Oxazoline as acceptor moiety for excited-state intramolecular proton transfer

Article abstract of DOI:10.1016/j.tet.2018.10.019

Excited state intramolecular proton transfer (ESIPT) is a widespread phenomenon that has been exploited in several analytical and technological applications. Here we describe the synthesis of two ESIPT-active halogen-substituted naphthol-oxazolines that c

Full text of DOI:10.1016/j.tet.2018.10.019

Accepted Manuscript
Oxazoline as acceptor moiety for excited-state intramolecular proton transfer
Joel S. Reis, Arthur B. Fernandes, Barbara C. Freitas-Dörr, Erick L. Bastos, Hélio A.
Stefani
PII:
S0040-4020(18)31213-4
10.1016/j.tet.2018.10.019
TET 29852
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 August 2018
Revised Date: 9 October 2018
Accepted Date: 10 October 2018
Please cite this article as: Reis JS, Fernandes AB, Freitas-Dörr BC, Bastos EL, Stefani HéA, Oxazoline
as acceptor moiety for excited-state intramolecular proton transfer, Tetrahedron (2018), doi: https://
doi.org/10.1016/j.tet.2018.10.019.
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ACCEPTED MANUSCRIPT
ARTICLE
Oxazoline as acceptor moiety for excited-state intramolecular
proton transfer
Joel S. Reisa,‡, Arthur B. Fernandesb,‡, Barbara C. Freitas-Dörrb,‡, Erick L. Bastos*,b and
Hélio A. Stefani*,a
aDepartamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São
Paulo, São Paulo, SP, Brazil.
bDepartamento de Química Fundamental, Instituto de Química, Universidade de São Paulo,
São Paulo, SP, Brazil.
‡These authors contributed equally to this work.
*Corresponding authors: elbastos@iq.usp.br; hstefani@usp.br.
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ABSTRACT
Excited state intramolecular proton transfer (ESIPT) is a widespread phenomenon that has
been exploited in several analytical and technological applications. Here we describe the
synthesis of two ESIPT-active halogen-substituted naphthol-oxazolines that can be
conveniently functionalized to develop tailored sensors, and a bis-oxazoline that showcases
the potential of oxazolines to undergo double ESIPT. The photophysical properties of these
compounds in solution were investigated using polar aprotic solvents and the results were
rationalized using DFT/TD-DFT calculations.
Keywords – oxazoline, fluorescence, ESIPT, ESIDPT, phototautomerization, solvent
effects.
GRAPHICAL ABSTRACT
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1. INTRODUCTION
Excited-state intramolecular proton transfer (ESIPT) is a common process in nature that has
several applications such as bioimaging probes, chemosensors, molecular switches, organic
light-emitting devices, and laser dyes.1 ESIPT requires a preformed intramolecular
hydrogen bond between photoacidic and photobasic groups. Upon photoexcitation, charge
redistribution leads to fast adiabatic proton transfer along the excited state potential energy
surface, resulting in tautomeric transformation.2–4
Photoexcitation can produce more than one electronically excited tautomer, which
eventually decays to the ground state by fluorescence.5,6 The maximum emission
wavelength of the ESIPT tautomer is red-shifted with respect to the emission of the other
tautomer, i.e. has Stokes' shift between 6,000 – 12,000 cm–1, preventing self-reabsorption.7
ESIPT dynamics depends on factors affecting hydrogen bond formation, such as molecular
structure, temperature, and solvent. Control of the intrinsic and extrinsic properties of
ESIPT systems led to the development of multi-emissive materials. For example, excited
state intramolecular double proton transfer, viz., ESIDPT or double ESIPT, was used to
generate multiple fluorescent intermediates.3,4
The type of proton donor and proton acceptor is fundamental to hinder or promote the
ESIPT process.1,3,8,9 Phenols and naphthols are common photoacids in ESIPT-active
molecules because their acid dissociation constants are much higher in the ground state
than in the excited state (pKa* < pKa).10 Additionally, the potential barrier for the occurrence
of ESIPT from O–H type donors is often very small.8 Heterocyclic compounds, such as
benzothiazoles, benzimidazoles, and benzazoles, are typical ESIPT acceptors.8,11 However,
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the search for alternative ESIPT-active systems has led to new emitters, which have been
used in myriad applications.4,12
Oxazolines are heterocyclic compounds found in many bioactive natural products13–17
and drugs, including anti-inflammatory, anti-HIV, and antitumor agents.18–20 The oxazoline
ring has low reactivity towards nucleophiles, radicals, oxidizing agents, and acids, being
used in applications requiring high chemical resistance.21,22 Examples include oxazolinic
linkers in asymmetric catalysis,23 monomeric building blocks,24,25 and ligands in cross-
coupling reactions26–30. Fluorescent oxazolines are stable ligands for biosensing
applications31–36 and ESIPT-active oxazolines were used as synthons for photoinduced
intramolecular cycloaddition reactions.37,38 Therefore, the development of functionalizable
ESIPT-active oxazolines can lead to versatile functional compounds, including sensors.
