Optical resolution of aromatic alcohols using silica nanoparticles grafted with helicene

Article abstract of DOI:10.1021/ol301206r

Optically active silica nanoparticles, with a 70-nm diameter, grafted with (P)-1,12-dimethyl-8-methoxycarbonylbenzo[c]phenanthrene-5-carboxyamide were synthesized, and their use in the kinetic resolution of aromatic alcohols was examined. Up to 61% ee for (S)-2,2-dimethyl-1-phenyl-1-propanol was obtained by a preferential precipitation of aggregates formed with (P)-nanoparticles.

Full text of DOI:10.1021/ol301206r

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3123–3125
Optical Resolution of Aromatic Alcohols
Using Silica Nanoparticles Grafted with
Helicene
Wataru Ichinose, Masamichi Miyagawa, Zengjian An, and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aoba, Sendai 980-8578, Japan
yama@m.tohoku.ac.jp
Received May 2, 2012
ABSTRACT
Optically active silica nanoparticles, with a 70-nm diameter, grafted with (P)-1,12-dimethyl-8-methoxycarbonylbenzo[c]phenanthrene-5-
carboxyamide were synthesized, and their use in the kinetic resolution of aromatic alcohols was examined. Up to 61% ee for (S)-2,2-dimethyl-
1-phenyl-1-propanol was obtained by a preferential precipitation of aggregates formed with (P)-nanoparticles.
Racemic organic compounds have been resolved by
recrystallizing diastereomeric salts, typically those derived
from 1:1 mixtures of carboxylic acids and amines, employ-
ing diastereomers with different solubilities.1 The method,
however, cannot be applied to nonpolar organic com-
pounds, which do not readily crystallize. In such cases,
chiral high performance liquid chromatography (HPLC)
separation has been conducted, which requires several
pieces of equipment.2 Other methods such as co-
crystallization3,4 and polymer imprinting5À7 were also
developed, although they were not quite common. In this
study, the use of optically active nanoparticles for the
resolution of aromatic alcohols by a preferential aggrega-
tion and precipitation of an enantiomer is described. This
method can be used for the resolution of nonpolar non-
crystalline compounds and has an advantage of using
smaller molar amounts of the resolving reagent compared
to racemic compounds. Although studies have been con-
ducted for the resolution of racemic acids or amino acid
derivatives with chiral nanoparticles,8À10 there are as yet
no studies of nonpolar alcohols.11
3-Aminopropylated silica nanoparticles12 (2.3 mmol/g)
of 70-nm mean diameter were grafted with (P)-1,
(1) Recent review: Faigal, F.; Forgassy, E.; Nogradi, M.; Palovics,
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2944.
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Hirotsu, K. J. Phys. Org. Chem. 2000, 13, 39–45.
(5) Nakano, T.; Satoh, Y.; Okamoto, Y. Macromolecules 2001, 34,
2405–2407.
(8) Choi, H. J.; Hyun, M. H. Chem. Commun. 2009, 6454–6456.
(9) Chen, X.; Rao, J.; Wang, J.; Gooding, J. J.; Zou, G.; Zhang, Q.
Chem. Commun. 2011, 47, 10317–10319.
(10) Xu, W.; Cheng, Z.; Zhang, L.; Zhang, Z.; Zhu, J.; Zhou, N.; Zhu,
X. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 1324–1331.
(11) The enantioselective interaction of chiral gold nanoparticles
with propylene oxide was examined. Shukla, N.; Bartel, M. A.; Gellman,
A. J. J. Am. Chem. Soc. 2010, 132, 8575–8580.
(6) Teraguchi, M.; Suzuki, J.; Kaneko, T.; Aoki, T.; Masuda, T.
Macromolecules 2003, 36, 9694–9697.
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r
10.1021/ol301206r
2012 American Chemical Society
Published on Web 05/23/2012

