Synthesis and Photophysical Characterization of 2,3-Dihydroquinolin-4-imines: New Fluorophores with Color-Tailored Emission

Article abstract of DOI:10.1002/chem.201703998

In this study, a series of variously substituted 2,3-dihydroquinolin-4-imines (DQIs) were synthesized from N-substituted propargylanilines by copper(I)-catalyzed annulation. The approach adopted in this study under mild, effective conditions exhibited broad substrate tolerance, particularly for functional groups substituted on anilines. Most of the DQI derivatives synthesized under optimal conditions were obtained in good isolated yields of 63–88 %. 2,3-Dihydroquinolinimine thus obtained was easily converted to important structures like 2,3-dihydroquinolone and tetrahydrobenzodiazepin-5-one, confirming the importance of this strategy in constructing various heterocycles. Surprisingly, 2,3-dihydroquinolinimines thus obtained exhibited bright fluorescence with quantum yields up to 66 %. The density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations were performed for understanding the excited-state nature of DQI system. Accordingly, a tailored DQI derivative bearing methoxy group at C-6 position and acetoxy group at C-7 position was designed and synthesized to give emission at 559 nm with redshift compared to the 7-methoxy substituted DQI. A detailed study of DQI structures with their photophysical properties was performed with five control molecules and consequently demonstrated the uniqueness of the chemical structures of DQIs.

Full text of DOI:10.1002/chem.201703998

A Journal of
Accepted Article
Title: Synthesis and Photophysical Characterization of 2,3-
Dihydroquinolin-4-imines: New Fluorophores with Color-Tailored
Emission
Authors: Chih-Hung Chou, Basker Rajagopal, Chien-Fu Liang, Kuan-
Lin Chen, Dun-Yuan Jin, Hsing-Yin Chen, Hsiu-Chung Tu,
Yo-Ying Shen, and Po-Chiao Lin
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201703998
Link to VoR: http://dx.doi.org/10.1002/chem.201703998
Supported by

10.1002/chem.201703998
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Synthesis and Photophysical Characterization of 2,3-
Dihydroquinolin-4-imines: New Fluorophores with Color-Tailored
Emission
Chih-Hung Chou,+,[a] Basker Rajagopal,+,[a] Chien-Fu Liang,[b] Kuan-Lin Chen,[a] Dun-Yuan Jin,[a] Hsing-
Yin Chen,*[c] Hsiu-Chung Tu,[a] Yu-Ying Shen,[a] and Po-Chiao Lin*[a]
Abstract: In this study, a series of variously substituted 2,3-
dihydroquinolin-4-imines (DQIs) were synthesized from N-
substituted propargylanilines by copper(I)-catalyzed annulation. The
approach adopted in this study under mild, effective conditions
exhibited broad substrate tolerance, particularly for functional groups
substituted on anilines. Most of the DQI derivatives synthesized
under optimal conditions were obtained in good isolated yields of
63–88%. 2,3-Dihydroquinolinimine thus obtained was easily
converted to important structures like 2,3-dihydroquinolone and
tetrahydrobenzodiazepin-5-one, confirming the importance of this
strategy in constructing various heterocycles. Surprisingly, 2,3-
dihydroquinolinimines thus obtained exhibited bright fluorescence
with quantum yields up to 66%. The density functional theory (DFT)
and time-dependent DFT (TD-DFT) calculations were performed for
understanding the excited-state nature of DQI system. Accordingly,
a tailored DQI derivative bearing methoxy group at C-6 position and
acetoxy group at C-7 position was designed and synthesized to give
emission at 559 nm with red-shift compared to the 7-methoxy
substituted DQI. A detailed study of DQI structures with their
photophysical properties was performed with five control molecules
and consequently demonstrated the uniqueness of the chemical
structures of DQIs.
