Solid-phase organic synthesis of 2-tridecanyl-1,4-naphthoquinone and 2-tridecanyl-1,4-naphthodiol that form redox-active micelles and vesicles

Article abstract of DOI:10.1016/j.bioorg.2014.06.005

The solid-phase synthesis of new amphiphilic compounds is reported. It is based on a newly designed 1,4-naphthoquinone derivative that contains polar and nonpolar groups and self-assembles into micelles or vesicles in water depending on the concentration. They also display redox-active properties.

Full text of DOI:10.1016/j.bioorg.2014.06.005

Bioorganic Chemistry 56 (2014) 62–66
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Solid-phase organic synthesis of 2-tridecanyl-1,4-naphthoquinone
and 2-tridecanyl-1,4-naphthodiol that form redox-active micelles
and vesicles
b
c
d
d
Alejandro Bugarin a, , Luis E. Martinez , Peter Cooke , Tadiqul Islam , Juan C. Noveron
⇑
a Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019, USA
b Department of Chemistry and Biochemistry, Trinity University, San Antonio, TX 78212, USA
c CURRL, New Mexico State University, 945 College Dr., Las Cruces, NM 88003, USA
d Department of Chemistry, University of Texas at El Paso, El Paso, TX 79968, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 December 2013
Available online 7 July 2014
The solid-phase synthesis of new amphiphilic compounds is reported. It is based on a newly designed 1,4-
naphthoquinone derivative that contains polar and nonpolar groups and self-assembles into micelles or
vesicles in water depending on the concentration. They also display redox-active properties.
Ó 2014 Elsevier Inc. All rights reserved.
Keywords:
Solid-phase synthesis
1,4-Naphthoquinone
Fischer carbenes
Redox
Vesicles
1. Introduction
emulsify into micelles or vesicles in water depending on the con-
centration. Our solid-phase strategy serves as a key method for
Naphthoquinones and their derivatives continue to attract the
attention of the chemical community and have been the subject of
several studies [1]. This interest stems from the fact that many nat-
urally occurring compounds contain the naphthoquinone skeleton
and possess a variety of biological and pharmacological activities
that include antibacterial, antifungal and anticancer, among others
[2]. Their biological activity arises primarily from the redox active
quinone that interferes with biochemical oxidation processes [3],
particularly microsomal lipid peroxidation. In view of their poten-
tial use in biology and medicine, a myriad of derivatives of naphtho-
quinones have been reported and recently reviewed [4]. However,
many derivatives of these compounds are insoluble in water and
require the addition of co-solvents such as DMSO to generate
aqueous solutions suitable for biological applications.
Another common strategy for their aqueous administration is to
introduce hydrophilic groups into the core structure, where this
approach has a significant impact on the bio-distribution and
activity of such derivatives. Herein, we report the solid-phase
organic synthesis (SPOS) [5] of novel amphiphilic naphthoquinones
that posses a single hydrocarbon chain at C-2 and a chemically
switchable head-group. In addition, these compounds are able to
the incorporation of functional groups on naphthoquinones. It is
well known that 1,4-naphthoquinones derivatives have a broad
spectrum of biological activities [6] such as; antimycobacterial
[7], antiparasitic [8], and cytotoxic activities [9]. This strategy has
the potential to generate large libraries with varied biological
activity by small changes on the naphthoquinone backbone or at
the hydrocarbon chain [10].
The previously reported Fischer carbene complex approach [11],
using solid-phase organic synthesis (FCC-SPOS), was employed to
synthesize our naphthoquinones [12]. This method is based on
immobilized Fischer carbene complexes, which undergo regioselec-
tive Dötz benzannulation [13] to afford naphthoquinones with pre-
determined substitutions [12]. This approach also allows for the
formation of single benzannulation adducts from alkynes, which
is an added advantage since in the absence of the solid support,
the reaction could generate several regioisomeric products and
would require extensive and difficult purification.
2. Results and discussion
2.1. Synthesis
⇑
The synthesis of amphiphilic naphthoquinone 8 started from
commercially available phenyl lithium and chromium hexacarbonyl
Corresponding author. Fax: +1 817 272 3808.
E-mail address: bugarin@uta.edu (A. Bugarin).
http://dx.doi.org/10.1016/j.bioorg.2014.06.005
0045-2068/Ó 2014 Elsevier Inc. All rights reserved.

A. Bugarin et al. / Bioorganic Chemistry 56 (2014) 62–66
63
using a modified method originally developed by Connor et al.
[14]. Thus, the polymer-supported Fischer carbene complex 5 was
obtained in four steps by first reacting phenyl lithium and chromium
hexacarbonyl, which produced adduct 2 that then underwent an
ion exchange to the corresponding tetramethyl-ammonium-[(2-
phenyl)oxidocarbene]pentacarbonyl-chromium
3
(Scheme 1).
O-acylation of 3 with acetyl chloride was followed by reaction with
the PL-Wang resin (Polymer Laboratories, 1% cross-linked
1.7 mmol/g) to produce resin-bound Fischer carbene complex 5 with
100% loading. The resin loading of the carbene complex can be easily
monitored qualitatively by colorimetric analysis; the beads turn dark
red in color, and appearance of characteristic Cr–CO stretches at 2060
and 1933 cmꢀ1 in the IR spectrum of 5, that correspond to the CO
stretches found in analogous aryl carbene complexes, were observed
[15]. With the polymer-supported Fischer carbene complex 5 on
hand, the key Dötz benzannulation reaction was performed with
1-pentadecyne 6 under optimized conditions [12] (microwave-
assisted) [16] and provided the amphiphilic naphthoquinone 8 after
oxidative cleavage of the resulting resin-bound naphthol 7 in overall
good yield (63%). It is noteworthy that no side products were
observed, due to the employment of the solid support strategy.
Scheme 2. Easy access to compounds 8 and 9.
Finally, sodium borohydride reduction of
8
in methanol/THF
Fig. 1. Dynamic Light Scattering (DLS) of 8 at 1% wt.
produced the corresponding of 2-tridecanyl-1,4-naphthodiol 9 in
92% yield. (See the Section 4 for more details.)
Compound 9 is very sensitive to oxidation under air. It was
observed by 1H NMR and other characterization methods a
promptly oxidation to compound 8 when adduct 9 is left open to
the atmosphere (Scheme 2).
with high-volume head groups have a preference to organize into
micelles due to their conical shape [17]. At this concentration,
the signal-to-noise ratio impeded DLS measurements of the
micelle dispersion.
Optical microscopy of the emulsion of compound 8 showed sev-
eral bilayer structures, characteristic of vesicles (Fig. 4, left). The
aqueous emulsion of 8 was treated with the phenoxazine dye Nile
red indicator, a fluorescent indicator used to localize lipid phases
within membranes, and optical fluorescent spectroscopy revealed
bilayer structures typical of vesicles (Fig. 4, right) [18].
2.2. Self-assembly in water
The self-assembly properties of the resulting amphiphilic naph-
thoquinones were studied in water at various concentrations.
Aqueous solutions of compound 8, at concentrations of 1%, wt,
were sonicated at room temperature for 30 min, which formed
stable emulsions. Dynamic Light Scattering (DLS) measurements
reveled vesicles with hydrodynamic Z-average diameter of
292.5 nm and a polydispersity index (PDI) of 0.231, as depicted
in (Fig. 1).
2.3. Redox-activity
The electrochemical properties of the amphiphilic naphthoqui-
none 8 were then studied by cyclic voltammetry [19]. Measure-
ments of 8 in dichloromethane revealed a quasi-reversible redox
potential of 0.504 V (Fig. 5), suggesting that the redox active prop-
erties are retained in the molecule.
Atomic Force Microscopy (AFM) of the aqueous emulsions of 8
confirmed the presence of vesicles at concentration of 1% wt and
revealed the spherical structure of the vesicles (Fig. 2).
Upon dilution to <0.1% wt, emulsions of 8 formed micellar
structures of 2 nm in diameter, according to AFM (Fig. 3). This
behavior is consistent with earlier observations that amphiphiles
In order to investigate if the redox-activity of the amphiphilic
naphthoquinone is retained while they exist as emulsions, we
prepared emulsions of 9 and react them with an aqueous iodine
Scheme 1. Solid-phase synthesis of 2-tridecanyl-1,4-naphthoquinone 8 and its reduction to 2-tridecanyl-1,4-naphthadiol 9.

64
A. Bugarin et al. / Bioorganic Chemistry 56 (2014) 62–66
Fig. 5. Cyclic voltammetry of 8.
Fig. 2. AFM of vesicles of 8 on mica. Inset: vertical analysis of selected vesicles.
Fig. 6. (a) UV–Vis spectrum of 484 mM iodine in water, titrated with (b) 1.3, (c) 2.6,
(d) 4.0, (e) 5.2, (f) 6.5 equiv. of vesicles of compound 9.
more than the theoretical 1:1 molar ratio. Presumably, this excess
results from the known aerobic oxidation of compound 9 to com-
pound 8 (Scheme 2). The acquired reduction data suggest an
iodine-water redox process associated with our amphiphilic
molecules.
Fig. 3. ATM of micelles of 8 on mica. Inset: vertical analysis of selected micelles.
solution (484 mM). Using UV–Vis spectroscopy, we observed
the immediate decrease in absorbance of the iodine band
(kmax = 350 nm), which has been used to follow iodine chemistry
in water [20]. This clearly indicates that the vesicles are redox
active in water and are capable of reducing iodine molecules
(Fig. 6). In total, 6.5 equivalents of compound 9 vesicles were
required to completely quench the iodine solution band. This is
3. Conclusions
A concise solid-support synthesis and characterization of 2-tri-
decanyl-1,4-naphthoquinone (8) and 2-tridecanyl-1,4-naphthadiol
(9) are reported. These molecules self-assemble into micelles or
vesicles in water depending on the concentration. They also exhibit
redox-active properties in water. The approach used for the
Fig. 4. Optical microcopy of vesicles of 8 before (a) and after (b) staining with Nile red indicator. Inset: DLS distribution of 8.

A. Bugarin et al. / Bioorganic Chemistry 56 (2014) 62–66
65
synthesis of these amphiphilic molecules can be easily applied to
the synthesis of naphthoquinone-derivative libraries that present
new functional groups on the surface of vesicles. These outstanding
properties (vesicles formation together with their redox potential)
of the new synthesized adducts 8 and 9, will aid as a platform for
an easier drug delivery strategy via vesicles under aqueous media.
Likewise, studies of naphthoquinones bioactivities might be per-
formed using our strategy.
solid. IR (KBr) m
2060, 1933 cmꢀ1. (Found: Cr, 5.99%. 100% loading
@ 1.7 mmol/g requires Cr, 5.99%.)
4.4. Synthesis of 2-tridecylnaphthalene-1,4-dione (8)
To
0.575 mmol) was added and the vial was sealed with an alumi-
num/Teflon crimp top. Then, a solution of 1-pentadecyne
a microwave process vial (10.0 mL), resin 5 (500 mg,
6
(2.875 mmol) in dry CH2Cl2 (5.0 mL) was added under Nitrogen
atmosphere. The reaction mixture was subjected to microwave
irradiation (Biotage EmrysTM Optimizer—300 W maximum
power) at 85 °C for 30 min. The reaction mixture was filtered and
the resin was washed sequentially with CH2Cl2 (50 mL), THF
(25 mL), and CH2Cl2 (25 mL) and dried under reduce pressure to
4. Experimental section
4.1. General considerations
All reactions were carried out under an oxygen free atmosphere
in either oven-dried glassware with magnetic stirring or micro-
wave resistant vials. All commercially obtained reagents were used
as received. Solvents were obtained from a solvent purification
system. Heating was accomplished by either; a heating mantle,
silicone oil bath, or a microwave apparatus. Cooling was performed
using ice bath or acetone/dry-ice bath. Purification of reaction
products was carried out by flash column chromatography using
silica gel if necessary. TLC visualization was accompanied with
UV light and/or potassium permanganate staining. 1H NMR spectra
were recorded at 300 MHz, and are reported relative to CDCl3 (d
7.27). 1H NMR coupling constants (J) are reported in Hertz (Hz)
and multiplicities are indicated as follows: s (singlet), d (doublet),
t (triplet), m (multiplet). Proton-decoupled 13C NMR spectra were
recorded at 75 MHz and reported relative to CDCl3 (d 77). UV–Vis
spectra were recorded using the Agilent Cary 50 Conc. UV–Vis
spectrophotometer, whereas for DLS analysis the Zetasizer Nano
ZS90 instrument was used.
afford resin-bound naphthol 7. Resin-bound naphthol
7
(0.575 mmol) was suspended in a mixture of 9.0 mL of CH2Cl2
and ceric ammonium nitrate (1.575 g, 2.875 mmol) in 3.0 mL of
water. The resulting suspension was stirred for 12 h and then fil-
tered through a fritted glass funnel. The resin was washed with
water (15.0 mL) and CH2Cl2 (15.0 mL). The resulting clear solution
was washed with 10% NaOH (15 mL) and water (10.0 mL). The
organic layer was dried over MgSO4 and filtered. The solvent was
removed under vacuum to afford 63% of pure 1,4-naphthoquinone
8 (112 mg, 0.329 mmol) as pale yellow solid; IR (thin film)
m 2956,
2918, 2852, 1663, 1623, 1595, 1337, 1247, 788 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz) d 8.06 (m, 2H), 7.72 (m, 2H), 6.78 (s, 1H), 2.56
(t, J = 7.01 Hz, 2H), 1.57 (quintet, J = 6.90 Hz, 2H), 1.25 (s, 20H),
0.87 (t, J = 6.51 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 185.2, 151.9,
134.6, 133.6, 133.5, 126.5, 125.9, 31.8, 30.02 29.8, 29.63, 29.6,
29.58, 29.54, 29.48, 29.34, 29.32, 29.07, 28.94, 28.9, 27.9, 22.6,
14.1. HRMS (ESI–) calcd for C23H31O2 requires m/z 339.2330, found
339.2326.
4.2. Synthesis of O-acylated Fischer carbene complex (4)
Chromium hexacarbonyl (3.00 g, 13.6 mmol) and dry THF
(20.0 mL) were placed in a 100 mL two-necked round bottom flask
under N2 atmosphere. The flask was cooled to 0 °C and a solution of
phenyllithium 1 (20.5 mmol, 1.9 M in cyclohexane-ether, 10.8 mL)
was slowly added over a period of 20 min and allowed to stir for
2 h. The solvent was removed under vacuum and the resulting
orange red residue (2) was added to a solution of tetramethyl
ammonium bromide (4.19 g, 27.2 mmol) in 20.0 mL of oxygen-free
water. The reaction mixture was allowed to stir at 0 °C for 2 h. The
product was extracted twice with CH2Cl2 (50 mL) and
the combined organic phases were dried over anhydrous MgSO4.
The solvent was concentrated under reduce pressure to afford 3
as a red solid. To a stirred solution of crude red solid 3 (4.64 g,
12.5 mmol) in 10.0 mL of CH2Cl2 at ꢀ78 °C, acetyl chloride
(1.27 g, 16.3 mmol) was added. After stirring at 0 °C for 1.5 h, the
reaction mixture was allowed to warm to room temperature. The
solvent and the unreacted acetyl chloride were removed under
reduced pressure to yield (4.54 g, 13.4 mmol) of the O-acetylated
adduct 4 in 98% yield as a bright red solid.
4.5. Synthesis of 2-tridecylnaphthalene-1,4-diol (9)
To a mixture of NaBH4 (14 mg, 0.365 mmol) in dry MeOH
(2.5 mL) was added salt a solution of 2-tridecylnaphthalene-1,4-
dione 8 (50 mg, 0.147 mmol) in dry MeOH (2.5 mL) at room tem-
perature under argon. The reaction mixture was stirred at room
temperature until completion (0.5 h). Then, the reaction mixture
was quenched using oxygen free water (15 mL) under argon.