12-dimethyl-8-methoxycarbonylbenzo[c]phenanthrene-
5-carboxylic acid chloride by treating them in refluxing
isopropyl ether for 4 h in the presence of ethyldiisopropy-
lamine. The grafted chiral (P)-nanoparticles were stored in
ethanol, and IR, CD, UVÀvis, and thermogravimetry (TG)
analyses were conducted (Figures S2, S4, S5). A loading
amount of 0.15 mmol/g was obtained by CD, UVÀvis, and
elemental analyses (Figure S5). No irreversible aggregation
was observed during grafting, as indicated by the results of
the dynamic light scattering (DLS) and atomic force micro-
scopy (AFM) analyses (Figures S6, S7). The nanoparticles
were stable in ethanol for 72 h, as indicated by the results of
the DLS analysis, and sonication did not affect the dispersed
state (Figure S7).
Figure 1. Enantioselective precipitation of 1 (0.18 mg) by (P)-
nanoparticles (1.0 mg) in m-bis(trifluoromethyl)benzene (0.2 mL)
at 25 °C.
Reversible aggregate formation was observed for the 70-
nm-diameter silica (P)-nanoparticles in different solvents
as well as for the 210 nm particles reported before.13 The
(P)-nanoparticles in ethanol (20 mg/20 mL) were centri-
fuged, and the collected nanoparticles were mixed with
trifluoromethylbenzene (20 mL). The aggregated particles
of 3100-nm mean diameter were formed asindicated by the
results of the DLS analysis. When the aggregated nano-
particles were mixed with iodobenzene, smaller aggregates
of 220-nm mean diameter were formed. Mixing with
chlorobenzene gave 620-nm-diameter aggregates, whereas
mixing with toluene gave 1300-nm-diameter aggregates.
The solvent exchange of (P)-nanoparticles in iodobenzene
to trifluoromethylbenzene changed the diameter of the
aggregated particles from 220 to 2700 nm. The (P)-nano-
particles were dispersed in soft aromatic solvents and
reversibly aggregated in hard solvents (Figure S3).
A notable observation was made when (P)-nanoparti-
cles were mixed with optically pure 1-phenylethanol 1. A
mixture of (P)-nanoparticles (1.0 mg) and (S)-1 (0.18 mg)
was dispersed in m-bis(trifluoromethyl)benzene (0.2 mL)
and was allowed to settle at room temperature (Figure 1).
Precipitates started to form after 7 h and were completed
after 12 h. The obsevation is in contrast to that of (R)-1,
which started to precipitate after 18 h and was completed
after 26 h. Without 1, (P)-nanoparticles started to pre-
cipitate only after 42 h in the same solvent. The higher
tendency of (S)-1 to form precipitates was ascribed to the
stronger interactions of (S)-1 and (P)-nanoparticles com-
pared to (R)-1, which is a chiral recognition phenomenon
in the interactions of chiral nanoparticles with small chiral
molecules. Both (S)-1 and (R)-1 formed similar aggregates
of 800-nm mean size at the start of the precipitation, as
indicated by the results of the AFM analysis (Figure S8).
The mechanism of precipitation and chiral recognition was
examined. The (P)-nanoparticles were washed with triethy-
lamine and dispersed in m-bis(trifluoromethyl)benzene.
When (S)-1 or (R)-1 was added, each solution formed a
precipitate within 10 min. In contrast, (P)-nanoparticles
washed with trifluoroacetic acid began precipitation with
(S)-1 in 14 h and completed in 24 h; precipitation with (R)-1
started at 24 h and completed in 36 h. These results indicated
that the amine groups on the surface were protonated,14 and
electrostatic repulsions between the positive charges on the
surface inhibited the aggregation of nanoparticles (Figure 2).
The adsorption of 1 on the surfaces reduced the electrostatic
repulsions and prompted aggregation, during which
process chiral recognition occurred. It may be consistent with
the experimental results that (P)-nanoparticles contained
2.3 mmol/g amines and 0.15 mmol/g (P)-helicene.
On the basis of our observations, optical resolution was
examined. To a mixture of (P)-nanoparticles (20 mg) in
m-bis(trifluoromethyl)benzene (4 mL), (()-1 (3.6 mg) was
added, and the mixture was allowed to settle for 12 h. The
precipitate wasseparatedby centrifugation and mixed with
2-propanol (1 mL). After insoluble materials were re-
moved by centrifugation, the solution was concentrated,
and (S)-1 was obtained in 18% yield (maximum yield of
50%), as indicated by the results of the UVÀvis analysis
Figure 2. Possible mechanism of aggregation.
and in 47% ee as indicated by those of the HPLC analysis.
From the supernatant, (R)-1 was recovered in 70% yield
(13) An, Z.; Yasui, Y.; Togashi, T.; Adschiri, T.; Hitosugi, S.; Isobe,
H.; Higuchi, T.; Shimomura, M.; Yamaguchi, M. Chem. Lett. 2010, 39,
1004–1005. Chiral recognition in aggregation of gold nanoparticles
grafted with helicenes was examined. An, Z.; Yamaguchi, M. Chem.
Commun., submitted.
(14) Wu, Z.; Xiang, H.; Kim, T.; Chun, S. M.; Lee, K. J. Colloid
Interface Sci. 2006, 304, 119–124.
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Org. Lett., Vol. 14, No. 12, 2012