Here we demonstrate the potential of oxazolines as proton acceptors for the
development of ESIPT-active molecules. Two ESIPT-active halogenated 1-naphthol
oxazolines and a potential ESIDPT system based on a twisted bis(o-phenol oxazoline) were
synthesized by using thionyl halide-promoted cyclization of aryl amides39, and the
occurrence of ESIPT was investigated in several polar aprotic solvents. The results were
rationalized using DFT/TD-DFT calculations.
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2. EXPERIMENTAL DETAILS
2.1 General
Starting materials were purchased from commercial sources and used without further
purification. Solvents were purified and dried immediately before use. Melting points were
measured using a Buchi B-545 apparatus. FTIR spectra were registered using a Agilent
Cary 630 spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker DPX 300
at 300 MHz and 75 MHz, respectively. Chemical shifts (δ) are reported in ppm, referenced
to the solvent signal of CDCl3 or tetramethylsilane (TMS) and coupling constants (J) are
reported in Hz. High-Resolution Mass Spectra were obtained using a Shimadzu LCMS-IT-
TOF mass spectrometer. Absorption spectra were recorded using a Varian Cary 50 Bio
spectrophotometer. Fluorescence excitation and emission spectra were acquired using a
Varian Cary Eclipse spectrometer using quartz cells (optical path length: 10 mm) at 25 ± 1
°C.
2.2 Synthesis
The following section describes the last step of the synthesis of 1–3. The complete
description of the syntheses and the characterization (1H and 13C NMR) of all intermediates
and products is presented in the Supporting Information (SI).
2.2.1 Dimethyl 2,2'-(3,3''-dihydroxy-[1,1':4',1''-terphenyl]-4,4''-diyl)(4S,4'S,5S,5'S)-
bis(5-methyl-4,5-dihydrooxazole-4-carboxylate) (1)
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A stainless steel reactor was loaded with compound 9 (0.38 mmol, 273 mg), Pd/C 10 wt.%
loading (20 mol%, 80 mg), MeOH (5 mL) and THF (5 mL). The system was closed and
pressurized with H2 (6 bar). The hydrogenolysis was carried out for 24 h at 25 ºC under
magnetic stirring. Next, the pressure was slowly released and the reactor opened. The
content was filtered off through a Celite pad, washing the pad with THF (5 × 5 mL). The
volatiles were evaporated and the crude mixture was purified by chromatography column
and eluted with hexane: EtOAc (3:2). Yield: 90%, white solid.
m.p. = 208-211 °C
1H NMR: (300 MHz, CDCl3): δ (ppm) 11.83 (bs, 1H), 7.75-7.68 (m, 3H), 7.34-7.25 (m,
1H), 7.21-7.15 (m, 1H), 5.13-5.00 (m, 2H), 3.80 (s, 3H), 1.45 (d, J = 5.7 Hz, 3H).
13C NMR: (75 MHz, CDCl3): δ (ppm) 169.8, 167.6, 160.6, 146.1, 139.9, 128.9, 127.8 (2C),
117.7, 115.3, 109.5, 70.5, 52.4, 16.2.
13C NMR APT: (75 MHz, CDCl3): δ (ppm) 169.8, 167.6, 160.5, 146.1, 139.8, 128.9, 127.7
(2C), 117.7, 115.2, 109.4, 77.5, 70.5, 52.3, 16.2.
IR: υmax (neat, cm-1) 2948, 1745, 1639, 1615, 1562, 1439, 1385, 1357, 1277, 1205, 1181,
1080, 1045, 812, 765.
HRMS: (ESI) m/z, calcd for [C30H28N2O8 + H+]: 545.1924; found: 545.1932.
2.2.2 Benzyl (4S,5S)-2-(4-chloro-1-hydroxynaphthalen-2-yl)-5-methyl-4,5-
dihydrooxazole-4-carboxylate (2)
In a 50-mL dry, two necked round bottom flask, under N2 atmosphere was added the amide
11 (1.57 mmol, 597 mg), anhydrous DCM (15 mL) and SOCl2 (40 equiv., 63 mmol, 4.6
mL). The reaction was stirred at 25 ºC until completion (48 h). The system was opened and
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solid Na2CO3 was added in small portions (evolution of CO2) until pH around 7 was
reached, as indicated by indicator paper. The resulting suspension was filtered off through
sintered glass funnel washing the pad with DCM (5 × 5 mL). The organic phase was dried
under MgSO4, filtered off and volatiles were evaporated. Yield: 85%, yellow solid
m.p. = 136-138 °C
1H NMR: (300 MHz, CDCl3): δ (ppm) 13.01 (bs, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.17 (d, J =
8.3 Hz, 1H), 7.75-7.65 (m, 2H), 7.62-7.55 (m, 1H), 7.40-7.30 (m, 5H), 5.23 (s, 2H), 5.12-
5.03 (m, 2H), 1.37 (d, J = 5.5 Hz, 3H).
13C NMR: (75 MHz, CDCl3): δ (ppm) 169.1, 167.8, 158.3, 135.2, 133.4, 129.7, 128.8 (2C),
128.7, 126.4, 126.0, 124.4, 124.4, 123.2, 121.2, 103.3, 77.9, 70.2, 67.3, 16.1.
IR: υmax (neat, cm-1) 3032, 2983, 1734, 1631, 1598, 1501, 1458, 1408, 1374, 1352, 1290,
1238, 1222, 1190, 1145, 1088, 1048, 1030, 961, 905, 883, 847, 760, 750, 735, 698, 674.
HRMS: (ESI) m/z, calcd for [C22H18ClNO4 + H+]: 396.0997; found: 396.0996.
2.2.3 Methyl (4S,5S)-2-(4-bromo-1-hydroxynaphthalen-2-yl)-5-methyl-4,5-
dihydrooxazole-4-carboxylate (3)
In a 50-mL dry, two necked round bottom flask, under N2 atmosphere was added the amide
12 (1.55 mmol, 472 mg), anhydrous DCM (15 mL) and SOBr2 (10 equiv., 15.5 mmol, 1.2
mL). The reaction was kept at 25 ºC and under stirring until the starting material was
completely consumed (24 h) The work up was performed as described for compound 2.
Yield: 90%, purple solid
m.p. = 175-180 °C (decomp.)
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1H NMR: (300 MHz, CDCl3): δ (ppm) 13.03 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 8.14 (d, J =
8.4 Hz, 1H), 7.92 (s, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 5.16 – 5.02 (m,
2H), 3.79 (s, 3H), 1.46 (d, J = 6.0 Hz, 3H).
13C NMR: (75 MHz, CDCl3): δ (ppm) 169.7, 167.6, 158.9, 134.5, 130.0, 127.1, 126.8,
126.4, 126.1, 124.4, 110.9, 104.1, 77.9, 70.2, 52.4, 16.2.
IR: υmax (neat, cm-1) 2957, 2928, 1749, 1631, 1601, 1505, 1460, 1410, 1380, 1357, 1244,
1225, 1203, 1153, 1100, 1089, 1046, 886, 802, 761.
HRMS: (ESI) m/z, calcd for [C16H14BrNO4 + H+]: 364.0184; found: 364.0157.
2.3 Fluorescence quantum yields
Fluorescence quantum yields (
Eq. 1.
φFl) relative to the secondary standard were calculated using
(Eq. 1)
where the superscript r refers to the standard, A is the absorbance at the selected excitation
wavelength, S is the area under the fluorescence emission curve and nD is the refraction
index of the solvent. Quinine sulfate (φFl = 0.546 in 0.1 mol L–1 H2SO4, EX 300-360 nm;
r
EM 400-600 nm) was used as secondary fluorescence standard. Samples were diluted to an
absorbance lower than 0.1 at the excitation wavelength to avoid inner filter effects.
Fluorescence spectra were recorded under the following experimental conditions:
photomultiplier tension: 600 V; compound 1, excitation wavelength (λex): 330 nm,
excitation and emission slits (sex, sem): 5 nm and 10 nm, compounds 2 and 3, λex: 360 nm,
sex, sem: 10 nm.
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2.4 Computational details
Ground state and first excited singlet state geometries were optimized without constraints at
the DFT B3LYP/6-31+G(d,p) level.40,41 Stationary points were characterized as minima by
vibrational analysis. Linear optical properties were calculated using single point energy
calculations at the TD-DFT SMD/B3LYP/6-31+G(d,p) level.40,42 All calculations were
carried out using the Gaussian 09 rev. D1 software package.43 VMD was used to render all
images of structures and surfaces.44
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3. RESULTS AND DISCUSSION
3.1 Synthesis and characterization of 2-aryl oxazolines
Compound 1 was synthesized in six steps from 4-iodo-2-hydroxybenzoic acid (4) (Scheme
1). The double Suzuki-Miyaura cross-coupling between compound 5 and dipotassium
phenylene-1,4-bis-trifluoroborate gives the triaryl adduct 6. Following ester hydrolysis,
amidation and SOCl2-promoted cyclodehydration led to the desired compound 1 in 65%
yield as a white solid. Oxazoline naphthoic derivatives 2 and 3 were synthesized in two
steps from 1-hydroxy-2-naphthoic acid (10) and two different esters of
L-threonine
(Scheme 1). Precursor compounds 11 and 12 were obtained in moderate yields (52 and
48%) and were converted into products 2 and 3 in 85 and 90% yields, respectively, via
combined cyclization and halogenation using thionyl halide.39 These halogenated 1-
naphthol oxazolines can be conveniently used as synthetic precursors of ESIPT-active
sensors.
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a
OBn
KF3B
BF3K
BnO
O
O
i
, ii
HO2C
I
BnO2C
BnO
I
OBn
HO
BnO
4
5
6
iii
OH
CO2Me
2
OBn
OBn
MeO2C
NH2
O
NH
O
HO
O
O
, iv
OH
HO
HN
OH
CO2Me
BnO
BnO
8
7
v
OH
OBn
CO2Me
CO2Me
O
N
N
O
O
N
N
vi
O
MeO2C
MeO2C
HO
BnO
9
1
b
CO2R
OH
OH
X
N
OH
O
OH
O
OH
O
i'
ii'
+
O
OH
OR
N
CO2R
H
NH2
10
2: X = Cl, R = Bn
3: X = Br, R = Me
Scheme 1. Synthesis of the bis-oxazoline 1 (a) and the naphthoic oxazolines 2 and 3 (b).
Reaction conditions: (a) i. BnBr, K2CO3, acetone, reflux, 24 h, 94%; ii.
Pd(dppf)Cl2ꢀCH2Cl2, K2CO3, THF:H2O, reflux, 24 h, 87%; iii. NaOH aq. (1 mol L–1), THF,
reflux, 24 h, 99%; iv. EDCꢀHCl, 1-HOBt, NMM, DMF, 80 ºC, 24 h, 93%; v. SOCl2,
CH2Cl2, r.t., 5 h, Na2CO3, 95%; vi. H2, Pd/C, THF:MeOH, r.t., 24 h, 91%; (b) i' (R = Bn).
EDCꢀHCl, 1-HOBt, NMM, DCM, ultrasound, r.t., 2 h, 52%; i' (R = Me). EDCꢀHCl, 1-
HOBt, NMM, DMF, r.t., 24 h, 48%; ii'. SOCl2, CH2Cl2, r.t., 24-48 h, Na2CO3, 85-90%.
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3.2 Photophysical properties of 2-aryloxazolines
Steady-state absorption and emission spectra of compounds 1, 2 and 3 in polar aprotic
solvents are shown in Figure 1; the derived photophysical parameters are compiled in Table
1. The solvent has minor influence on the absorption and fluorescence profiles of the bis-
oxazoline 1. For all solutions of compound 1, absorption spectra show a major peak at
around 330 nm (mean molar absorption coefficient is 33,000 L mol–1 cm–1) and a vibronic
shoulder at roughly 290 nm. The fluorescence spectra of the bis-oxazoline 1 have a
maximum at around 475 nm. The large Stokes shift (> 9,000 cm–1, > 140 nm from 330 nm),
characteristic of double ESIPT systems,5,45,46 originates from the proton transfer (keto)
tautomer of 1. Dual emission is observed in acetone and DMSO, i.e., at 400 nm and 475
nm, due to the presence of small amounts of the excited enol tautomer. The average
fluorescence quantum yield is low (φFL around 10%), possibly due to vibrational
deactivation of the singlet excited state.
The absorption spectra of naphthyl oxazoles 2 and 3 show the characteristic vibronic
resolution of C2-substituted 1-naphthol compounds.10,39,47 In DMF and DMSO, additional
bands between 390 – 450 nm are observed. Data for 2 and 3 are similar since the the
exchange of chlorine by bromine is not expected to affect the acidity of the naphthol group,
e.g., the pKas of 4-bromo-1-naphthol and 4-chloro-1-naphthol are 8.72 and 8.86,
respectively.48 Excitation of 2 and 3 at 360 nm results in broad emission bands with
maxima at roughly 450 nm. Minor fluorescence solvatochromism is observed when DMSO
and DMF are used as solvent. Excitation of solutions of 2 and 3 in DMSO or DMF at either
360 nm or 420 nm resulted in emission at 445 nm. The large Stokes shift observed (ca.
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6,000 cm–1) can be explained by the occurrence of ESIPT, resulting in emission from the
excited keto tautomers of 2 and 3. In all solvents, compound 3 presented much lower φFl
values compared to compound 2 (Table 1), probably due to the heavy atom effect of the
bromine atom.49–51 The nature of the ester group is not expected to affect the photophysical
properties of naphthyl oxazoles 2 and 3.52,53
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1.0
1
2
3
DCM
Chloroform
THF
0.8
0.6
0.4
0.2
0.0
Ether
Ethyl Acetate
Acetonitrile
Acetone
DMSO
DMF
FL, λex = 330 nm
ABS
300
400
500
600
Wavelength (nm)
1.0
0.8
0.6
0.4
0.2
0.0
DCM
Chloroform
THF
Ether
Ethyl Acetate
Acetonitrile
Acetone
DMSO
DMF
FL, λex = 360 nm
ABS
300
400
500
600
Wavelength (nm)
1.0
0.8
0.6
0.4
0.2
0.0
DCM
Chloroform
THF
Ether
Ethyl Acetate
Acetonitrile
Acetone
DMSO
DMF
FL, λex = 360 nm
ABS
300
400
500
600
Wavelength (nm)
Figure 1. Normalized absorption and emission spectra of compounds 1, 2, and 3 in polar
aprotic solvents at 25 ºC. [1]: 2 µmol L–1, [2]: 30 µmol L–1, and [3]: 30 µmol L–1.
Table 1. Photophysical properties of compounds 1–3 in polar aprotic solvents.
