. Ott* .................................................... 1–9
Hydrogen Bonded Phenol-Quinol-
ines with Highly Controlled Proton-
Transfer Coordinate
Do the twist! The strength of the intra- is controlled by the conformational
molecular hydrogen bond between preference and size of 1,3-cycloalkadi-
the phenolic OH and the quinoline ene tethers annelated to the hetero-
nitrogen atom in the title compounds cycles.
DOI: 10.1002/ejoc.201600460
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim