Synthesis and Structure-Photophysics Evaluation of 2-N-Amino-quinazolines: Small Molecule Fluorophores for Solution and Solid State

Article abstract of DOI:10.1002/asia.202100534

2-N-aminoquinazolines were prepared by consecutive S_NAr functionalization. X-ray structures display the nitrogen lone pair of the 2-N-morpholino group in conjugation with the electron deficient quinazoline core and thus representing electronic push-pull systems. 2-N-aminoquinazolines show a positive solvatochromism and are fluorescent in solution and in solid state with quantum yields up to 0.73. Increase in electron donor strength of the 2-amino substituent causes a red-shift of the intramolecular charge transfer (ICT) band (300–400 nm); whereas the photoluminescence emission maxima (350–450 nm) is also red-shifted significantly along with an enhancement in photoluminescence efficiency. HOMO-LUMO energies were estimated by a combination of electrochemical and photophysical methods and correlate well to those obtained by computational methods. ICT properties are theoretically attributed to an excitation to Rydberg-MO in SAC-CI method, which can be interpreted as n-π* excitation. 7-Amino-2-N-morpholino-4-methoxyquinazoline responds to acidic conditions with significant increases in photoluminescence intensity revealing a new turn-on/off fluorescence probe.

Full text of DOI:10.1002/asia.202100534

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Synthesis & Structure-Photophysics Evaluation on 2-N-
Aminoquinazolines – Small-Molecule Fluorophores for Solution
and Solid State
Authors: Bernhard Witulski, Miho Motoyama, Thu Hong Doan, Paulina
Hibner-Kulicka, Ryo Otake, Malgorzata Lukarska, Jean-
Francois Lohier, Kota Ozawa, Shinkoh Nanbu, Carole
Alayrac, and Yumiko Suzuki
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Synthesis & Structure-Photophysics Evaluation of 2-N-Amino-
quinazolines – Small-Molecule Fluorophores for Solution and
Solid State
Miho Motoyama,[a] Thu-Hong Doan,[b] Paulina Hibner-Kulicka,[b] Ryo Otake,[a] Malgorzata Lukarska,[b]
Jean-Francois Lohier,[b] Kota Ozawa,[a] Shinkoh Nanbu,[a] Carole Alayrac,[ b] Yumiko Suzuki,*[a] and
Bernhard Witulski *[b]
[a]
Prof. Dr. Y. Suzuki, Prof. Dr. Nanbu, M. Motoyama, R. Otake, K. Ozawa
Department of Life and Material Sciences, Faculty of Science and Technology, Sophia University,
7-1 Kioicho, Chiyodaku, 102-8554 Tokyo, Japan
[b]
Prof. Dr. B. Witulski, Dr. T.-H. Doan, P. Hibner-Kulicka, M. Lukarska, J.-F. Lohier, Dr. C. Alayrac
Laboratoire de Chimie Moléculaire et Thio-organique, CNRS UMR 6507, ENSICAEN & UNICAEN, Normandie Univ.
6 Bvd Maréchal Juin, 14050 Caen, France
E-mail: bernhard.witulski@ensicaen.fr
Supporting information for this article is given via a link at the end of the document.
Abstract: 2-N-aminoquinazolines were prepared by consecutive
SNAr functionalization. X-ray structures display the nitrogen lone pair
of the 2-N-morphilino group in conjugation with the electron deficient
quinazoline core and thus representing electronic push-pull systems.
2-N-aminoquinazolines show a positive solvatochromism and are flu-
orescent in solution and in solid state with quantum yields up to 0.73.
Increase in electron donor strength of the 2-amino substituent causes
a red-shift of the intramolecular charge transfer (ICT) band (300-400
nm); whereas the photoluminescence emission maxima (350-450 nm)
is also red-shifted significantly along with an enhancement in photo-
luminescence efficiency. HOMO-LUMO energies were estimated by
a combination of electrochemical and photophysical methods and
correlate well to those obtained by computational methods. ICT
properties are theoretically attributed to an excitation to Rydberg-MO
in SAC-CI method, which can be interpreted as n-* excitation. 7-
Amino-2-N-morpholino-4-methoxyquinazoline responds to acidic
conditions with significant increases in photoluminescence intensity
revealing a new turn-on/off fluorescence probe.
antagonists, are - for example - bunazosin, alfuzosin, terazosin,
and prazosin.[15]
Introduction
Figure 1. (A) Representative quinazoline-based pharmacophores & drugs, (B)
photochromic materials used for DSSCs and OLEDs, and (C) small-molecule
fluorescent quinazolines as molecular probes.
Quinazolines are an important class of heterocyclic aromatic com-
pounds providing a privileged molecular platform for medicinal
chemistry and materials sciences.[1-2] The quinazoline motif is
found in a broad variety of pharmaceutical active molecules pos-
compounds exhibit selective CYP1A2 inhibition and might func-
tion in cancer chemoprevention.[16] Other 2,4-diaminosubstituted
quinazolines have been revealed as interesting candidates for de-
veloping agents to treat Alzheimer’s disease.[17] Notably, very re-
cently the quinazoline C5 was identified as selectively binding and
stabilizing an attenuator hairpin in the SARS-CoV-2 RNA genome.
When C5 was linked to a RIBOTAC (ribonuclease-targeting chi-
mera) a considerable lead for future therapeutics against SARS-
CoV-2, the virus that causes COVID-19, evolved.[18]
Besides such a broad and diversified spectrum of biological activ-
ities, quinazolines have also attracted emergent interest in mate-
rials research. The electron deficient nature of the heteroaromatic
core turns it to an unique molecular scaffold for the design of do-
nor--spacer-acceptor chromophores,[19] low-band gap materials
sessing
anti-inflammatory,[3]
antitubercular,[4]
antiviral,[5]
antimalarial,[6] antibacterial,[7] antifungal,[8] antimutagenic,[9]
antileishmanial,[10] antiobesity,[11] and particularly anticancer
activities.[12] Quinazoline-based compounds are widely used in
the search for new anti-cancer agents that led to several marketed
drugs. Examples are gefitinib, lapatinib and erlotinib,[13] being
used as single- and dual-target epidermal growth factor receptor
(EGFR), as well as human epidermal growth factor receptor-2
(HER-2) drugs for the treatment of non-small-cell lung or
metastatic breast cancer (Figure 1).[14] Other available
quinazoline-based pharmaceuticals, which have N-amino
functions in 2,4-position and act as 1- adrenergic receptor
1
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for organic electronics and organic light emitting diodes
(OLEDs),[20] exciplex-forming and/or dual emissive com-
pounds,[21,22] and chemical sensors.[23] For instance, the donor--
spacer-acceptor chromophore I has been used in dye sensitized
solar cells (DSCCs),[24] and the quinazoline ligated iridium com-
plex II was used as a yellow-red light emitting phosphorescent
dopant in polymer matrixed OLEDs.[25] The quinazoline moiety is
a suitable electron acceptor in thermally activated delayed
fluorescence (TADF) systems for high performance OLEDs,[26]
and compound III was used in a pure organic molecular white
light-emitting OLED with dual light emission due to conformational
isomerization.[22a,27]
Accordingly, a first set of quinazolines needed for our study
having N-morpholino substituents in either 4-, 2-, or 2,4-position
became available through nucleophilic aromatic substitution
(SNAr). Adding an excess of morpholine to a solution of the corre-
sponding chloroquinazolines 1, 3a-c, or 5a in 1,4-dioxane under
elevated temperature gave the expected N-morpho-
linoquinazolines 2 and 4a-d in high yield (Scheme 1). Notably, the
efficiency of the SNAr reaction at the 2-position of the quinazoline
core was not affected by the kind of substituent at the 4-position.
This procedure also allowed a twofold amination to give the 2,4-
bis-N-morpholino-quinazoline 4d in a “one-flask reaction” in 95%
yield.
Whereas the significance of the quinazoline molecular scaf-
fold for pharmaceutical research is widely known, less information
is available about their potential use for the development of new
small-molecule fluorescent dyes. UV-vis absorption, solvato-
chromism and photoluminescence properties of 2,4-disubstituted
aryl, arylvinyl, arylethynyl quinazolines in solution have been re-
ported.[19a,28] Likewise, fluorescence properties of the N-phenyl-4-
aminoquinazolines IV targeting the ATP-binding pocket of the
ERBB family of receptor tyrosine kinases were investigated.[29]
Compounds IV have weak to moderate fluorescence quantum
yields in solution (F = 0.17-0.37) and their emission properties
are attributed to polar charge transfer excited states. Furthermore,
series of 2-(thiophen-2-yl)-4-(N-morpholino)-quinazolines were
investigated along their photophysical properties with V showing
a solvent dependent green emission (em (CH3CN) = 544 nm; F
= 0.23).[30]
Recently, we reported on the fluorescent anti-cancer
quinazoline VI as a molecular probe showing bright solvent de-
pendent fluorescence in solution (em (H2O) = 460 nm; F = 0.15;
em (hexanes) = 414 nm; F = 0.53) that was blue shifted with
emission intensity enhancement when binding to the colchicine
site of -tubulin.[31] These preliminary results indicated that 2-N-
amino substituted quinazolines resemble a new class of small-
molecule fluorophores which have - due to their underlying phar-
macophore - great potential for application as molecular probes
for sensing and imaging. However, less is known about the de-
tailed photophysical properties of 2-N-aminoquinazolines and
their derivatives, i.e. the influence of substituents on the fluores-
cence emission efficiency.
Here, we report on a first full investigation of the photophys-
ical properties of a set of 2-N-aminoquinazolines in solution and
solid state together with cyclic voltammetry and computational
studies to evaluate HOMO/LUMO energy levels and charge dis-
tribution. This study aims gaining insight into fluorescence-struc-
ture-property relationship (FSPR) which will be instructive for the
development of new 2-N-aminoquinazoline small-molecule fluor-
ophores with unique applications.
Scheme 1. Synthesis of a set of 4-, 2-, or 2,4-disubstituted quinazolines. Yield
of isolated material after column chromatography on silica gel in parentheses.
A second set of fluorescent quinazolines was obtained
through side-selective consecutive SNAr reactions starting from
the 2,4-dichloroquinazolines 5a-k (Scheme 2). An initial SNAr re-
action using sodium methanolate in methanol proceeded at the
more reactive 4-position of the 2,4-dichloroquinazoline core to
give the 2-chloroquinazolines 6a-k selectively (60-90% yield, Ta-
ble 1). The amino function in 2-position was thereafter introduced
at slightly higher reaction temperatures (up to 100 °C) through a
second nucleophilic displacement of the quinazoline-2-chlorine by
various amines having different sizes and nucleophilicities.[34] No-
tably, the less nucleophilic aziridine yielded the product 7e in only
20% yield in a sole SNAr reaction in 1,4-dioxane as the solvent.
However, the aziridine moiety could be introduced much more ef-
ficiently into the desired 2-position by Buchwald-Hartwig arylami-
nation:[35] With the pre-catalyst Pd(OAc)2/Xantphos and Cs2CO3
as base the reaction of 6a with aziridine in toluene provided the
N-aziridine bearing quinazoline 7e in 73% yield.[36]
Side-selective functionalizations of quinazolines were also
effective for gaining access to the quinazolines 8a-d, 9a-d, 10 and
11 bearing respectively methoxy-, chloro- or nitro-groups. Reduc-
tion of the 7-nitro group in compound 11 with iron powder and HCl
made the 7-amino-2-morpholino-4-methoxyquinazoline (12)
available (85% yield). Molecular structure and purity of the ob-
tained quinazoline derivatives 2, 4a-d, 7a-g, 8a-d, 9a-d, 10-12
were unequivocally confirmed by 1H and 13C NMR, elemental
analysis, and HRMS data. All compounds are thermally stable
Results and Discussion
Synthesis, Characterization, and Crystallographic Analysis
Numerous syntheses of 2-, 4-, and 2,4-disubstituted quinazolines
have been reported allowing access to a broad variety of substi-
tution pattern.[32] One of the most reliable procedures for introduc-
ing an N-amino group in either 2- and/or 4-position of the quinazo-
line core is based on readily available 2- or 4-chloro-, as well as
2,4-dichloroquinazolines and primary or secondary amines.[33]
with
decomposition
temperatures
determined
by
thermogravimetric analysis (TGA) for compounds 8b, 8c, and 8d
to be 233, 212, and 204 °C, respectively.
2
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Scheme 2 Synthesis of 2-amino-4-methoxyquinazolines by side selective SNAr reactions starting from substituted 2,4-dichloroquinazolines 5a-k. Yield of 6a-k, see
[a]
Table 1; yield of isolated compounds 7a-g, 8a-d, 9a-d, and 10-12 after column chromatography in parenthesis.
bis(diphenylphosphino)-9,9-dimethylxanthene), Cs2CO3, toluene, aziridine, 3 d at 100 °C in a sealed Schlenk tube.
3 mol% Pd(OAc)2, 4 mol% Xantphos (4,5-
Table 1. Reaction of 2,4-dichloroquinazolines 5 with sodium methanolate to
give 2-chloro-4-methoxyquinazolines 6.
5
R1
R2
R3
R4
6
Yield, %[a]
5a
5b
5c
5d
5e
5f
H
OMe
Cl
H
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
60
74
49
59
67
91
82
56
57
87
66
H
H
H
OMe
Cl
H
H
8d
10
H
H
H
H
H
OMe
Cl
H
5g
5h
5i
H
H
H
6g
6h
6i
H
H
H
OMe
Cl
H
H
H
H
5j
H
OMe
H
OMe
NO2
6j
5k
H
H
6k
[a] Yield based on isolated material after column chromatography on silica gel.
The x-ray crystal structures of compounds 8d, 10, and 11
are displayed in Figure 2. Notably, all three solid state molecular
structures show the N-morpholino substituent at the quinazoline
2-position in a conformation allowing efficient conjugation of the
morpholino nitrogen lone pair with the electron deficient heteroar-
omatic core – as one would expect for a rational electronic push-
11
Figure 2. Molecular structure of quinazolines 8d (CCDC: 2081760), 10 (CCDC:
2081761), and 11 (CCDC: 2081759) in the single crystal.
3
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30000
25000
20000
15000
10000
5000
0
pull system. Here, the N-morpholino group is acting as the elec-
tron donor and the electron deficient heteroaromatic core as the
acceptor. The extent of conjugation is also displayed by an es-
sentially trigonal planar morpholino N-atom, as given by the sum
of the angles around the nitrogen atom (N) which is 359°, 357°,
and 351° for 8d, 10, and 11 respectively. The crystal packing of
quinazolines 8d and 10 show no significant intermolecular con-
tacts and that is one reason why PLE properties of solution and
solids are very similar (see next paragraph on photophysical prop-
erties). In contrast, the packing of quinazoline 11 in the single
crystal shows a “-stacked” molecular arrangement with a 339 pm
distance between two heteroaromatic units (for details, see sup-
porting information). Its solid state PLE differs significantly from
the one in solution.
4a
4b
4c
4d
2
4a
4b
4c
4d
1
Photophysical properties in solution and solid state
The quinazolines 2, 4a-d, 7a-g, 8a-d, 9a-d, and 10-12 were ex-
amined by UV-vis absorption and steady-state fluorescence spec-
troscopy in solution and solid state together with their respective
quantum yields. Relevant photophysical data are compiled in Ta-
ble 2. Solution spectra were taken in concentrations of 10-5 M in
order to avoid intermolecular interaction or aggregation of the so-
lutes. Quantum yields were determined with an absolute photolu-
minescence quantum yield measurement system (Hamamatsu
C9920-02).[37] All samples were deoxygenated by purging the re-
spective solution with argon for 20 minutes prior to measurement.
Examples of UV-vis and photoluminescence emission (PLE)
spectra of the quinazolines 2 and 4a-d are displayed in Figure 3
(for the complete set of UV-vis & PLE spectra, see supporting in-
formation).
0
600
250
300
350
400
450
500
550
Wavelength (nm)
Figure 3. UV-vis absorption (solid lines) and photoluminescence emission (dot-
ted lines) of the quinazolines 4a-d (c = 10-5 M). 4-(N-morpholino)quinazoline 2
is non-emissive in solution.
absorption maxima absmax tend to be red-shifted – as does the
corresponding em
max in the PLE spectra – with an increase of the
donor strength of the 2-N-amino substituent (Figure 4). This
bathochromic shift of the ICT absorption band follows the order
7e (N-aziridine), 7g (-NHMe), and 7f (-NMe2) with abs

max (CH2Cl2)
= 318, 353, and 339 nm respectively. The same trend is observed
for the PLE spectra with em
max (CH2Cl2) = 376, 392, and 411 nm
With a low-energy band at abs
max (CH2Cl2) = 326 nm and a
molar absorption coefficient of  = 6700 L mol-1 cm-1 the UV-vis
absorption spectra of 4-N-morpholinoquinazoline 2 significantly

for respectively 7e, 7g, and 7f having Stokes shifts of 3990-4850
cm-1. The N-morpholino moiety at position 2 of the quinazoline
scaffold is a considerable weaker electron donor than the
respectively N-piperidine unit as the former has an
electronegative oxygen in the heterocyclic 6-membered ring -
compared to a –CH2- unit of the latter. Although this effect is small
it can be seen by a slight hypsochromic shift of both the maxima
of the ICT absorption (8 nm) as well as the PLE emission band (4
nm) of the N-morpholinoquinazoline 7a compared to the N-
piperidino derivative 7b in CH2Cl2 (Table 2). The influence of the
electron donor strength of the 2-N-amino substituent on the
photoluminescence properties is furthermore visualized by a
correlation attempt of the Hammett substitution parameter p of
different amine substituents with the PLE maxima of the
quinazolines 7a-g (Figure 4, insert).[38, 39]
Notably, the solution quantum yields within this set of 2-N-
aminoquinazolines also differ significantly with the amino donor
capacity. For instance, the quinazolines 7e (N-aziridine) and 7g (-
NMeH) have solution quantum yields of F (CH2Cl2) = 0.38 and
0.49 respectively; whereas the quinazolines 7a-d, and 7f have
much higher solution PLE quantum yields of F (CH2Cl2) = 0.61-
0.68. In the quinazoline-(7a-g)-series, the highest quantum yield
in solution was found for the 2-N-azetidino-4-methoxyquinazoline
distinguishes from its regioisomer 4a with a characteristic broad
abs
red-shifted absorption at

(CH2Cl2) = 372 nm ( = 2900 L
max
mol-1 cm-1). Such a characteristic low-energy absorption band with
its underlying n-* intramolecular charge transfer (ICT) is also
found for other 2-N-morpholino quinazolines; i.e. 4b-d with re-
spectively abs
max (CH2Cl2) = 372, 366, 384, and 362 nm.
Notably, quinazoline 2 with a 4-N-morpholino group is non fluo-
rescent in solution and solid state, whereas the quinazolines 4a-
d having a 2-N-morpholino group reveal a bright fluorescence with
PLE intensity maxima ranging from em
max (CH2Cl2) = 426-446 nm
and with quantum yields of F = 0.39-0.65 (Table 2). This clearly
indicates that the N-amino group in 2-position of the quinazoline
scaffold is essential for an intense light emission and acts as a
fluorescence “turn-on unit” with respect to fluorescence-structure-
property relationships (FSPR). Likewise, the substituent in 4-
position alters the light emission wavelength with em
max (CH2Cl2)
= 446, 440, and 478 nm, for a N-morpholino-, methyl-, or phenyl
group respectively (Table 2).
Further insight into the FSPR of 2-N-aminoquinazolines was ob-
tained with the 2-N-amino-4-methoxyquinazolines 7a-g having N-
amino substituents of varying ring size and electron donor
strength. Their UV-vis absorption spectra all display the charac-
teristic broad ICT band in the 300-400 nm region and the
4
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Table 2. Spectroscopic properties of quinazolines 2, 4a-d, 7a-g, 8a-g, 9a-d, and 10-12 in solution and solid state.
Solution (10-5 M in CH2Cl2)
Solid (crystals)
Compd.a
UV-vis
absmax, nm, (, M-1 cm-1)
UV-vis
absonset, nm
PLEsolution
emmax, nm
Fb, solution
(ex, nm)
Stokes shift
cm-1
PLEsolid
emmax, nm
F, solid
(ex, nm)
c
c
c
c
c
2
326 (6700)
372 (3000)
366 (3300)
384 (3900)
362 (5200)
347 (3000)
355 (3100)
354 (3500)
346 (3600)
318 (3400)
353 (3400)
339 (3300)
345 (3000)
365 (3600)
332 (4900)
350 (3100)
354 (3200)
361 (3100)
350 (2900)
358 (3700)
345 (6200)
412 (1700)
335 (6800)
-5
358
419
412
433
401
386
393
391
385
346
388
372
380
404
366
386
393
400
389
395
380
480
366
[b]
-
-
-
-
-
4a
4b
4c
4d
7a
7b
7c
7d
7e
7f
446
440
478
426
411
415
415
410
376
411
397
405
430
395
412
416
425
415
420
404
0.39 (330)
0.42 (340)
0.43 (380)
0.65 (340)
0.62 (340)
0.61 (330)
0.64 (330)
0.68 (330)
0.38 (310)
0.61 (330)
0.49 (330)
0.50 (330)
0.73 (330)
0.43 (330)
0.67 (330)
0.35 (330)
0.47 (330)
0.28 (330)
0.54 (330)
0.65 (345)
4460
4600
5120
4150
4550
4010
4150
4510
4850
4000
3990
4300
4140
4800
4300
4210
4170
4480
4120
4230
-
449
0.23 (330)
c
c
-
-
475
434
423
417
413
426
400
415
418
412
435
389
417
437
425
425
455
407
552
0.03 (380)
0.55 (330)
0.16 (330)
0.37 (330)
0.35 (330)
0.54 (330)
0.12 (310)
0.49 (320)
0.04 (320)
0.15 (360)
0.41 (340)
0.30 (320)
0.37 (340)
0.05 (330)
0.12 (330)
0.21 (330)
0.03 (330)
0.37 (340)
0.07 (400)
7g
8a
8b
8c
8d
9a
9b
9c
9d
10
11
12
c
c
-
-
c
c
395
0.13 (330)
4540
-
-
[a]
37 [c]
Spectra were recorded at room temperature at c = 10 M in dichloromethane. Determined with an integration sphere after purging the solution with argon for 20 min.
Compound is non fluorescent.
1.0
0.5
0.0
40000
30000
20000
10000
0
7c
7d
7e
7f
7c
7d
7e
7f
7g
3.6
3.4
3.2
3.0
2.8
2.6
7g
-0.8
-0.6
-0.4
-0.2
p
350
400
450
500
550
600
650
250
300
350
400
Wavelength (nm)
Wavelength (nm)
Figure 4. Comparative absorption (left) and photoluminescence emission spectra (right) of representative 2-N-amino -4-methoxyquinazolines with varying N-amino
substituents recorded in CH2Cl2 (c = 10 -5 M). Insert: Correlation of the Hammett substitution parameter p with the PLE intensity maxima (eV).
5
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(7d) with F (CH2Cl2) = 0.68. Such an increase in fluorescence
efficiency is most likely due to a comparable higher rigidity of the
4-membered ring paired with its still present strong electron donor
capacity. Evidently, the increase in electron donor strength of the
2-N-amino substituents is along with an increase of the ICT per-
formance of the excited state following the n-* transition to the
1CT* state and therefore, effecting an increase in the photolumi-
nescence efficiency. This trend is preserved by quantum yields
determined from the solid state (Table 2).
state must be quite similar. Consequently, intermolecular interac-
tions affecting fluorescence emission are very weak or absent in
the solid state (Figure 6, for the complete set of solid state PLE
spectra, see supporting information).
1.0
10 (solution)
10 (solid)
11 (solid)
0.8
The UV-vis absorption and PLE emission characteristics of
methoxy-(8a-d) and chloro-(9a-d) substituted 2-N-morpholino-4-
methoxyquinazoline having a substituent in either 5-, 6-, 7-, or 8-
position were also evaluated (Table 2). Both sets show alternating
influences in affecting absorption and PLE wavelengths by shift-
ing the substituent from the 5- to the 6-, to the 7-, and finally to the
8-position. Within each set the largest red-shift in PLE is observed
with a substituent at the 6-position of the quinazoline core - i.e. for
0.6
10
11
0.4
0.2
0.0
8b and 9b with em
max = 430 and 425 nm, respectively. This trend
is conserved by quantum yield measurements in solution, that
give with F = 0.73 and 0.47 for respective 8b and 9b the highest
values in each series.
400
500
600
700
800
Wavelength (nm)
Fluorescence spectra of quinazoline 7b were recorded in
solvents of different polarity and the respective Stokes shifts were
correlated with Reichardt’s normalized solvent polarity parameter
퐸T푁 (Figure 5).[40] The observed positive solvatochromism displays
the stabilization of a highly polarized excited charge transfer state
(1CT*) by a more polar solvent. It clearly confirms a considerable
intramolecular charge transfer (ICT) on excitation from a less di-
polar ground state to a highly dipolar excited state molecule. Such
a positive solvatochromism is also found with all other investi-
gated 2-N-aminoquinazolines (see supporting information).
Figure 6. PLE spectra of 2-N-morpholino-4,6,7-trimethoxyquinazoline (10) in
solution and from solid state; and solid state PLE spectra of 2-N-morpholino-7-
nitro-4-methoxyquinazoline (11). Compound 11 is non-fluorescent in solution.
Insert: Quinazolines 10 and 11 (solid) under UV-lamp.
A notable exception is the 7-nitro-quinazoline 11 that is non-
fluorescent in solution but displays a yellow solid state fluores-
cence with em
max = 552 nm. This remarkable red-shifted fluores-
cence that distinguishes 11 from all other investigated 2-N-mor-
pholinoquinazolines is most likely originated from “-stacked”-
type aggregates in the crystal and points to excimer-type light
emission.[41] However, the possibility of room temperature phos-
phorescence due to a “locked conformation” in the crystal lattice
cannot be ruled out at this point.
5000
CH CN
4500
3
THF
Electrochemical properties & HOMO/LUMO energy levels
Electrochemical properties of the quinazolines 2, 4a-d, 7a-g, 8a-
d, and 9a-d were investigated by cyclic voltammetry and the re-
sults are summarized in Table 3. Cyclic voltammetry experiments
were carried out at a scan rate of 100 mV/s with a three-electrode
set-up under an argon atmosphere and with a Pt electrode as the
working and calomel (SCE) as the reference electrode. nBu4NPF6
(0.1 M in CH2Cl2) was used as the electrolyte solution and Fc/Fc+
(ferrocene / ferrocenium redox couple: 0.46 V vs SCE) as the in-
ternal standard for calibration purpose. Representative cyclic
voltagram curves of the quinazolines 2, 4a, 7a, and 8b with re-
spect to their oxidation potential are displayed in Figure 7.
Reduction potentials could not be measured as the electro-
chemical window in CH2Cl2 used ranged from -1.9 to 1.9 V (for
the full set of cyclic voltagrams, see supporting information).
Within the solvent/electrolyte electrochemical window the 2-N-
morpholinoquinazoline 2, the 4-N-morpholinoquinazoline 4a and
1,4-dioxane
4000
3500
3000
CH Cl
2 2
n-hexane
0.0
0.2
0.4
0.6
0.8
1.0
ETN
Figure 5. Solvatochromism of 2-N-piperidino-4-methoxyquinazoline (7b). Cor-
relation of Reichardt’s normalized polarity parameter 퐸T푁 with obtained Stokes
shift. 퐸T푁 values: 0.009 (n-hexane), 0.164 (1,4-dioxane), 0.207 (THF), 0.309
(CH2Cl2), and 0.460 (CH3CN).
Although photoluminescence emission from solids is often
quenched by molecular aggregates, most of the 2-N-amino-4-
methoxyquinazolines show a bright fluorescence from the solid
state with considerable high quantum yields (Table 2). The solid
state PLE spectra are very similar to the ones obtained from so-
lution with respect to emission maxima and band shape indicating
that the respective molecular conformation in solution and solid
the 2-N-morpholino-4-methoxyquinazoline 7a display an irreversi-
ox
ble first oxidation potential of
E
1/2
= 1.60, 1.32 and 1.18 eV re-
spectively (Figure 7 and Table 3). Notably, the first oxidation prod-
uct of the 4,6-dimethoxy-2-N-morpholinoquinazoline (8b) is more
stable under the reaction conditions and displays a quasi-reversi-
ble first oxidation potential with oxE1/2 = 1.09 V.
6
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Table 3. Experimental Data for HOMO, LUMO, and Band Gap Energies and
Calculated Data for HOMO, LUMO, and Excited State Energies.
1,0
2
4a
7a
8b
Compd.
Experimental data
Calculated dataa
ox
ox
calc
calc
E
E
optEg EHOMO ELUMO
calcEg
E
E
LUMO
1/2
onset
HOMO
0,5
0,0
(V)
(eV) (eV)
(eV)
(eV)
(eV)
(eV)
(eV)
2
1.60
1.32
1.33
1.38
1.13
1.18
1.17
1.19
1.27
--
1.52 3.47 -6.16 -2.69
1.31 2.97 -5.95 -2.99
1.24 3.01 -5.88 -2.87
1.27 2.86 -5.91 -3.05
1.07 3.09 -5.71 -2.62
1.14 3.24 -5.78 -2.54
1.04 3.17 -5.68 -2.51
1.03 3.17 -5.67 -2.50
1.13 3.22 -5.77 -2.55
1.48 3.57 -6.12 -2.55
1.10 3.17 -5.74 -2.57
1.20 3.29 -5.84 -2.55
1.09 3.27 -5.73 -2.46
0.96 3.03 -5.60 -2.57
1.16 3.39 -5.80 -2.41
1.04 3.19 -5.68 -2.49
1.26 3.15 -5.90 -2.75
1.22 3.10 -5.86 -2.76
1.30 3.19 -5.94 -2.75
1.28 3.14 -5.92 -2.78
3.89
3.37
3.41
3.24
3.48
3.62
3.53
3.53
3.60
3.96
3.58
3.63
3.69
3.34
3.72
3.58
3.53
3.46
3.57
-6.32 -1.89
-5.91 -2.04
-5.85 -1.82
-5.88 -2.07
-5.73 -1.66
-5.82 -1.58
-5.68 -1.53
-5.65 -1.51
-5.78 -1.56
-6.26 -1.71
-5.73 -1.54
-5.82 -1.59
-5.72 -1.40
-5.52 -1.64
-5.81 -1.47
-5.60 -1.43
-5.91 -1.76
-5.86 -1.80
-5.95 -1.75
-5.90 -1.77
4a
4b
4c
4d
7a
7b
7c
7d
7e
7f
-0,5
0,0
0,5
1,0
1,5
2,0
Potential Vf (V)
Figure 7. Cyclic voltammetry of 2-N-morpholinoquinazoline (2), 4-N-morpho-
linoquinazoline (4a), 2-N-morpholino-4-methoxyquinazoline (7a), and 4,6-dime-
thoxy-2-N-morpholinoquinazoline (8b). Each sample was recorded in deoxy-
gentated solutions with c = 10-3 M in CH2Cl2/0.1 M nBu4NPF6 at room tempera-
ture. Scan rate 100 mV/s, working electrode Pt, auxiliary electrode Pt wire, and
SCE as the reference electrode. The potentials were corrected against Fc/Fc+
as internal reference.
1.24
1.35
1.13
1.09
1.22
1.14
1.35
1.38
1.35
1.36
7g
8a
8b
8c
8d
9a
9b
9c
9d
The decrease of oxidation potentials in this set of
quinazolines 2, 4a, 7a and 8b clearly reveals the influence of the
N-amino substituent and its position by lowering the oxidation po-
tential significantly when placed from the 4-position (quinazoline
2) to the 2-position (quinazoline 4a).
Furthermore, the influence of the two methoxy groups acting as
electron donor in compound 8b, that additionally lower the oxida-
tion potential, is also disclosed by these measurements.
From the onset of the first oxidation half-wave (oxEonset) the
HOMO energy level for the quinazolines 2, 4a-d, 7a-g, 8a-d, and
9a-d were estimated with: EHOMO = -(oxEonset
,
+ 5.10) (eV)
vs Fc/Fc+
for measurements in dichloromethane solution with 0.1 M
nBu4NPF6 as the supporting electrolyte.[42] The half-wave poten-
tial for the Fc/Fc+ redox-couple was set to E1/2 = 0.46 eV for
calibration purpose.[43] We chose -5.10 eV as the formal potential
of the Fc/Fc+ redox couple in the Fermi scale.[44] The HOMO
energy level for the 4-N-morpholino-2-methoxyquinazoline 7a
was thus estimated to EHOMO = -5.78 eV. The energy level of the
lowest unoccupied molecular orbital (LUMO) was calculated by
adding the value of the optical band gap (optEg) taken from the
onset of the long-wavelength absorption band of the UV-vis
absorption spectra in CH2Cl2 to the HOMO energy level with
3.51
a calculated with DFT using TDDFT/BLYP3 functional in CH2Cl2 (PCM).
well as the 5-, 6-, 7, or 8-positions. For instance, in the compara-
ble series of 2-N-amino-4-methoxyquinazolines 7a-g, 8a-d, and
9a-b, the 2-N-morpholino-4,6-dimethoxy-quianzoline (8b)
displays the highest fluorescence quantum yield (F = 0.73),
together with the highest HOMO energy level (EHOMO = -5.60 eV)
and the lowest optical band gap (optEg = 3.03 eV).
ELUMO = EHOMO
+
optEg. For quinazoline 7a the LUMO energy was
therefore found to be ELUMO = -2.54 eV. The experimentally
established HOMO/LUMO energy levels, together with the values
for the optical band gap of all synthesized and investigated N-
aminoquinazolines are listed in Table 3.
Theoretical calculations
Ab initio molecular orbital (MO) and configuration interaction (CI)
calculations on the synthesized quinazolines were carried out with
the aim to gain further insight into HOMO-LUMO energy levels,
the first electronically excited state (S1) energies, and their elec-
tronic structures, and to compare the value of experimental data
with ab initio result.
Polarizable continuum model (PCM)[45] was assumed to
take account of solvation effect with dichloromethane at each ab
initio calculation. Møller–Plesset second-order perturbation
theory (MP2) and density functional theory (DFT) with B3LYP[46]
and M062X[47] functionals were first employed to optimize
molecular geometries for the electronic ground state (S0, X1A).
The vertical excitation-energies to five lower-lying electronic
A comparison of photoluminescence emission data (Table
2) with empirical HOMO/LUMO energy values (Table 3) and with
the corresponding band gap energies (optEg) reveals that 2-N-ami-
noqunazolines with high HOMO energy levels and small band gap
values display the highest fluorescence quantum yields. Concern-
ing FSPR this points to that the fluorescence properties of 2-N-
aminoquinazolines are basically attributed to the extent of ICT and
polar charge transfer in the excited state. The latter is influenced
by a strong electron donor (N-amino group) in 2-position and is
enforced/quenched by peripheral donor substituents on the 4-, as
7
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10.1002/asia.202100534
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excited states (21A(S1), 31A, 41A, 51A and 61A in C1 symmetry)
were then determined by a single-point calculation for the sym-
metry-adapted cluster/configuration interaction (SAC-CI)[48]
calculations at the MP2-optimized geometry, while time-
dependent DFT (TDDFT)[49] calculation was used at B3LYP and
M062X functionals with DFT-optimized geometry. All the ab initio
computations were performed using Gaussian 16 program
package[50] with the aug-cc-pVDZ basis set.[51-52]
The orbital energy-values for the calculated HOMO and
LUMO levels with DFT TDDFT/B3LYP are listed in Table 3 (for
other levels of calculation, see supporting information). These
energy-levels are linearly correlated with experimentally
determined band gaps. Figure 8 displays the comparison of
(
optEg) - that is assumed to correspond to the energy of the lowest
electronic transition via absorption of a single photon is affected
by the strong binding energy between hole and electrons (exciton
binding energy) - per se differs (is lower in energy) from the
calculated HOMO-LUMO gap
( – that provides an
calcEg)
approximation of the fundamental gap[53-54] - we found a fair trend
of optEg vs calcEg. Both follow the respective changes in the
substitution pattern of the quinazoline luminophore and mirror the
quality of the obtained data (Figure 8 and Figure 9). However, the
orbital energy-differences between HOMOs and LUMOs are
larger than the experimental data by ca. 0.5 eV. The results
obtained by DFT/M062X showed large differences by ca. 3.0 eV
(see supporting information). These errors can be attributed to
ignoring Coulomb- and exchange-integrals. On the other hand,
TDDFT/ B3LYP and TDDFT/M062X showed better values which
are given by vertical electronic excitation energies for S1 state.
This result implies that the molecules are not aggregated.
However, there is still an error of ca. 0.5 eV between
TDDFT/B3LYP and experimental data (Table 3 and Figure 8).
However, the data follow the overall experimentally observed
empirically determined HOMO/LUMO energy levels via
a
combination of electrochemical and optical measurements, and
calculated ones obtained from DFT methods using the
TDFFT/BLYP3 functions. Figure 9 shows the correlation between
experimentally estimated optical band gaps (optEg) and the
calculated first excitation energies (calcEg), as well as the
correlation between empirical HOMO energies obtained by
electrochemical methods and the calculated HOMO energy levels. trend in HOMO/LUMO energy changes with variations in the
substitution pattern; i.e. the donor strength in position 2 of the
quinazoline (Figure 8).
0
-1
-2
-3
-4
-5
-6
-7
calc. LUMO
exp. LUMO
calc. HOMO
exp. HOMO
Table 4. Electron correlation interaction (CI) coefficients and electron configu-
ration state functions (CSF) of the S1 (21A in C1 symmetry) state determined by
SAC-CI calculation; digit with “a” in parenthesis shows molecular orbital (MO) in
C1 and “(57a) → (64a)” is a single-electron excitation from 57th MO to 64th.
(MOs shown in Figure 10 and supporting information).
Compound
CI coefficient
CSF
Character of excitation
2
-0.79620
0.27858
0.21625
0.89667
0.14357
0.80843
0.36835
-0.71178
-0.44801
0.35266
-0.83333
0.27774
0.79086
-0.39161
-0.60684
0.54282
-0.37324
-0.88260
0.15897
(57a) → (64a)
(57a) → (65a)
(56a) → (64a)
(57a) → (64a)
(56a) → (74a)
(65a) → (75a)
(65a) → (76a)
(61a) → (72a)
(61a) → (71a)
(61a) → (73a)
(57a) → (66a)
(57a) → (65a)
(53a) → (61a)
(53a) → (60a)
(54a) → (63a)
(54a) → (62a)
(54a) → (64a)
(50a) → (58a)
(50a) → (57a)
*
Ryd
*
4a
7a
7c
*
4a
4d 7a 7b 7c 7d 7e 7f 7g 8a 8b 8c 8d 9a 9b 9c 9d
4b 4c
2
Ryd
*
Figure 8. Compilation of empirical and theoretical obtained HOMO-LUMO en-
ergy levels. Calculation level DFT TDDFT/B3LYP in CH2Cl2.
Ryd
Ryd
Ryd
Ryd
Ryd
Ryd
*
4,0
y = 1,019x + 0,318
y = 1,059x + 0,358
-5,5
-5,6
-5,7
-5,8
-5,9
-6,0
3,8
3,6
3,4
3,2
7d
7e
7f
2,8
3,0
3,2
3,4
3,6
3,8
-6,0
-5,9
-5,8
-5,7
-5,6
-5,5
Observed optical gap optEg (eV)
Empirical determined HOMO energy EHOMO (eV)
Figure 9. (left) Correlation between HOMO energy levels obtained by
electrochemical methods (EHOMO) and calculated HOMO energies (calcEHOMO).
(right). Correlation of observed and calculated gaps: optEg vs calcEg. Calculation
level DFT TDDFT/B3LYP in CH2Cl2 (PCM) for both.
Ryd
Ryd
Ryd
Ryd
*
We observe a reasonable good linear correlation between the
experimentally obtained HOMO energy by electrochemical
means and the respective calculated ones by DFT TDDFT/BLYP
in CH2Cl2 (PCM) (Figure 9, left). And although the optical gap
7g
Ryd
8
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In order to confirm the effect of the electron-correlation en-
ergy, we also performed SAC-CI calculations (Table 4). SAC-CI
theory could provide us the similar result to Full-CI approach.
The electronic character of 2 was described by a single-electron
excitation to Rydberg (Ryd) type of MO (65a) from HOMO, “(57a)
excitation with the minor contribution of -Ryd (see Table 4), the
ICT-character is weak and the S1 state could not be stabilized in
polar solution. On the other hand, the only ICT-characters (-Ryd
excitation) appear as the primary configurations for 7c, 7d and 7f.
S1 could be strongly stabilized in polar solution, and thus the PLE
would happen red-shifted - at the lower energy side - compared
to 7e and 7g. A fact that is confirmed by empirical photophysical
and fluorescence spectroscopy results in Figure 4.


(65a)”, with the main configuration of -* which is “(57a)
(64a)” excitation. The ICT property was theoretically described as
the excitation to Rydberg-MO at Hartree-Fock (HF) level—SAC-
CI theory is based on HF theory. If multi-configuration (MC) /
multi-reference (MR) theory such as MCSCF and MR-CI were
employed, the MOs would be different from Ryd-MOs described
Proton sensitive “turn-on” fluorescence molecular probe
UV-vis absorption and photoluminescence emission of 7-amino-
in SAC-CI, which can be interpreted as the MOs for n-* excitation. 2-N-morpholino-4-methoxyquinazoline 12 change both signifi-
The HF theory can, however, optimize only electronically occu-
pied orbitals at variation principle. Virtual orbitals including Ryd-
MOs are not optimized at self-consistent field (SCF) calculation.
This problem could be resolved in multi-electron excitations (up to
quartet-electron excitation) computed by SAC-CI method as it
would be also done by Full-CI. As shown in Figure 10, there ap-
pear to be two groups in spectra for a series of 7c–7g: One group
cantly under acidic conditions. Light absorption at the low-energy
ICT band of 12 (abs
max = 335 nm) increases on subsequent addi-
tion of aliquots of trifluoro acetic acid (TFA) to a solution of

quinazoline 12 in dichloromethane and the fluorescence emission
em
intensity with band maxima at

= 395 nm increases in the
max
same extent. This makes quinazoline 12 suitable as “turn-on” flu-
orescence molecular probe for ratiometric sensing of acidic envi-
ronments (Figure 11).
A
B
Figure 11. A) Successive changes of UV-vis absorption bands of 7-amino-2-
morpholino-4-methoxyquinazoline (12) on addition of aliquots of trifluoro acetic
acid (TFA). B) Fluorescence emission intensity enhancement of quinazoline 12
on ratiometric titration with TFA.
The fluorescence “turn-on” property of 12 is based on the 4.6-fold
increase in fluorescence quantum yield, as verified with the help
of an integration sphere. The solution quantum yield of “pure” non-
protonated 12 was found to be F (CH2Cl2, exc = 330 nm) = 0.13
and increased to F (CH2Cl2 + excess TFA, exc = 330 nm) = 0.60
for the “protonated” 12. The ratiometric titration of a 10-5 M solu-
tion of 7-aminoquinazoline 12 in CH2Cl2 at the excitation wave-
length ex = 293 nm (isobestic point in the UV-vis spectrum of 12)
by recording the fluorescence intensity at F = 390 nm is shown
in Figure 11-A. Saturation of the light emission intensity is reached
with an approximate 10-fold excess of TFA. Notably, this increase
in emission intensity upon protonation is reversible: Adding an
excess of triethylamine (TEA) to a solution of 12 / TFA in CH2Cl2
results in a “turn-off” fluorescence and brings back the PLE
spectra of the parent non-protonated 12 (Figure 11-B). An inter-
or intramolecular photoinduced electron transfer (PET)[55] from the
amino group at the 7-position towards the electron deficient
quinazoline core of compound 12 is proposed to be the working
principle of this molecular turn-on/off fluorescence probe. On
protonation of the 7-amino group the PET is inhibited and
Figure 10. Molecular orbitals (MOs) to describe the S1 state in SAC-CI calcula-
tions; digit with “a” in parenthesis shows molecular orbital (MO) in C1 symmetry
and “56a” is the 56th MO in C1.
consists of 7e and 7g, and the other consists of 7c, 7d and 7f.
Since the primary electronic configurations of 7e and 7g are -*
9
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quinazoline 12 turns into a more efficient fluorophore comparable
to those found with all other investigated derivatives of 2-N-amino-
4-methoxy-quinazolines. However, other underlying mechanisms
of fluorescence enhancement and quenching including reversible
aggregate formation through hydrogen bonding cannot be ruled
out yet and are objectives of future investigation.
hexane/ethyl acetate = 4:1(v/v)) afforded compound 7a (121 mg,
87% yield) as colorless solid; mp 90-91 °C; Rf = 0.24 (SiO2, hex-
ane/ethyl acetate = 1:4 (v/v)). 1H NMR (300 MHz, CDCl3):  3.80
(t, J = 4.8 Hz, 4H,), 3.91 (t, J = 4.8 Hz, 4H), 4.08 (s, 3H), 7.12-
7.17 (m, 1H), 7.48-7.62 (m, 2H), 7.90-7.93 (m, 1H); 13C NMR (125
MHz, CDCl3):  44.6, 53.7, 67.0, 111.7, 122.0, 123.6, 125.0, 133.5,
153.2, 158.4, 167.4; HRMS (EI) m/z calcd for C13H15N3O2 (M+):
245.1164, found: 245.1169.
2-N-piperidino-4-methoxyquinazoline (7b): To a solution of 2-
chloro-4-methoxyquinazoline (6a) (200 mg, 1.03 mmol) in dry tol-
uene (15 mL) was added piperidine (1.0 mL, 10.30 mmol). The
reaction mixture was stirred at 110 °C overnight. Column chroma-
tography (SiO2, ethyl acetate/n-pentane = 1:20 (v/v)) afforded
compound 7b (213 mg, 85% yield) as solid, mp 58-60 °C; Rf =
Conclusion
We reported on the side-selective synthesis and full structure-
photophysics characterization of a set of differently substituted N-
amino-quinazolines as new small molecule fluorescence com-
pounds. Aiming to disclose basic insights into fluorescence-struc-
ture-property relationship (FSPR) the synthesized quinazolines
were evaluated by their photophysical and electrochemical prop-
erties. The amino group at position 2 of the quinazoline core
proved to be essential for the fluorescence. The increase of elec-
tron donor strength of the 2-amino groups led to red-shifts in ab-
sorption and emission wavelengths and enhanced fluorescence
efficiency in agreement with an effective ICT. Methoxy and chloro
substituents at the position 6 caused larger bathochromic shifts
than those at positions 5, 7, and 8. HOMO-LUMO energy levels
were estimated by a combination of electrochemical and photo-
physical methods. Reasonable good linear correlations between
empirical and theoretical HOMO/LUMO energies on the DFT
TDDFT/BLYP in CH2Cl2 (PCM) were found. Furthermore,
computation studies revealed that the excitation to the Rydberg-
MOs in SAC-CI contributed to the ICT. The weakly fluorescent 7-
amino derivative showed a significant increase in fluorescence
emission intensity under acidic conditions and its quenching by
the subsequent addition of a base revealed fluorescence “turn-
on/off” properties. We believe that those 2-N-aminoquinazolines
can function as fluorescent probes that sensitively respond to the
environment, and can be utilized in molecular recognition as
fluorophores.
1
0.47 (SiO2, ethyl acetate/n-pentane = 1:20 (v/v)). H NMR (400
MHz, CDCl3):  1.73 – 1.59 (m, 6H), 3.90 - 3.88 (m, 4H), 4.08 (s,
3H), 7.09 (ddd, J = 7.9 Hz, J = 7.1 Hz, J = 0.8 Hz, 1H), 7.47 (d, J
= 8.4 Hz, 1H), 7.56 (ddd, J = 8.3 Hz, J = 7.0 Hz, J = 1.3 Hz, 1H),
7.88 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):  25.1, 26.1,
45.2, 53.7, 111.4, 121.4, 123.7, 124.9, 133.4, 153.8, 158.7, 167.3.
HRMS (ESI) m/z calcd for C14H18N3O (M+H)+: 244.1450, found:
244.1454.
2-N-Pyrrolidino-4-methoxyquinazoline (7c): Pyrrolidine (0.266
mL, 3.07 mmol) was added to a solution of 2-chloro-4-methox-
yquinazoline (6a) (300 mg, 1.54 mmol) in 1,4-dioxane (20 ml), and
the mixture was heated to refluxed for 2 h. Column chromatog-
raphy (SiO2, hexane/ethyl acetate = 4:1 (v/v)) gave 7c (159 mg,
45% yield) as colorless solid, mp 93-94 °C; Rf = 0.30 (SiO2, hex-
ane/ethyl acetate = 4:1 (v/v)). 1H NMR (500 MHz, CDCl3):  7.89
(d, J = 8.1 Hz, 1H), 7.58-7.56 (m, 2H), 7.09 (m, 1H), 4.09 (s, 3H),
3.70 ( t, J = 6.6 Hz, 4H), 2.00 (t, J = 6.7 Hz, 4H); 13C NMR (125
MHz, CDCl3):  25.5, 46.7, 53.5, 111.2, 121.0, 123.6, 124.5, 133.3,
153.5, 157.3, 166.9. HRMS (FAB) m/z calcd for C13H16N3O
(M+H)+: 230.1293, found: 230.1302. Anal calcd for C13H15N3O: C,
68.10; H, 6.59; N, 18.33, found: C, 67.95; H, 6.72; N, 18.33.
2-N-Azetidino-4-methoxyquinazoline (7d): According to the
general procedure the compound was obtained in 74% yield (165
mg) by the reaction of 2-chloro-4-methoxyquinazoline (6a) (200
mg, 1.03 mmol), K2CO3 (86 mg, 0.62 mmol) and azetidine (125
L, 2.6 mmol) in dry toluene (15 mL) at 100 °C. Column chroma-
tography (Al2O3- Alox(III/N), ethyl acetate/n-pentane = 1:20 (v/v))
afforded compound 7d as solid, mp 124-126 °C; Rf = 0.25 (Al2O3,
ethyl acetate/n-pentane = 1:20 (v/v)). 1H NMR (400 MHz, CDCl3)
2.36 (“quint”, 2H), 4.07 (s, 3H), 4.23 (t, J = 7.5 Hz, 4H), 7.12
(ddd, J = 8.0 Hz, J = 6.5 Hz, J = 1.4 Hz, 1H), 7.54-7.52 (m, 1H),
7.58 (ddd, J = 8.2 Hz, J = 6.7 Hz, J = 1.4 Hz, 1H), 7.91 (d, J = 8.0
Hz, 1H); 13C NMR (100 MHz, CDCl3)  16.3, 50.3, 53.8, 111.8,
121.7, 123.8, 124.8, 133.6, 153.4, 160.0, 167.6. HRMS (ESI) m/z
calcd for C12H14N3O (M+H)+: 216.1137, found: 216.1138.
Experimental Section
General procedure for the synthesis of 4-methoxy-2-chloro-
quinazolines
2-Chloro-4,5-dimethoxyquinazoline (6b): A mixture of 2,4-di-
chloro-5-methoxyquinazoline[10, 56] (5a) (49.0 mg, 0.21 mmol) and
sodium methoxide (17.4 mg, 0.32 mmol) was stirred in dry MeOH
(10 mL) at 50 °C for 2 h. Column chromatography (SiO2,
hexane/ethyl acetate = 9:1 (v/v)) afforded compound 6b (34.9 mg,
74% yield) as colorless solid, mp 112-113 °C; Rf = 0.18 (SiO2,
EtOAc/n-hexane = 1/9 (v/v)). 1H NMR (300 MHz, CDCl3):  3.98
(s, 3H), 4.18 (s, 3H), 6.90 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 5.2 Hz,
1H), 7.71 (dd, J = 4.8, J = 5.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3):  55.4, 56.3, 106.6, 107.2, 119.1, 134.7, 154.4, 156.1,
157.4, 168.7. HRMS (EI) m/z calcd for C10H9ClN2O2 (M+):
224.0353, found: 224.0350.
2-N,N-Dimethylamino-4-methoxyquinazoline (7f): According
to the general procedure the compound was obtained in 89% yield
(93 mg) by the reaction of 2-chloro-4-methoxyquinazoline (6a)
(100 mg, 0.51 mmol) with dimethylamine (5.1 mL, 10.2 mmol, 2M
in THF) in dry 1,4-dioxane (10 mL) at 100 °C (12h) in a sealed
Schlenk tube. Column chromatography (SiO2, ethyl acetate/n-
pentane = 1:10 (v/v)) afforded compound 7f as solid, mp 59-61 °C
(colorless needles, n-pentane at -28 °C), Rf = 0.64 (SiO2, ethyl
General procedure for the synthesis of 2-amino-4-methox-
yquinazolines via SNAr reaction.
2-N-Morpholino-4-methoxyquinazoline (7a): A mixture of 2-
chloro-4-methoxyquinazoline (6a) (110 mg, 0.57 mmol) and mor-
pholine (0.1 mL, 1.10 mmol) was stirred in 1,4-dioxane (5 mL)
while heating to reflux for 5 h. Column chromatography (SiO2,
1
acetate/n-pentane = 1:10 (v/v)). H NMR (400 MHz, CDCl3): 
3.27 (s, 6H), 4.09 (s, 3H), 7.09 (ddd, J = 8.0 Hz, J = 6.6 Hz, J =
1.0 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.57 (ddd, J = 8.2 Hz, J =
6.6 Hz, J = 1.4 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H); 13C NMR (125
10
This article is protected by copyright. All rights reserved.

10.1002/asia.202100534
Chemistry - An Asian Journal
FULL PAPER
MHz, CDCl3):  37.2, 53.7, 111.2, 121.3, 123.7, 124.9, 133.5,
153.8, 159.4, 167.1. HRMS (ESI) m/z calcd for C11H14N3O
(M+H)+: 204.1137, found: 204.1141.
CDCl3):  3.80 (t, J = 4.8 Hz, 4H), 3.93 (t, J = 4.8 Hz, 4H), 3.98 (s,
3H), 4.09 (s, 3H), 7.00-7.11 (m, 2H), 7.51-7.54 (m, 1H); 13C NMR
(125 MHz, CDCl3):  44.6, 53.8, 56.1, 67.0, 112.0, 112.3, 115.3,
121.5, 145.0, 152.6, 158.1, 167.4; HRMS (EI) m/z calcd for
C14H17N3O3 (M+): 275.1270, found: 275.1251. Anal calcd for
C14H17N3O3: C, 61.08; H, 6.22; N, 15.26, found: C, 60.98; H, 6.24;
N, 15.24.
4,6,7-Trimethoxy-2-N-morpholinoquinazoline (10): According
to the general procedure the compound was obtained in 98% yield
(343 mg) after column chromatography (SiO2, hexane/ethyl ace-
tate = 4:1(v/v)). Compound 10 was obtained as solid, mp 217-
218 °C (CHCl3/n-hexane); Rf = 0.09 (SiO2, ethyl acetate/n-hexane
= 1:4 (v/v)). 1H NMR (300 MHz, CDCl3):  3.80 (t, J = 4.8 Hz, 4H),
3.86 (t, J = 4.8 Hz, 4H), 3.94 (s, 3H), 3.98 (s, 3H), 4.07 (s, 3H),
7.21 (s, 1H), 7.26 (s, 1H); 13C NMR (125 MHz, CDCl3):  44.7,
53.5, 56.0, 56.1, 67.0, 102.1, 104.8, 104.9, 146.2, 150.3, 155.3,
158.3, 166.2. HRMS (FAB) m/z calcd for C15H19N3O4 (M+H+):
306.1454, found: 306.1462. Anal calcd for C15H19N3O4: C, 59.01;
H, 6.27; N, 13.76, found: C, 59.12; H, 6.35; N, 13.65.
2-N-Methylamino-4-methoxyquinazoline (7g): According to the
general procedure the compound was obtained in 55% yield (40
mg) after column chromatography (SiO2, n-hexane/ethyl acetate
= 4:1 (v/v)). Compound 7g was obtained as solid, mp 127-129 °C;
1
Rf = 0.33 (SiO2, hexane/ ethyl acetate = 1:1 (v/v)). H NMR (300
MHz, CDCl3):  3.09 (d, J = 5.2 Hz, 3H), 4.07 (s, 3H), 5.05 (bs,
1H), 7.13 (m, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.59 (m, 1H), 7.91 (dd,
J = 7.6, J = 1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3):  28.5, 53.8,
112.1, 121.7, 123.7, 124.5, 133.5, 153.0, 159.5, 167.5. HRMS
(ESI) m/z calcd for C11H12N3O (M+H+): 190.0975; found:
190.1004. Anal calcd for C10H11N3O: C, 63.48; H, 5.86; N, 22.21,
found: C, 63.23; H, 6.12; N, 22.06.
2-N-morpholino-4,5-dimethoxyquinazoline (8a): According to
the general procedure the compound was obtained in 84% yield
(30 mg) by the reaction of 2-chloro-4,5-dimethoxyquinazoline (6b)
(29 mg, 0.13 mmol) and morpholine (0.023 mL, 0.26 mmol) in 1,4-
dioxane (2 mL) under reflux for 5 h. Column chromatography
(SiO2, n-hexane/ethyl acetate = 4:1 (v/v)) afforded compound 8a
as solid, mp 154-155 °C (colorless needles, CHCl3/pentane); Rf =
0.30 (SiO2, ethyl acetate/n-hexane = 1:4 (v/v)). 1H NMR (300
MHz, CDCl3):  3.77-3.81 (m, 4H), 3.86-3.90 (m, 4H), 3.93 (s, 3H),
4.07 (s, 3H), 6.56 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H,),
7.47 (dd, J = 7.5 Hz, J = 8.6 Hz, 1H); 13C NMR (125 MHz, CDCl3):
 44.4, 54.0, 56.0, 66.9, 102.6, 103.0, 117.8, 133.5, 156.0, 157.6,
158.2, 167.5; HRMS (EI) m/z calcd for C14H17N3O3 (M+):
275.1270, found: 275.1262. Anal calcd for C14H17N3O3: C, 61.08;
H, 6.22; N, 15.26, found: C, 61.09; H, 6.12; N, 15.15.
4,6-Dimethoxy-2-N-morpholinoquinazoline (8b): According to
the general procedure the compound was obtained in 62% yield
(21 mg) after column chromatography (SiO2, n-hexane/ethyl ace-
tate = 4:1 (v/v)). Compound 8b was obtained as colorless solid,
mp 152-153 °C (needles, CHCl3/pentane); Rf = 0.27 (SiO2, ethyl
acetate/n-hexane = 1/4 (v/v)). 1H NMR (300 MHz, CDCl3):  3.78-
3.81 (m, 4H), 3.82-3.88 (m, 4H), 3.86 (s, 3H), 4.09 (s, 3H), 7.24-
7.30 (m, 2H), 7.46 (d, J = 8.9 Hz, 1H); 13C NMR (125 MHz, CDCl3):
 44.7, 53.7, 55.6, 67.0, 102.1, 111.5, 125.3, 126.6, 148.7, 154.7,
157.6, 166.7; HRMS (EI) m/z calcd for C14H17N3O3 (M+):
275.1270, found: 275.1260. Anal calcd for C14H17N3O3: C, 61.08;
H, 6.22; N, 15.26, found: C, 61.14; H, 6.16; N, 15.21.
5-Chloro-4-methoxy-2-N-morpholinoquinazoline (9a): Ac-
cording to the general procedure the compound was obtained in
86% yield (1159 mg) after column chromatography (SiO2, n-hex-
ane/ethyl acetate = 4:1(v/v)). Compound 9a was obtained as solid,
mp 131-133 °C; Rf = 0.28 (SiO2, n-hexane/ethyl acetate = 4:1
(v/v)). 1H NMR (600 MHz, CDCl3):  7.44-7.41 (m, 2H), 7.16 (m,
1H), 4.09 (s, 3H), 3.91 (m, 4H), 3.79 (m, 4H); 13C NMR (150 MHz,
CDCl3):  44.4, 53.9, 66.9, 109.9, 124.3, 124.7, 130.8, 132.9,
155.7, 157.7, 166.8. HRMS (ESI) m/z calcd for C13H15ClN3O2
(M+H+): 280.0847, found: 280.0836. Anal calcd for C13H14ClN3O2:
C, 55.82; H, 5.04; N, 15.02, found: C, 55.75; H, 5.09; N, 14.89.
6-Chloro-4-methoxy-2-N-morpholinoquinazoline (9b): Ac-
cording to the general procedure the compound was obtained in
89% yield (179 mg) after column chromatography (SiO2, n-hex-
ane/ethyl acetate = 3:1 (v/v)). Compound 9b was obtained as
solid, mp 99-100 °C; Rf = 0.28 (SiO2, n-hexane/ethyl acetate = 4:1
1
(v/v)). H NMR (600 MHz, CDCl3):  7.88 (d, J = 2.8 Hz, 1H), 7.53-
7.47 (m, 2H), 4.08 (s, 3H), 3.91 (m, 4H), 3.80 (m, 4H); 13C NMR
(150 MHz, CDCl3):  44.6, 54.0, 66.9, 112.1, 122.9, 126.4, 127.0,
134.2, 151.6, 158.3, 166.6. HRMS (ESI) m/z calcd for
C13H15ClN3O2 (M+H+): 280.0847, found: 280.0853. Anal calcd for
C13H14ClN3O2: C, 55.82; H, 5.04; N, 15.02, found: C, 55.77; H,
5.04; N, 14.91.