effects.2a-b In addition, its reduced form, 2,3-dihydroquinolinone,
is an important privileged structural subunit found in a number of
bioactive small molecules. For instance, 2,3-dihydroquinolinone
is found in the acronycine family of alkaloids, exhibiting potent
anti-cancer properties,3 as antagonists of the CRTH2 receptor,4
and in several antitumor and antimitotic agents.5 However, only
a few methods have been reported for the preparation of 2,3-
dihydroquinolone, limiting the prospects for extensive study of
these compounds. Typically, corrosive reagents like
orthophosphoric acid, acetic acid, or strong alkalis have been
used for catalyzing the isomerization of substituted 2-
aminochalcones to 2,3-dihydroquinolones, which possibly limits
the substrate scope considerably (Scheme 1 (a)).6a-f Recently,
intramolecular cyclization under milder conditions using
transition metal catalysts or organocatalysts have emerged as
important strategies. Sierra and co-workers have reported the
Pd-catalyzed synthesis of 2,3-dihydroquinolinones from (2-
iodoanilino)-aldehydes (Scheme 1(b)).7 Lu and co-workers have
reported the asymmetric synthesis of 2-aryl-2,3-dihydro-4(1H)-
quinolinones using
a chiral tertiary amine tethered to a
bifunctional thiourea derivative (Scheme 1(c)).8 Bunce and co-
workers have reported a strategy for the synthesis of substituted
2,3-dihydro-4(1H)-quinolinones by the addition of an imine via
the SNAr approach (Scheme 1(d)).9 As shown in Scheme 1, all
the above-mentioned methods have utilized suitable ortho
substituents of anilines or fluorobenzene for participating in
cyclization. The preparation of the starting disubstituted
benzenes is tedious and time-consuming. Hence, there is an
emerging need for new synthetic strategies from easily
accessible starting compounds, which affords diverse range of
these molecules.
Introduction
The development of effective synthetic methodologies for
preparing alkaloids owing to their ubiquitous presence in natural
products, pharmaceuticals, and material chemistry is of great
interest for modern organic chemistry.1 Since the early 1960s,
quinolone and its analogs have been considered ideal antibiotics,
attributed to their high potency and low incidence of side
To this end, we reported a simple methodology for preparing
2,3-dihydroquinolin-4-imine (DQI) from aniline-tethered N-
sulfonyltriazole by thermal-assisted denitrogenative annulation
[Scheme 1 (e)].10 The DQIs thus obtained could be easily
transformed to various 2,3-dihydroquinolones. This metal-free
approach involves the decomposition of N-sulfonyltriazoles into
a ketenimine intermediate by the heat obtained from the release
of nitrogen, followed by the intramolecular trapping of the
electrophilic ketenimine intermediate by the aryl ring. As the
thermal reaction is significantly promoted by the presence of
electron-donating groups (EDGs) at the meta position of anilines,
the substrate scope is restricted, considerably limiting its use.10
For expanding the substrate scope under milder conditions,
instead of with thermal activation, transition-metal catalysis can
be employed for constructing DQIs, which might overcome the
need for the electron-donating effect. In 2005, Chang and co-
[a]
+Chih-Hung Chou, +Basker Rajagopal, Kuan-Lin Chen, Dun-Yuan
Jin, Hsiu-Chung Tu, Yu-Ying Shen, Prof. Po-Chiao Lin
Department of Chemistry, National Sun Yat-sen University
70 Lienhai Rd., Kaohsiung 80424, Taiwan
E-mail: pclin@mail.nsysu.edu.tw
[b]
[c]
Prof. Chien-Fu Liang
Department of Chemistry, National Chung-Hsing University
145 Xingda Rd., South Dist., Taichung City 402, Taiwan
Prof. Hsing-Yin Chen
Department of Medicinal and Applied Chemistry, Kaohsiung Medical
University
100,Shih-Chuan 1st Road,Kaohsiung,80708,Taiwan
E-mail: hychen@kmu.edu.tw
+
Chih-Hung Chou and Basker Rajagopal are in equal contribution.
Supporting information for this article is given via a link at the end of
the document.
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workers have reported
a
highly efficient copper-catalyzed
Optimization of conditions for Cu(I)-catalyzed annulation.
The Cu(I)-catalyzed reaction is expected to trigger the
intramolecular annulation of N-propargylanilines, thereby DQIs.
multicomponent strategy, in which sulfonyl azides react with a
wide range of alkynes and amines to form amidines.11 This
reaction forms a highly reactive ketenimine intermediate that can
be trapped with various nucleophiles and subsequently used for
synthesizing various important heterocyclic structures12 like 4-
According
to
a
previous
study,23
N,N-disubstituted
propargylanilines were directly transformed into acrylamidines in
the presence of CuCl and triethylamine, indicated as 3a' in Table
1. For the elegant synthesis of a desired DQI, the ketenimine
intermediate generated in situ should be attacked by the
benzene π-electrons instead of the non-bonding electrons of
nitrogen, resulting in the formation of acrylamidines. For
preventing the formation of undesired acrylamidines, different
Cu(I) complexes, solvents, and reaction temperatures were
carefully screened using 2a as the model substrate. The
synthesis of compound 2 from mono-substituted N-propargyl
aniline 1 is included in the Supporting Information. In the
presence of a catalytic amount of copper iodide and potassium
carbonate (K2CO3), 2a was treated with tosyl azide in anhydrous
dichloromethane (DCM) at room temperature for 12 h, affording
acrylamidine 3a' (35%) along with a trace amount of desired
compound 3a (Table 1, entry 1).
sulfonamidoquinolines,13
1,2-dihydroisoquinolines,14
3-
aminopyrazoles,15 indolines,16 fused indolines,17 and 2-imino-3-
pyrrolines.18 Inspired by this ketenimine chemistry, we have
reported an easier route to dihydropyrimidin-4-ones and β- and
β3-amino acid analogs from propargylamides using this reactive
Table 1. Optimization of conditions
a)Formation of multiple spots; b)Recovered 2a (30%); c) Triazole obtained
ketenimine intermediate by an intramolecular synthetic
strategy.19
Scheme 1. Preparation of 2,3-dihydro-4-quinolones from reported methods
and our recent study
Based on this easily accessible method, the Cu(I)-catalyzed
denitrogenative annulation of N-propargylanilines using
a
copper(I) catalyst is proposed for facilitating a series of DQIs, as
shown in Scheme 1e. The desired 2,3-dihydroquinolones were
then easily obtained by basic hydrolysis. The coupling of sulfonyl
azide and terminal alkyne using a simple copper(I) catalyst into
the ketenimine intermediate exhibits a distinct advantage as
compared to the reported hydroarylation using expensive metal
catalysts.20a-c Accordingly, the more easily accessible
propargylanilines are considered starting materials for
synthesizing the desired annulation products in one pot without
the isolation of triazoles.
Furthermore, while monitoring the progress of the reaction on a
thin-layer chromatography (TLC) chip under a UV lamp, the
DQIs thus obtained exhibited bright emission. The quinoline
fluorescence method had been employed for quantitatively
monitoring histochemically reactive zinc in the brain21 and for
tracking zinc ions in living cells.22a-b As compared to that in
quinolines, surprisingly, the deficiency of aromaticity and the
short conjugation length of DQIs can result in strong emission
from visible blue-green to yellow fluorescence with fluorescent
quantum yields up to 66%. Details of fluorescence properties in
DQIs were discussed in terms of the structure-oriented effects.
(28%); d)Triazole obtained (18%); e)Triazole obtained (14%)
In N,N-dimethylacetamide (DMF) as the solvent, multiple spots
were observed, but 3a was not isolated (entry 2). Moreover,
using acetonitrile (ACN) as the solvent, 3a was obtained in only
4% yield (entry 3). Both copper bromide (CuBr) and copper
chloride (CuCl) were also employed in this transformation in
ACN and DCM. The use of CuCl in DCM afforded 3a in 54% as
the major product, along with minor acrylamidine 3a' (11%; entry
6). According to a reported mechanistic study,24 base additives
and reaction temperature are factors important for controlling
product distribution, thus for suppressing the formation of the
undesired 3a'. Hence, 5 equivalents of K2CO3 afforded the
desired 3a in 63%, with the unreacted intermediate triazole in
14%, without the formation of 3a' (Table 1, entry 8). For
enhancing annulations without forming undesired acrylamidines,
5 equivalents of K2CO3 under mild heating at 40C were used,
exclusively affording 3a in 73% yield (Table 1, entry 9).
Results and Discussion
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Scheme
2
shows the reaction mechanism, which was
effect for facilitating annulation, the undesired acrylamidine 3j'
was exclusively obtained in 69% yield, which relocates the
methoxy group from meta position to para position.
rationalized by two competing pathways. Tosyl triazole
intermediate I could be prepared by treating N-propargylaniline
with tosyl azide and the Cu(I) catalyst, which was in equilibrium
with the α-imino diazo intermediate.
Table 2: Substrate scope with different substituents on the R1 position.
By a Wolff-type 1,2-rearrangement, highly reactive sulfonyl
ketenimine II was obtained with the release of nitrogen gas24,
which then permitted intramolecular cyclization by phenyl π-
electrons to form annulated intermediate IV. Then, the
subsequent recovery of aromaticity and tautomerization afforded
3a as the desired DQI, shown in Scheme 2 (path a).
Scheme 2. Proposed divergent pathways for the formation of cyclized 3a and
a) Compound 3g'' : 14%
acrylamidine 3a'
Surprisingly, by changing the N-substituent to the phenyl group
2k instead of the benzyl group, two annulation regioisomers 3k
and 3k’ were isolated in 21% and 37% yields, respectively. The
introduction of the phenyl group on the nitrogen atom is believed
to delocalize the non-bonding electrons, thereby resulting in
annulation but not a nitrogen-directed nucleophilic attack. The
substitution of 4-anisole in 2l increased steric hindrance for
avoiding the formation of acrylamidine and successful formation
of the annulation product 3l in 70% yield. Based on these results,
the resonance effect due to the methoxy substituent at the para
position can increase the electron density on the nitrogen atom
and promote pathway b, as shown in Scheme 2. For efficiently
controlling the formation of the desired annulation product with
specific regioselectivity, the electronic and steric properties of
the N-substituents (R1) and the R2 substituents on the phenyl
ring are crucial, so as to prevent attack on the ketenimine
intermediate to form acrylamidine and forming the desired
annulation product.
The applicability of this method was further discussed for
substrates by varying the R2 substituents (2m–2z) and
maintaining the R1 substituent as the benzyl group. The
replacement of the methoxy group with other substituents
produced a number of substrates (2m–z, Table 3), which were
subjected to the optimal reaction conditions. The electronic
nature of the meta substituent on the benzene ring with either
EDGs (2m–u) or EWGs (2w–y) resulted in the formation of
products in moderate-to-good yields (47–87%).
Alternatively, ketenimine II could be attacked by a tethered
nitrogen nucleophile, forming 4-membered-ring intermediate III,
followed by sequential rearrangement to afford acrylamidine 3a',
as shown in path b.23 Apparently, the desired annulation
products are converted from the thermodynamically stable 6-
membered-ring IV instead of the kinetically favored 4-
membered-ring intermediate III, and the increasing reaction
temperature could reasonably facilitate the formation of the
desired cyclized product over the acrylamidine side products.
Expansion of substrate scope. Under the optimal reaction
conditions, the substrate scope with respect to the N-
substituents of 1 was carefully investigated (Table 2). Reactions
with substrates 2b–2h substituted with EDGs, such as alkyl
groups and benzyl groups, proceeded smoothly, affording the
corresponding products 3b–3h, respectively, in good yields (63–
88%), and only in case of the propyl substituent, the triazole
intermediate was isolated as a byproduct 3g" (14%).
However, reactions in which the tethered nitrogen of the
substrates was protected by electron-withdrawing groups
(EWGs) benzoyl group (R1 = Bz) and tosyl group (R1 = Ts), or
without protecting groups (R1 = H), multiple products were
formed, except the desired products. (3i in Table 2) EWGs can
destabilize the α-imino diazo and ketenimine intermediates,
thereby resulting in decomposition. As the methoxy substituent
at the meta position is thought to contribute to the resonance
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As compared to the reported thermal condition,10 Cu(I)-catalyzed
annulation overcame the limitation of substrate scope,
particularly for halo substituents (2w and 2x) as well as the
trifluoromethyl substituent (2y). Nevertheless, the introduction of
a strong electron-withdrawing nitro substituent (2z) only formed
acrylamidine (3z', 72%). The nucleophilicity of the π-electrons is
considerably reduced by the strong electron-withdrawing
property of the nitro group, subsequently deactivating cyclization.
In addition, the benzene ring without any substituent (2v)
afforded the desired cyclized product in 80% yield, along with
8% acrylamidine as the byproduct (3v and 3v', respectively;
Table 3).
it also exhibits important biological activities.25 Similarly, imine
reduction in the cyclized product with sodium borohydride
afforded amine 5b in 83% yield, which is also a vital structural
core unit in medicinal chemistry.26
Scheme 3: Synthetic utility
Table 3: Substrate scope with different R2 groups on the benzene ring
NTs
CuCl (0.2 eq),
TsN3 (1.2 eq)
R2
N
Bn
(2m-z)
R2
N
Bn
(3m-z)
K2CO3 (5.0 eq),
DCM, reflux, 12h
The creation of the amine and keto functionalities from the imine
allows for further functionalization by various conjugation
methods like Schiff base formation and amide bond formation.
Importantly, the synthesis of tetrahydrobenzodiazepin-5-one via
the Schmidt rearrangement of 3b was also performed by the
treatment of sodium azide under acidic conditions, affording
synthetically valuable ring-expansion compound 6b in 66%
yield.27 The methodology developed herein can be employed for
the construction of not only various quinolone analogs but also
alkaloids.