a
a
Solvent λabs
εb
λEM
ꢀυc ΦF × 102
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1
DCM
CHCl3
THF
330 39,000 475 9,250 6.6
330 41,000 474 9,210 9.6
330 31,000 476 9,300 10.2
327 29,000 477 9,620 9.4
Et2O
AcOEt 329 31,000 475 9,340 6.1
MeCN 327 32,000 474 9,480 9.7
Acetone 333 31,000 475 8,980 6.1
DMSO 332 31,000 481 9,330 8.6
DMF
330 32,000 478 9,380 10.2
2
DCM
CHCl3
THF
360 5,200 462 6,130 3.5
362 4,800 465 6,120 3.1
360 4,900 458 5,940 4.7
361 5,000 459 5,910 2.4
Et2O
AcOEt 359 4,500 459 6,070 4.5
MeCN 358 4,600 459 6,150 4.1
Acetone 358 4,800 459 6,150 4.8
DMSO 360 4,500 434 4,740 20.0
DMF
359 5,400 435 4,870 18.6
3
DCM
360 4,500 461 6,090 0.8
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CHCl3
THF
362 4,300 464 6,070 0.8
359 4,800 457 5,970 1.1
359 3,800 457 5,970 0.6
Et2O
AcOEt 359 3,800 455 5,880 1.1
MeCN 357 3,900 448 5,690 1.0
Acetone 359 4,100 454 5,830 0.8
DMSO 360 5,000 441 5,100 1.4
DMF
358 4,200 433 4,840 1.0
a
b
in nm, in (L mol–1 cm–1); determined by weight considering the Beer-Lambert
relationship, c in cm–1.
Geometry optimization of compounds 1–3 in the ground state indicates that the O–
HꢀꢀꢀN hydrogen-bonded conformer is more stable than the O–HꢀꢀꢀO conformer, e.g., ꢁrG0
for isomerization of 2 is 20 kJ mol–1. The tautomerization of compounds 1–3 is endergonic
in the ground state (Figure 2a). For the bis-oxazoline 1, single and double tautomerization
have an energetic cost of 39 and 75 kJ mol–1, respectively. However, considering the
experimental energy for the S1 → S0 transition, tautomerization is thermodynamically
allowed on the singlet excited state potential surface. Results are similar for compounds 2
and 3. Excitation of the bis-enol tautomer of compound 1 (enol2) implies the initial
formation of a locally excited (LE) state. Single and double ESIPT produce the keto-enol
and the keto2 tautomers, respectively, resulting in charge transfer towards the keto centers
upon S1 → S0 transition. Analysis of frontier orbitals involved in the excitation of 2 and 3
1
(Figure 2b) shows the nodal plane typical of C1/C2-substituted naphtalenes, viz., the La
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state (π-π*, polarization along the short axis) of 1-naphthols is lower in energy than the 1Lb
state (π-π*, polarization along the long axis).53–55 Consequently, charge delocalization is not
extended through the naphthalene ring; instead, functionalization of the ring by substitution
of the halogen atom is expected to have a major influence on the electronic properties of the
derivatives of 2 and 3.
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Figure 2. Electronic properties of oxazolines 1–3. (a) Relative energies for electronic
transitions involving the enol and keto tautomers. Numbers in parentheses correspond to
the experimental data; the theoretical excitation energy and tautomerization energies are
marked in bold. (b) Frontier molecular orbital relevant for the occurrence of ESIPT
involving oxazolines 1–3.
In conclusion, the use of thionyl halide-promoted cyclization of aryl amides allowed
the synthesis of three prototype ESIPT-active 2-aryloxazolines. The bis-oxazoline 1
exhibits double ESIPT evidenced by a large Stokes shift and dual emission with
fluorescence quantum yields of around 10%. Halogen-substituted oxazolines 2 and 3 show
ESIPT in polar aprotic solvents. Fluorescence quantum yields are reduced by replacing the
chlorine substituent by bromine, reinforcing the potential of these compounds to act as
synthetic precursors of ESIPT-active sensors.
ACKNOWLEDGEMENTS
This research was supported by FAPESP (grants J.S.R. 2016/02392-1; A.B.R. 2015/25629-
4; B.C.F.D. 2014/10563-5; E.L.B. 2014/22136-4, 2016/21445-9; H.A.S. 2017/24821-4),
and CNPq (E.L.B 303341/2016-5; H.A.S.-306119/2014-5).
AUTHOR CONTRIBUTIONS
H.A.S. and E.L.B. proposed the concept and directed the research. J.S.R. conducted the
synthesis; B.F.D. and A.B.R. acquired the absorption and fluorescence spectra and
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analyzed the results. E.L.B. performed the theoretical calculations. All authors contributed
to the writing and reviewing of the manuscript.
ADDITIONAL INFORMATION
The authors declare no competing financial interests.
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