4,7-Dimethoxy-2-N-morpholinoquinazoline (8c): According to
the general procedure the compound was obtained in 60% yield
(441 mg) after column chromatography (SiO2, n-hexane/ethyl ac-
etate = 4:1 (v/v)). Compound 8c was obtained as solid, mp 143-
144 °C (colorless needles, CHCl3/pentane); Rf = 0.36 (SiO2, ethyl
acetate/n-hexane = 1:4 (v/v)). 1H NMR (300 MHz, CDCl3):  3.78-
3.82 (m, 4H), 3.87-3.91 (m, 4H), 3.88 (s, 3H), 4.05 (s, 3H), 6.76
(dd, J = 2.4 Hz, J = 8.7 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 7.79 (d,
J = 8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3):  44.6, 53.5, 55.4,
67.0, 104.1, 105.9, 114.0, 125.0, 155.5, 159.1, 164.1, 167.0;
HRMS (EI) m/z calcd for C14H17N3O3 (M+): 275.1270, found:
275.1251. Anal calcd for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26,
found: C, 60.95; H, 6.09; N, 15.26.
7-Chloro-4-methoxy-2-N-morpholinoquinazoline (9c): Ac-
cording to the general procedure the compound was obtained in
96% yield (390 mg) after column chromatography (SiO2, n-hex-
ane/ethyl acetate = 9:1 (v/v)). Compound 9c was obtained as
solid, mp 116-117 °C (CH2Cl2/n-hexane), Rf = 0.33 (SiO2, ethyl
acetate/n-hexane = 1:9 (v/v)). 1H NMR (300 MHz, CDCl3):  3.77-
3.82 (m, 4H), 3.87-3.92 (m, 4H), 4.07 (s, 3H), 7.08 (dd, J = 2.0 Hz,
J = 8.6 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H,), 7.82 (d, J = 8.6 Hz, 1H);
13C NMR (125 MHz, CDCl3):  44.5, 53.8, 66.9, 110.0, 122.6,
124.2, 125.0, 139.6, 154.1, 158.9, 167.2; HRMS (EI) m/z calcd for
C13H14ClN3O2 (M+): 279.0775, found: 279.0780. Anal calcd for
C13H14ClN3O2: C, 55.82; H, 5.04; N, 15.02, found: C, 55.77; H,
5.06; N, 15.00.
4,8-Dimethoxy-2-N-morpholinoquinazoline (8d): According to
the general procedure the compound was obtained in 99% yield
(437 mg) after column chromatography chromatography (SiO2, n-
hexane/ethyl acetate = 4:1 (v/v)). Compound 8d was obtained as
solid, mp 174-175 °C (colorless needles, CHCl3/pentane); Rf =
8-Chloro-4-methoxy-2-N-morpholinoquinazoline (9d): Ac-
cording to the general procedure the compound was obtained in
82% yield (66 mg, 0.24 mmol) after Column chromatography
(SiO2, n-hexane/ethyl acetate = 3:1 (v/v)). Compound 9d was ob-
tained as a solid, mp 123-124 °C; Rf = 0.35 (SiO2, n-hexane/ethyl
0.18 (SiO2, ethyl acetate/n-hexane = 1:4 (v/v)). 1H NMR (300 MHz, acetate = 4:1 (v/v). 1H NMR (500 MHz, CDCl3):  7.84 (dd, J = 8.1
11
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10.1002/asia.202100534
Chemistry - An Asian Journal
FULL PAPER
Hz, 1.4 Hz, 1H), 7.70 (dd, J = 7.6 Hz, 1.3 Hz, 1H), 7.05 (t, J = 7.8 Supporting information
Hz, 1H), 4.10 (s, 3H), 3.98 (m, 4H), 3.82 (m, 4H); 13C NMR (126
MHz, CDCl3):  44.5, 54.1, 66.9, 112.8, 121.4, 122.5, 129.0, 133.5,
149.4, 158.2, 167.6. HRMS (FAB) m/z calcd for C13H15ClN3O2
(M+H+): 280.0847, found: 280.0834. Anal calcd for C13H14ClN3O2:
C, 55.82; H, 5.04; N, 15.02, found: C, 55.92; H, 4.70; N, 14.88.
Additional experimental procedures, analytical and spectroscopic
data including UV-vis absorption and PLE spectra in solution and
solid state, cyclic voltammetry data, thermogravimetric analyses
(TGA), crystallographic data (CCDC 2081759, 2081760 and
2081761) molecular orbitals, Cartesian coordinates of optimized
ground states, excitation energies for the excited states 1-5, and
orbital transition assignment and oscillator strengths for selected
compounds are provided in the supplementary information.
Synthesis of 2-amino-4-methoxyquinazolines via the Buch-
wald-Hartwig reaction.
2-N-Aziridino-4-methoxyquinazoline (7e): Into a Schlenk tube
was added 2-chloro-4-methoxyquinazoline (6a) (100 mg, 0.51
mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), Xantphos (11.6 mg, 0.02
mmol) and Cs2CO3 (332 mg, 1.02 mmol). Then, the tube was
evacuated and filled with nitrogen and anhydrous toluene (10 mL)
and aziridine (53 µL, 1.02 mmol) were added. The mixture was
stirred at 100 °C for 3 days. The reaction mixture was filtered
through a plug of Celite® and afterwards all volatile solvents were
evaporated. Column chromatography (Al2O3-Alox(III/N), ethyl ac-
etate/n-pentane = 1:10 (v/v)) afforded 7e (75 mg, 73% yield) as
solid, mp 68-70 °C; Rf = 0.39 (Al2O3, ethyl acetate/n-pentane =
1:10 (v/v)). 1H NMR (400 MHz, CDCl3):  2.46 (s, 4H), 4.17 (s, 3H),
7.36 (ddd, J = 8.1 Hz, J = 5.8 Hz, J = 2.2 Hz, 1H), 7.74-7.69 (m,
2 H), 8.03 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):  27.7
(t), 54.4 (q), 114.1 (s), 123.7 (d), 124.8 (d), 126.3 (d), 133.8 (d),
152.2 (s), 166.0 (s), 168.3 (s); HRMS (ESI) m/z calcd for
C11H12N3O ([M+H]+): 202.0980; found: 202.0985.
Acknowledgements
Financial support of the Ministère de l’Enseignement Supérieur et
de la Recherche (MESR), the Centre National de la Recherche
Scientifique (CNRS, France) and the Conseil Régional de Nor-
mandie and the Fonds Européen de Développement Régional
(FEDER) is gratefully acknowledged.
Keywords: fluorescence spectroscopy • quinazolines • cyclic
voltammetry • push-pull chromophores • intramolecular charge
transfer (ICT) • HOMO/LUMO • fluorescence-structure-property
relationship (FSPR)
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4-Methoxy-7-nitro-2-N-morpholinoquinazoline (11):[57] A mix-
ture of 2-chloro-4-methoxy-7-nitroquinazoline (6k) (350 mg, 1.46
mmol), morpholine (0.26 mL, 2.95 mmol) and 1,4-dioxane (15 mL)
was heated to reflux for 16 h. Column chromatography (SiO2, n-
hexane/ethyl acetate = 4:1 (v/v)) afforded compound 11 (407 mg,
96% yield) as a solid; mp 177-178 °C (yellow needles, CHCl3/pen-
tane). 1H NMR (300 MHz, CDCl3):  3.79-3.82 (m, 4H), 3.93-3.96
(m, 4H), 4.12 (s, 3H), 7.84 (dd, J = 2.0 Hz, J = 8.9 Hz, 1H), 8.02
(d, J = 8.9 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3):  44.5, 54.2, 66.9, 114.9, 115.0, 120.5, 125.5, 151.4,
153.4, 159.1, 167.1; HRMS (EI) m/z calcd for C13H14N4O4 (M+):
290.1015, found: 290.1002. Anal calcd for C13H14N4O4: C, 53.79;
H, 4.86; N, 19.30, found: C, 53.85; H, 4.62; N, 19.23.
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4-Methoxy-2-N-morpholino-7-aminoquinazoline (12):[58] A 1 M
aq. HCl solution (0.6 mL) was added to a mixture of compound 11
(58.0 mg, 0.20 mmol) and iron powder (35 mg, 0.60 mmol) in
EtOH (10 mL) and kept reflux for 3 h. The mixture was cooled
down and filtered. Aqueous ammonium solution was added and
the product was extracted with ethyl acetate and washed with
brine. After being dried with sodium sulfate, the organic layer was
concentrated. Column chromatography (SiO2, n-hexane/ethyl ac-
etate = 1:1 (v/v)) gave compound 12 (44 mg, 85% yield) as solid;
mp 205-206 °C; Rf = 0.21 (SiO2, ethyl acetate/n-hexane = 1/1
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Entry for the Table of Contents
1,0
1,0
500
450
0,5
400
0,5
350
-0,7
-0,6
-0,5
-0,4
-0,3
-0,2
0,0
p
-0,5
0,0
350
0,5
1,0
1,5
2,0
400
450
500
550
600
65
Side-selective
Synthesis
Potential Vf (V)
Wavelength (nm)
Structure &
Photophysics
Solution &
Solid State
Fluorescence
HOMO
LUMO
Side-selective synthesis provides sets of new fluorescent 2-N-aminoquinazolines whose fluorescent-structure-property relationships
(FSPRs) were revealed by steady-state absorption and light emission spectroscopy, electrochemical and computational (DFT-
TDDFT/BLYP3 and SAC-CI calculations) chemistry.
15
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