Extracted with degassed chloroform and dried with Na2SO4 under
argon. The solution was concentrated under reduce pressure, to
afford pure compound 9 (47 mg, 92% yield) as white solid; IR (thin
film)
m
3247, 2920, 2850, 1386, 1204, 949, 756 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz)
d
8.09 (t, J = 9.08 Hz, 2H), 7.44 (quintet,
J = 7.46 Hz, 2H), 6.62 (s, 1H), 2.67 (t, J = 7.61 Hz, 2H), 1.63 (quintet,
J = 8.37 Hz, 2H), 1.24 (s, 20H), 0.87 (t, J = 6.85 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 145.5, 125.6, 124.5, 121.7, 121.1, 110.4, 31.8,
30.2, 30.1, 29.7, 29.62, 29.58, 29.57, 29.4, 29.3 (6C), 29.2, 22.6,
14.1. HRMS (ESI) calcd for C23H34O2 requires m/z 342.2559, found
341.2557.
4.3. Synthesis of resin-bound Fischer carbene complex (5)
4.6. Procedures to micelles and vesicles formation
All the bright red solid 4 was diluted with 20.0 mL of CH2Cl2 and
this solution was transferred via cannula to a 50.0 mL fritted funnel
(solid-phase peptide synthesizer) containing poly-styrene PL-
Wang resin (1.47 g, 2.5 mmol–1.7 mmol/g specified by manufac-
turer). The reaction mixture was shaken on a wrist shaker at room
temperature for 3 h, after which the mixture was filtered. Then, the
resin was washed sequentially with CH2Cl2 (50 mL), THF (25 mL),
and CH2Cl2 (25 mL) and dried under vacuum to constant weight
to give 2.28 g (3.88 mmol) of the resin-bound complex 5 as a red
4.6.1. Preparation of micelles/vesicles
In a 50 mL round-bottom flask, 40.0 mg of compound 8 were
treated with distilled water (20 mL) and sonicated to obtain a tur-
bid vesicle dispersion. This dispersion was analyzed using normal
conditions and standards for Dynamic Light Scattering. Different
dilutions of compound 8 were performed to obtain vesicles or
micelles. Upon dilution to <0.1% wt, emulsions of 8 formed micellar
structures of 2 nm in diameter, according to AFM.

66
A. Bugarin et al. / Bioorganic Chemistry 56 (2014) 62–66
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4.6.2. Preparation of vesicles from compound (9)
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41.5 mg of 9 were treated with distilled water (20 mL) and son-
icated to obtain a turbid vesicle dispersion. This dispersion was
used to titrate iodine as describe below.
4.6.3. Preparation of stock iodine solution
(d) S. Klapdohr, K.H. Dötz, W. Assenmacher, W. Hoffbauer, N. Hüsing, M.
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3006.
First, a saturated iodine solution was prepared by sonication of
excess iodine in water for 30 min. To a 1.0 mL of the freshly pre-
pared saturated iodine solution were added 5 mL of distilled water
to afford our stock iodine solution (484 mM). Once iodine is dis-
solved into water, it establishes the following equilibrium.
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ꢁ
ꢁ
I2 þ H2O ꢀ OIðaqÞ þ 2HðꢂaqÞ þ IðaqÞ
Since UV–Vis spectra cannot be accurate acquired on disper-
sions, the vesicles and the iodine mixture were filtered through
0.45 lm pore size PTFE syringe filter before the measurement
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Acknowledgments
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We are grateful to the University of Texas at Arlington and at El
Paso for financial support and to the NSF for Grants CHE-0234811
and CHE-0840509 for additional instrumentation, CHE-0748913
and DMR PREM-1025302 for research support. The authors also
thank Juan C. Camacho and Dr. Itzia Cruz for assistance with the
Nile red indicator assay and Dr. Omar Robles for insightful
discussions.
(c) K.H. Dötz, Angew. Chem., Int. Ed. Engl. 23 (1984) 587;
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