Effect of the o-Acetamido Group on pH-Dependent Light Emission of a 3-Hydroxyphenyl-Substituted Dioxetane Luminophore

Article abstract of DOI:10.1021/acs.orglett.8b03913

A pioneering chemiluminescent molecule reported by Schaap and co-workers, 3-(2′-spiroadamantane)-4-methoxy-4-(3″-hydroxy)phenyl-1,2-dioxetane (AMPD), does not require enzymatic activation but is unsuitable for use under physiological conditions. To overco

Full text of DOI:10.1021/acs.orglett.8b03913

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Effect of the o‑Acetamido Group on pH-Dependent Light Emission
of a 3‑Hydroxyphenyl-Substituted Dioxetane Luminophore
Yosuke Hisamatsu, Takehiro Fukiage, Kojiro Honma, Andrii G. Balia, Naoki Umezawa, Nobuki Kato,†
and Tsunehiko Higuchi*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
S
* Supporting Information
ABSTRACT: A pioneering chemiluminescent molecule
reported by Schaap and co-workers, 3-(2′-spiroadaman-
tane)-4-methoxy-4-(3″-hydroxy)phenyl-1,2-dioxetane
(AMPD), does not require enzymatic activation but is
unsuitable for use under physiological conditions. To
overcome this limitation, we have developed a new AMPD
derivative that contains an acetamido group at the ortho
position of the hydroxy group as an intramolecular hydrogen-
bonding site in order to lower the pKa value. This compound
exhibits a superior chemiluminescence response to AMPD in
the physiologically relevant pH range.
any fluorescent probes are routinely utilized for
greater thermal and chemical stability.4 Several AMPD
Minvestigations of cellular biology, screening for drug derivatives have already been applied in clinical laboratory
discovery, bioimaging, and so on.1 Analysis based on
chemiluminescence (CL) is almost 10 000-fold more sensitive
than that based on fluorescence,2 and detection is very simple
because CL does not require excitation with photoirradiation.
The luciferin−luciferase system is widely applied in
biological studies, but the requirement for luciferase limits its
applicability to intact living cells and its availability for in vivo
studies. On the other hand, a phenolic moiety directly linked
to the 1,2-dioxetane structure can emit light triggered by
phenoxy anion formation without enzymatic assistance.
Among such compounds, 3-(2′-spiroadamantane)-4-methoxy-
4-(3″-hydroxy)phenyl-1,2-dioxetane (AMPD) (1), reported by
Schaap and co-workers, was a pioneering organic light emitter
for chemiluminescence sensing (Scheme 1).3 Matsumoto et al.
have also extensively investigated related 1,2-dioxetanes with
tests for evaluating enzyme activity.2
However, AMPD and its analogues generally have two major
problems that limit their usefulness. One is they are only
usable over a restricted pH range. The other is the low
efficiency of light emission under aqueous conditions,2,3d−i,5 as
compared with organic solvents such as MeCN, DMSO, and
so on.3,4 AMPD emits light under basic conditions because the
pKa of its phenolic hydroxy group is ca. 10, and formation of
the phenoxy anion as an intramolecular electron donor is
essential for the chemiexcitation process. Therefore, several
1,2-dioxetane compounds having an electron-withdrawing
group, such as a chloro group, on the phenolic ring have
already been developed in order to lower the pKa of the
phenolic hydroxy group by decreasing the electron density of
the phenolic aromatic ring.5,6a,c−e Surfactants have been used
as enhancers in order to improve the CL quenching of AMPD
derivatives in aqueous solutions.6
Scheme 1. Structures of AMPDs 1 and 2 and Methyl 3-
Hydroxybenzoates 3 and 4
Shabat et al. reported a new class of AMPD derivatives
containing acrylate or acrylonitrile as an electron-withdrawing
group to improve the emission under aqueous conditions.2e,f,5,7
These probes exhibit excellent CL properties and are suitable
for use under physiological conditions without any enhan-
cer.2f,5,7,8
We hit on a different strategy for lowering the pKa of the
phenol moiety. Our group and Ueyama’s group separately
investigated the effect of intramolecular hydrogen bonding of
an amide to a thiolate on the chemical properties of heme,
based on the fact that native cytochrome P450 has an NH···S
Received: December 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03913
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrogen bond involving the axial thiolate ligand.9 We were
also interested in Ueyama’s related report that an acylamido
group at the ortho position of a phenolic hydroxy group
decreases the pKa value of the phenolic hydroxy group due to
the formation of an intramolecular NH···O hydrogen bond.10
Alkanoylamido groups are somewhat electron donating11
and may affect the chemiexcitation step of AMPD derivatives
in a different manner from electron-withdrawing groups.