of the solvent effect. The time of the start of precipitation
was examined for (R)-1 and (S)-1 in various solvents. In all
the solvents, (S)-1 precipitated faster than (R)-1, and the
ratios of the time are summarized in Table S1. Notably, the
ratio showed good correlation with the enantiomeric excess
of (S)-1 obtained by the resolution of (()-1. The results
indicate the kinetic nature of this resolution method. In
general, the fluorine-containing benzenes showed higher
enantiomeric excesses of (S)-1: CF3C6H5, 40% ee; p-(CF3)2-
C6H4, 34% ee; m-F2C6H4, 30% ee; FC6H5, 29% ee. Polar
solvents such as DMSO, NMP, THF, CH3CN, EtOH,
morpholine, and AcOEt showed selectivities below 25% ee.
The substituent effect on aromatic alcohols was exam-
ined (Table 1). Bulkier alkyl derivatives showed high
enantiomeric excesses, and 2-methyl-1-phenyl-1-propanol,
2,2-dimethyl-1-phenyl-1-propanol, and 1-phenyl-1-buta-
nol gave 52% ee, 61% ee, and 55% ee, respectively. In
contrast, a relatively small effect of the aromatic substitu-
ent was observed. (p-Fluorophenyl)-1-ethanol gave an (S)-
isomer of 35% ee and (p-chlorophenyl)-1-ethanol gave an
(S)-isomer of 32% ee.
To summarize, racemic aromatic alcohols were kineti-
cally resolved using 70-nm-diameter optically active
silica (P)-nanoparticles grafted with (P)-1,12-dimethyl-8-
methoxycarbonylbenzo[c]phenanthrene-5-carboxyamide,
and up to 61% ee of the (S)-isomer was obtained. The
different rates of precipitation between the enantio-
mers were exploited for the resolution, which could
visually be monitored. This method can be used for
the resolution of noncrystalline substances using a
small nonstoichiometric amount of the resolving
reagent.
Table 1. Optical Resolutions of Aromatic Alcohols
(See Supporting Information for Experimental Detail)
a Enantiomeric excess values were determined by HPLC. b Yields
were determined by HPLC. c Absolute configurations of alcohols were
determined by the order of elution in HPLC.3,15
with 3% ee. The reaction time was critical, and treatment
for 9 and 18 h gave (S)-1 in 11% ee (5% yield) and 19% ee
(19% yield), respectively. An intermediate period of 12 h
between the start of precipitation for (S)-1 and (R)-1 was
employed. The (P)-nanoparticles could be reused, and use
of recovered (P)-nanoparticles provided (S)-1 in 44% ee
(11% yield). Preparative resolution was conducted using
(()-1 (36 mg) and (P)-nanoparticles (200 mg), and (S)-1
(5.1 mg, 14%, 44% ee) was obtained.
Acknowledgment. Financial support from JSPS (No.
21229001) and G-COE is acknowledged. W.I. thanks the
JSPS for a Fellowship for Young Japanese Scientists. We
thank Professor Hiroyuki Isobe (Graduate School of
Science, Tohoku University) for DLS use.
The above procedures employed 10 equiv of (()-1 based
on (P)-helicene on a silica surface. An intriguing aspect of
the nanoparticle resolution method is that an excess amount
of a racemic substrate can be used over the resolving reagent.
When 1 equiv of (()-1 was employed, (S)-1 was obtained in
35% yield with 53% ee. (S)-1 was obtained in 18% yield
with 29% ee even with the use of 20 equiv of (()-1. The
stoichiometries of (()-1 and (P)-nanoparticles have rela-
tively small effects on the efficiency of resolution.
Supporting Information Available. Experimental pro-
cedures for synthesis of (P)-nanoparticles and optical
resolution, CD and UVÀvis spectra of (P)-nanoparticles,
AFM images of the (P)-nanoparticles, TG, and DLS of
(P)-nanoparticles. This material is available free of charge
via the Internet at http://pubs.acs.org.
Precipitation analysis could be conveniently used for the
optimization of conditions, asindicated inthe examination
(15) Yamamoto, Y.; Shirai, T.; Watanabe, M.; Kurihara, K.;
Miyaura, N. Molecules 2011, 16, 5020–5034.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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