NTs
NTs
Me NTs
NTs
Me
N
1-(Naph)
N
N
Ph
N
Bn
Bn
Bn
Bn
3n' (24%)
3o (87%)
3n (38%)
3m (73%)
NTs
NTs
OH NTs
NTs
TBSO
AllylO
N
Me2N
N
N
HO
N
Bn
3q (87%)
Bn
Bn
Bn
3r (5%)
3r' (79%)
3p (66%)
NTs
NTs
NTs
NTs
Table 4. Spectroscopic properties of fluorophores
iPrO
N
H
N
N
BnO
N
Bn
Bn
Bn
Bn
3v (80%)a
3u (80%)
3t (76%)
3s (73%)
NTs
NTs
NTs
NTs
O2N
N
N
F3C
N
Cl
F
N
Bn
Bn
Bn
Bn
3z' (72%)
3y (72%)
3x (72%)
3w (47%)
a) Compound 3v' : 8%
Interestingly, 3-methyl substituent 2n afforded two cyclized
isomers, one cyclized at the C-6 of benzene (3n, 38%) and the
other cyclized at the C-2 (3n', 24%) position. Substrate 2r with
the hydroxyl group at the meta position afforded annulation
product 3r' at the C-2 position (79% yield) instead of the C-6-
directed annulation product, along with a trace of desired
cyclization product 3r in 5% yield. Such regioselectivity is
attributed to the fact that intramolecular hydrogen bonding
between the hydroxyl and imine groups can direct annulation.
The ORTEP diagram (Figure S1) of 3r' shown in the Supporting
Information also supports this conclusion.
Synthetic applications of 2,3-dihydroquinolin-4-imines.
Furthermore, for extending the functionality of the DQIs obtained
by this method, the N-sulfonylimine group of 3b was transformed
into other functional groups. In Scheme 3 (path a), the hydrolysis
of sulfonyl imine using mild conditions, i.e., K2CO3 and MeOH,
efficiently afforded 2,3-dihydro-4-quinolone 4b in 74% yield,
which is an important structural motif in several natural products;
a)Absorption maximum. b) Emission maximum. c)Fluorescence is too weak to
be considered significant.
Photophysical properties of 2,3-dihydroquinolin-4-imines.
Quinoline and its analogs are ideal fluorescent cores for metal
ion sensors. However, the photophysical properties of quinolone
and its reduced form, 2,3-dihydroxyquinolone are never
addressed. To our surprise, during the analysis of the
transformation proposed herein, the obtained DQIs exhibited
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bright emission under a handy UV lamp on TLC chips. The
development of small-molecule fluorescent probes accelerates
the understanding of pathological and psychological roles of
biomolecules in their native environments.28a-b To this end, the
simple and easily modified structures of DQIs might potentially
did not affect emission characteristics, but the phenyl substituent
(3c) considerably shifted the emission maxima to 551 nm.
Interestingly, the presence of the methoxy group in 3d produced
an emission at 505 nm, instead of λem at 515 nm in 3k'.
Figure 1a shows the emission spectra of the representative
molecules, which clearly indicates the shift depending on the
chemical structures. The fluorescent quantum yields of 3a-3y
were determined in DCM by comparison with coumarin 153 as
the standard.29 Remarkably, an unusual high fluorescent
quantum yield was observed up to 66% in 3n along with several
DQIs (3g, 3m, 3o and 3v) determined with more than 60%.
To provide a deeper understanding of the excited-state nature of
DQI system, detailed DFT and TD-DFT calculations were
performed for 3v. The calculations reveal that only the first
excited state falls in the energy range of visible light, whereas
the remaining excited states are characterized by absorption
wavelengths shorter than 300 nm. The wavelengths of S0-S1
vertical transitions with ground-state and excited-state
geometries were calculated to be 405 and 539 nm, respectively,
agreeing well with the experimental absorption and emission
maxima (Figure 2). The S0-S1 electronic transition predominantly
involves promotion of electron from HOMO to LUMO. Inspection
of the pattern of HOMO and LUMO suggests that the electronic
transition can be considered as -* transition with a certain
degree of electron transfer from nitrogen in the ring to the N-
sulfonylimido site. This can be confirmed by Mulliken population
analysis, which reveals that the nitrogen atom in the ring
becomes more positively charged and the N-sulfonylimido group,
especially the C=N moiety, becomes more negatively charged
upon electronic excitation (Figure S2).
be
a new series of molecular fluorophores with tunable
photophysical properties. As this synthetic method was well
established, various DQIs can be elegantly synthesized, and
their photophysical properties were characterized.
For this purpose, the absorption and emission maxima along
with fluorescent quantum yields of 3a–3y were carefully
measured; they are summarized in Table 4. The DQI
fluorophores exhibited wavelengths of absorption maximum
(λmax) in the range of 394–460 nm, with emission maxima from
495 to 549 nm, resulting in blue-green to yellow fluorescence.
The unexpectedly bathochromically shifted absorption is most
probably resulting from intramolecular charge transfer from
amino functionality to N-sulfonylimido group. Remarkably, the R2
substituents, consisting of π-donating groups such as amino
group (3p), alkoxy groups (3q, 3r, 3s, 3u,), and fluoro group
(3w), exhibited λmax values near 410 nm. In contrast, the
presence of EWGs such as chloro (3x), trifluoromethyl (3y), as
well as no substituent (3v), clearly exhibited a red shift in
absorption near 425 nm. In the case of compound 3r’ the
absorption in further shifted to 447 nm. The 5-hydroxy group of
3r' may contribute to intramolecular hydrogen bonding with the
sulfonimido group, thereby affecting the chemical structure
during photoexcitation.
Figure 1. Fluorescence emission spectra of 3b, 3p, 3r, 3v, 3w, 3y, and 4b.
Figure 2. TD-DFT results for DQI 3v, including absorption and emission
wavelength, oscillator strength (f), and dominant configuration.
The emission maximum of 3v was observed at 541 nm. On the
other hand, the substitution of π-donating groups at the position
7 of DQI, the blue-shift of emission was observed for the alkoxy
groups (3b, 3d, 3e, 3f, 3g, 3h, 3q, 3u, and 3w), amino group
(3p), and hydroxyl group (3r and 3r'). The alkyl and phenyl
substituents of the benzene ring, such as 3m (λem: 527 nm) as
well as 3n and 3n' (λem: 522 and 528 nm), slightly affected
emission maxima. In contrast, the red-shift of emission was
observed when an EWG (3y) or a naphthalenyl group (3o) was
introduced at the position 7 of DQIs. As compared to 3v, large
Stokes shift of 127 nm and 110 nm were observed for 3o and 3y,
respectively. Considering the N-substituents, alkyl substituents
Subsequently, the variation of bond lengths caused by electronic
excitation was estimated, as shown in Figure S3. The most
apparent changes occur at C4N bond and NS bond that are
elongated and shortened by 0.05 Å, respectively. These
changes are consistent with the pattern of LUMO exhibiting
significant anti-bonding character along the C4N bond and
bonding character along the NS bond. In addition, non-
negligible variations in bond lengths take place at the C2C3,
C5C6, C7C8, C8C9, and N1C9 bonds.
Population analysis for the HOMO and LUMO shown in Figure 3
indicates that while the former has significant distribution on the
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C6 and C8 positions and negligible distribution on the C5 and
C7 positions, the latter displays an opposite distribution on these
positions. This feature provides an opportunity to individually
adjust the energy of HOMO by substitution on C6 and C8 and
adjust the energy of LUMO by substitution on C5 and C7,
thereby tuning the HOMO-LUMO gap and modulating the
absorption and emission wavelengths.
To extend the fluorescence emission to longer wavelength,
according to the DFT guideline, an EDG should be introduced at
the position 6 of DQI to increase the energy level of HOMO
along with an EWG at the position 7 of DQI to decrease the
energy level of LUMO. This assumption has been validated by a
tailored DQI 3aa. In the 3aa structure, a methoxy group was
introduced at its position 6 as well as a weakly electro-
withdrawing acetoxy group at the neighboring position 7.
Compared to 3b, which contains a methoxy group at the position
7, a significant red shift can be observed in both UV-VIS
absorption and fluorescence emission spectra, as shown in
Figure 4. The absorption wavelength shifts from 409 nm to 446
nm, indicating the reduction in energy gap between the HOMO
and LUMO. Accordingly, a substantially increase in emission
wavelength (up to 59 nm) is observed. The fluorescence
emission of 3aa is at 559 nm and its Stokes shift is 113 nm. The
fluorescence quantum yield of 3aa is determined as 28%.
To further understand the contribution of DQI structures in the
corresponding photophysical properties, five control molecules
7–11 were synthesized and carefully characterized. First, the
absorption of quinolin-4-imine 7, the aromatic oxidized form of
DQI, was determined at the wavelength of 361 nm, which could
be mainly attributed its aromaticity instead of the charge transfer
proposed in the DQI. Moreover, a blue fluorescence emission is
observed at 456 nm but the intensity is too weak to be
quantitatively analyzed. (Entry 1, Table 5) When oxygen atom
replaces the nitrogen atom in the structure of DQI, the weaker
charge transfer ability of oxygen atom reduces the absorption
wavelength to 340 nm and the molecule shows no fluorescence
under irradiation (control molecule 8, Entry 2).
Figure3.Population analysis of HOMO and LUMO for 3v (only fractional
contributions larger than 0.01 are shown) and scheme for modulation of
HOMO and LUMO energy.
The proposed strategy for modulating absorption and emission
wavelengths of DQIs based on the DFT calculations has been
further validated by experiments. From the data in Table 4, it can
be seen that the absorption of 3c is blue-shifted with respect to
that of 3k; in addition, the absorption and emission of 3d are
blue-shifted and the absorption of 3l is red-shifted compared to
unsubstituted 3k’, respectively. This is because EDGs at C7 of
3c and 3d raise the LUMO energy level, leading to an increased
HOMO-LUMO gap; EDGs at C6 of 3k and 3l, on the other hand,
raise the HOMO energy level, reducing the HOMO-LUMO gap.
Similar explanation can also be applied to the series of 3b, 3n,
3n’, 3p, 3q, 3r, 3s, 3u, 3w, and 3x in which EDGs are
introduced at C5 or C7; all these compounds display the blue-
shift of absorption and emission in comparison with the
unsubstituted 3v due to the rise of LUMO.
Table 5. Spectroscopic properties of control molecules
a)Absorption maximum. b)Emission maximum. c)Fluorescence quantum yield
is too weak to be determined. (λex:370 nm)
The carbon-linked analogue, 3,4-dihydronaphthalenimine 9,
shows no charge transfer and therefore, absorbs at 278 nm due
to the benzylimine moiety.(Entry 3) For compound 10, a seven-
membered ring analogue of DQI, in which the charge transfer
system is present but the ring size is larger, the absorption
wavelength was determined to be 390 nm and it provides a very
weak fluorescence at 481 nm.(Entry 4) The charge-transfer
process is still available in this molecule, but with poor efficiency
due to the greater flexibility of the bigger ring. Very importantly,
an open-ring molecule 11 was synthesized, having a structure
similar to 3v but disconnects the fused cyclohexanimine. Notably,
Figure 4. UV-Vis and fluorescence emission spectra of compound 3b and 3aa
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10.1002/chem.201703998
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the absorption of 11 at 401 nm, which is close to the absorption
range of DQIs indicates that the 2-iminaniline moiety solely
contributes to the intramolecular charge transfer process.
Furthermore, the emission λmax of 11 was observed at 551 nm
and its fluorescence quantum yield was determined to be 5%.
Compared to DQI 3v, the emission λmax considerably shifts from
541 nm to 551 nm and the fluorescence quantum yield is
reduced from 62% to 5%. This red-shift of emission and the loss
in fluorescence quantum yield can be rationalized by the
external relaxation process of 11 through internal rotation or a
twisted intramolecular charge transfer (TICT) state with rapid
rotations of the flexible open-chain framework. The relaxation
process may also contribute to the reduction in fluorescence
quantum yield. Therefore, the unique structure of DQIs with
strong charge transfer motif, as well as the rigid ring structure,
makes them new types of organic fluorophores with strong and
modulable fluorescence.
Experimental Section
All reactions were performed under an atmosphere of nitrogen
and the workups were carried out in air. All the solvents used for
the condition optimization were dried using reported procedures.
Unless noted, all materials were purchased from commercial
suppliers and used as received. Tosylazide was prepared in
house using conventional procedure. Cuprisorb resin was
purchased from Seachem Laboratory and dried in high vacuum
before used. 1H &13C NMR spectra were recorded on
BrukerUltrasheildTM 300 & 75 MHz spectrometer respectively.
NMR data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants (Hz). Solvent Residual peaks calibrations: for
1H NMR: CDCl3: 7.2600 ppm. For 13C NMR: CDCl3 : 77.23 ppm.
Melting Points of the products were calculated in open capillary
tubes using Fargo Melting Point Apparatus MP-2D. Infra-Red
spectra were recorded using Perkin Elmer 100 FTIR
Spectrometer. High Resolution Mass Spectra (HRMS) were
performed on an Electronspray Ionization Time-of-Flight (ESI-
TOF), Fast Atom Bombardment (FAB), Electron Ionization (EI),
and Atmospheric-pressure chemical ionization Time-of-Flight
(APCI-TOF) mass spectrometer. Flash chromatography was
performed using silica gel (43-60 mm, Merck).
Conclusions
In summary, 2,3-dihydroquinolin-4-imines (DQIs) were
successfully synthesized by Cu(I)-catalyzed annulation, and
were easily converted to 2,3-dihydroquinolones and various
heterocyclic molecules. This synthetic strategy used easily
available starting materials, N-substituted propargylanilines,
which allows for the rapid expansion of substrate scope and
accelerates the formation of a series of DQIs and molecular
libraries of their analogs. The obtained DQIs exhibited
unexpected photophysical properties with fluorescence quantum
yields up to 66%. With the introduction of appropriate
substituents, the emission wavelength of DQIs could be
modulated from 495 nm to 559 nm to present corresponding
blue-green to yellow color. The strong absorption of DQIs is due
to the intramolecular charge-transfer process that may induce
instantaneous change in the dipole moment. The development
of similar donor-acceptor or energy transfer dyes attracts many
attentions in the studies of material science and biological
imaging.30,31 A variety of DQIs synthesized in this research
promise to emerge as a new class of environment-sensitive
fluorophores with modulable fluorescence wavelengths. To
understand the details of these structure-based DQI
Representative procedure for the synthesis of 3a-3h, 3k-3y:
Preparation of N-(1-benzyl-7-methoxy-2,3-dihydroquinolin-
4(1H)-ylidene)-4-methyl benzenesulfonamide (3b). To
a
stirred solution of N-benzyl-3-methoxy-N-(prop-2-yn-1-yl)aniline
(100 mg, 0.397 mmol) in Dichloromethane (10 mL) was added
potassium carbonate (273.9 mg, 1.985 mmol), copper (I)
chloride (7.8 mg, 0.0794 mmol) and tosylazide (94 mg, 0.477
mmol) at room temperature under nitrogen atmosphere. The
reaction mixture was refluxed over a period of 12 h. After TLC
confirmed the completion of the reaction, the reaction mixture
was allowed to cool to the room temperature, quencehed with
saturated NH4Cl solution (5 ml), diluted with DCM (20 mL) and
washed with H2O (2 x 10 mL). The mixture was then dried over
anhydrous MgSO4, filtered and concentrated under reduced
pressure to afford the crude mixture and then purified by
silicagel column chromatography to afford the desired product
(3b) (147 mg, 88%) as a yellow solid.
Computational Methods. The hybrid functional PBE0 (i.e.,
PBE1PBE)32 in combination with the 6-31+G* basis set were
used in the present density functional theory (DFT) and time-
dependent DFT (TD-DFT) calculations. In fact, three additional
DFT functionals, CAM-B3LYP33, M06-2X34, and B97XD35, have
also been tested and it turned out that PBE0 possesses the best
performance for reproducing the absorption wavelength for the
present DQI system. It is well-known that conventional DFT
methods fail to describe van der Waals dispersion forces. To
remedy the deficiency, the D3 version of Grimme’s dispersion
correction36 was added. The calculations were performed in the
presence of dichloromethane solvent ( = 8.93) treated by SMD
continuum solvation model.37 All calculations were accomplished
by Gaussian 09 program.38
fluorophores, DFT calculations were performed and
a
reasonable design of DQI structures was obtained for specific
photophysical properties. The tailored DQI 3aa was synthesized
and showed a considerable emission red shift as expected. In
this research, an efficient Cu(I)-catalyzed synthesis of DQIs has
been proposed with wide substrate scopes and the obtained
DQIs present enhanced fluorescent quantum yields with
modulable emission wavelengths. The unique photophysical
property of DQIs makes them important for the study of
biosensing and bioimaging applications.
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10.1002/chem.201703998
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All spectra were collected at room temperature. In general,
emission spectra were obtained by exciting at 409 nm. The
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Ф
= = quantum yield of
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Chih-Hung Chou,+,[a] Basker
Rajagopal,+,[a] Chien-Fu Liang,[b] Kuan-
Lin Chen,[a] Dun-Yuan Jin,[a] Hsing-Yin
Chen,*[c] Hsiu-Chung Tu,[a] Yu-Ying
Shen,[a] and Po-Chiao Lin*[a]
Page No. – Page No.
Synthesis and Photophysical
Characterization of 2,3-
Dihydroquinolin-4-imines: New
Fluorophores with Color-Tailored
Emission
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