Matsumoto and co-workers examined the effect of intra-
molecular hydrogen bonding between a phenoxy anion and an
amidomethyl (e.g., −CH2NHCOPh) or a hydroxymethyl
(−CH2OH) group on the CL efficiency under fairly basic
conditions (NaOH/H2O−MeCN solvent system), but without
considering the effect of pH on the intramolecular hydrogen
bonding.12
acidity of the phenolic hydroxy group of the neutral form and
stabilizing the anionic form.10
Because the actual CL-emitting moiety of 1 and 2 is the
methyl 3-oxybenzoate anion, which is formed by O−O bond
cleavage of the 1,2-dioxetane moiety,3 we designed and
synthesized 2 containing the acetamido group at the ortho
position of the hydroxy group and examined the effect of the
acetamido group on the CL behavior at neutral pH.
Compound 2 was synthesized as shown in Scheme 2. The
hydroxy group of 5 was protected with triisopropylsilyl
Scheme 2. Synthesis of 2
Here we report the design and synthesis of an AMPD
derivative 2 containing an acetamido group at the ortho
position of the hydroxy group as an intramolecular hydrogen
bonding site to lower the pKa of the phenolic hydroxy group
(Scheme 1). Notably, the CL properties of 2 containing the
acetamido group were significantly improved over those of 1 in
the physiologically relevant pH range.
Prior to the synthesis of 2, we investigated the pKa values of
methyl 3-hydroxybenzoate 3 and its derivative 4 containing an
acetamido group (Scheme 1) by means of UV−vis measure-
ments in MeCN/100 mM buffer = 1/9 (v/v) (Figure S1 in
Supporting Information).13 Based on nonlinear least-squares
analysis of the pH dependence of absorbance, the pKa values of
3 and 4 were estimated to be 9.4
0.1 and 8.5
0.1,
chloride (TIPSCl), and then the nitro group of 6 was reduced
by hydrogenation to give 7, followed by acetylation to give 8.
The alkene derivative 9 was obtained by the McMurry
coupling reaction of 2-adamantanone with 8.16 After
deprotection of 9 with tetra-n-butylammonium fluoride
(TBAF), [2 + 2] cycloaddition of singlet oxygen was
accomplished by bubbling oxygen through a solution of 10
and methylene blue under visible-light irradiation to afford the
desired dioxetane derivative 2, which was thermally stable
enough to permit handling at room temperature.17
Next, the pH dependence of the CL of 1 and 2 was
examined using freshly prepared sample solutions.18 The CL
spectra of 1 and 2 were measured in MeCN/100 mM
carbonate buffer (pH 11.0) = 1/9 (v/v) containing 0.01%
AcOH at 25 °C. As shown in Figure 1a, the CL spectrum of 1
at pH 11.0 (emission maximum: ca. 469 nm) is in agreement
with reported results.3g The emission maximum of the CL
spectrum of 2 bearing the acetamido group at pH 11.0 lies at
ca. 458 nm which is ca. 11 nm shorter than that of 1.19 The CL
spectrum of 2 at pH 11.0 overlapped with the fluorescence
emission spectrum of the corresponding methyl benzoate ester
4 measured under the same solvent conditions (Figure S9a in
Supporting Information). This result suggests that the emitting
species of 2 generated by chemiexcitation is the deprotonated
form of 4.
respectively. Thus, the introduction of the acetamido group on
the methyl 3-hydroxybenzoate ester resulted in a decrease of
ca. 0.9 units in the pKa value. Moreover, 1H NMR spectra of 3
and 4 were collected in DMSO-d6/100 mM carbonate buffer
(pD = 11.0) = 1/3 (v/v) (Figure S2 in Supporting
Information). Under these conditions, 3 and 4 should be
present as anionic forms due to the deprotonation of the
hydroxy group. The Hb proton signal of 4 was observed at 8.00
ppm, which is 0.71 ppm downfield from the Ha proton signal
of 3 (δ = 7.29 ppm), indicating the deshielding effect of the
nearby carbonyl group of the amide on the Hb proton of 4.14
Since secondary amides generally adopt trans configuration,
the proposed conformation of 4 suggests that the neighboring
NH proton of the amide forms an NH···O hydrogen bond with
the oxyanion of 4 and stabilizes the phenoxy anion.10 The
formation of the NH···O hydrogen bond was also supported
by the optimized structure of the anionic form of 4 obtained by
DFT calculations (Figure S3a in Supporting Information).
On the other hand, 3 and 4 should be present as neutral
forms in DMSO-d6/100 mM acetate buffer (pD = 5.5) = 1/3
(v/v). The signals of the Ha proton of 3 and Hb proton of 4
were observed at 7.52 and 7.91 ppm, respectively (Figure S4 in
Supporting Information). Thus, the deshielding effect of the
carbonyl group of the amide on the Hb proton of 4 is also seen
in the neutral form of 4. Therefore, it appears that the
formation of the intramolecular NH···O hydrogen bond
between the NH proton of the amide and oxygen of the
hydroxy group can occur, even though the neutral form of 4
may exist as several conformers in equilibrium.15
As shown in Figure 1b, negligible CL of 1 was observed in
MeCN/100 mM phosphate buffer (pH 7.4) = 1/9 (v/v). On
the other hand, the clear CL spectrum of 2 (emission
maximum: ca. 454 nm) was observed at the same pH, as
expected.
The CL kinetic profiles of 1 and 2 at pH 4.0−11.0 are shown
in Figures S11 and S12 in the Supporting Information. Figures
2 and 3 show the CL kinetic profiles of 1 (emission at 470 nm)
and 2 (emission at 450 nm) at pH 11.0, 8.0, and 7.4. The
Taking the reported data10 and experimental and calculation
results together, we consider that the formation of the
intramolecular NH···O hydrogen bond in neutral and anionic
forms of 4 should decrease the pKa value of 4 by increasing the
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DOI: 10.1021/acs.orglett.8b03913
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Letter
Figure 1. Chemiluminescence spectra of 1 (dotted line) and 2 (solid
line) in (a) MeCN/100 mM carbonate buffer (pH 11.0) = 1/9 (v/v)
containing 0.01% AcOH and (b) MeCN/100 mM phosphate buffer
(pH 7.4) = 1/9 (v/v) containing 0.01% AcOH at 25 °C. [1] or [2] =
100 μM, scan speed = 60 000 nm/min.
Figure 3. Chemiluminescence kinetic behavior (emission at 450 nm)
of 2 (100 μM) at (a) pH 11.0, (b) pH 8.0, and (c) pH 7.4.
Conditions: MeCN/100 mM buffer = 1/9 (v/v) containing 0.01%
AcOH at 25 °C (pH 11.0: carbonate buffer, pH 8.0 and pH 7.4:
phosphate buffer).
maximum emission intensities of 1 at 470 nm and 2 at 450 nm
at pH 4.0−11.0 are summarized in Figure 4a.
At pH 11.0, 1 exhibits an initial increase in emission
intensity to a maximum, followed by a decrease to zero (Figure
2a). In contrast, a significant increase in the emission intensity
of 2 at 450 nm was observed at pH 11.0 (Figures 3a and 4a).
The maximum emission intensity of CL of 2 at pH 11.0 is ca.
23-fold higher than that of 1 (Figure 4a). Because the hydroxy
groups of 1 and 2 should be mostly deprotonated at pH 11.0,
the difference of pKa values between 1 and 2 should be
eliminated at this pH. Therefore, it is suggested that the
significant increase in the maximum emission intensity of 2 is
caused by the electron-donating effect of the acetamido
group.11,20,21 Moreover, the emission intensity of 2 at both pH
8.0 and 7.4 is significantly higher than that of 1 at the same pH
values (Figure 2b vs 3b, Figure 2c vs 3c, and Figure 4a).22 The
CL of 2 was detectable at pH > 6.4 (Figure S12 in Supporting
Information).
The areas obtained from the emission decay curve of 1 at
470 nm (0 to 2940 sec) and 2 at 450 nm (0 to 240 sec) in
solutions of various pH values are shown in Figure 4b. At pH >
8.4, the emission area of 1 was larger than that of 2 due to the
longer-lived emission, even though the emission intensity of 1
is very weak. Based on the CL data at pH 11.0, the CL
quantum yield (ΦCL) of 2 was determined to be 2.7 × 10−6,
which is ca. 3-fold lower than that of 1.23,24 On the other hand,
a larger emission area of 2 was observed at pH 6.4−8.0,
compared to that of 1.
Figure 2. Chemiluminescence kinetic behavior (emission at 470 nm)
of 1 (100 μM) at (a) pH 11.0, (b) pH 8.0, and (c) pH 7.4.
Conditions: MeCN/100 mM buffer = 1/9 (v/v) containing 0.01%
AcOH at 25 °C (pH 11.0: carbonate buffer, pH 8.0 and pH 7.4:
phosphate buffer).
C
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Organic Letters
Letter
In conclusion, we have designed and synthesized an AMPD
derivative 2 in which the pKa of the phenolic hydroxy group is
lowered by the introduction of an acetamido group at the ortho
position of the hydroxy group. To our knowledge, this work is
the first to show that intramolecular hydrogen bonding can
lower the pH profile of light emission of a phenolic
chemiluminogenic compound. The CL properties of 2 in
aqueous medium at physiological pH range are superior to
those of 1, supporting the practical value of this approach.
Further photophysical studies and improvements (e.g.,
enhancement of the CL signal and color tuning) should afford
useful CL probes. We are currently working on the
development of CL probes based on a combination of
dioxetane−fluorophore conjugation26 and our concept of
utilizing intramolecular hydrogen bonding.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03913.
Detailed experimental procedures, pH-dependent
change in absorbance, study of thermal stability,
chemiluminescence spectra, fluorescence emission spec-
tra, chemiluminescence kinetic profiles, NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: higuchi@phar.nagoya-cu.ac.jp.
ORCID
Naoki Umezawa: 0000-0003-3966-2303
Tsunehiko Higuchi: 0000-0002-3586-4680
Present Address
†Graduate School of Science, Tohoku University, 6−3, Aoba,
Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Figure 4. (a) Maximum emission intensity of 1 at 470 nm (blue
circles) and 2 at 450 nm (red circles) at various pH values. Inset:
expanded portion of the weak emission intensity region. (b) Areas
under the emission decay curves of 1 (intensity at 470 nm*sec) (blue
circles) and 2 (intensity at 450 nm*sec) (red circles) at various pH
values. Conditions: MeCN/100 mM buffer (pH 4.0−11.0) = 1/9 (v/
v) containing 0.01% AcOH at 25 °C. Error bars represent standard
deviation of three independent experiments.
Author Contributions
All authors contributed to writing the manuscript and
approved the final version of the manuscript.
Notes
Based on the results of Figures 2−4, it appears that the
introduction of the acetamido group as an intramolecular
hydrogen-bonding site at the ortho position of the hydroxy
group worked as expected, lowering the pKa value and leading
to an increased contribution of the phenoxy anion species in
the physiological pH range. The much greater emission
intensity per unit time of 2, compared to 1, suggests that 2
will serve as a more effective chemiluminescence probe than 1.
Furthermore, the shorter lifetime of the deprotonated form of
2 should provide a higher time resolution in measuring analyte
concentration changes. The 1,2-dioxetane decomposition
reaction is believed to be initiated by intramolecular electron
or charge transfer from the negatively charged phenolate
oxygen to the O−O bond.2−4 Therefore, the faster kinetics of 2
than 1 may reflect not only the increased formation of the
phenoxy anion species but also the electron-donating effect of
the acetamido group11 on the phenoxy anion, resulting in
enhancement of the chemiexcitation rate.25 However, other
factor(s) may also be involved in accelerating light emission.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI (No. 18K06551
for Y.H. and No. 17H04000 for T.H.)
REFERENCES
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E
DOI: 10.1021/acs.orglett.8b03913
Org. Lett. XXXX, XXX, XXX−XXX