Nanocellulose enriches enantiomers in asymmetric aldol reactions

Article abstract of DOI:10.1039/d0ra07412h

Cellulose nanofibers obtained from wood pulp by TEMPO-mediated oxidation acted as a chiral enhancer in direct aldol reactions of 4-nitrobenzaldehyde and cyclopentanone with (S)-proline as an organocatalyst. Surprisingly, catalytically inactive TEMPO-oxidi

Full text of DOI:10.1039/d0ra07412h

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Nanocellulose enriches enantiomers in asymmetric
aldol reactions†
Cite this: RSC Adv., 2020, 10, 37064
b
Naliharifetra Jessica Ranaivoarimanana, ‡a Xin Habaki,‡a Takuya Uto,
a
c
a
*
Kyohei Kanomata,
Toshifumi Yui
and Takuya Kitaoka
Cellulose nanofibers obtained from wood pulp by TEMPO-mediated oxidation acted as a chiral enhancer in
direct aldol reactions of 4-nitrobenzaldehyde and cyclopentanone with (S)-proline as an organocatalyst.
Surprisingly, catalytically inactive TEMPO-oxidized cellulose nanofibers enriched the (R,R)-enantiomer in
this reaction, affording 89% ee in the syn form with a very high yield (99%). Conversely, nanocellulose-
free (S)-proline catalysis resulted in poor selectivity (64% ee, syn form) with a low yield (18%). Green
organocatalysis occurring on nanocellulose solid surfaces bearing regularly aligned chiral carbons on
hydrophobic crystalline facets will provide new insight into asymmetric synthesis strategies for interfacial
catalysis.
Received 29th August 2020
Accepted 25th September 2020
DOI: 10.1039/d0ra07412h
rsc.li/rsc-advances
on nanocellulose have been widely studied and demonstrated
to have excellent catalytic performance.13,14 The high specic
Introduction
surface area and structural rigidity of nanocellulose are key to
enhancing catalytic efficiency in heterogeneous reactions.15
Although nanocellulose has only been reported as a solid
support in immobilized catalysts to date, the direct contribu-
tion of nanocellulose to heterogeneous catalysis16 will attract
much attention in academia and industry because such novel
catalytic systems would expand the potential practical applica-
tions of nanocellulose and will open up new horizons in
nanocellulose engineering and catalysis science. We have
recently reported that typical nanocellulose, especially 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO)-oxidized cellulose nano-
bers (TOCNFs),17 signicantly accelerate catalytic carbon–
carbon bond-forming reactions. We discovered that the simple
addition of TOCNFs to the reaction media drastically improved
the catalytic efficiency of proline, a low-performance organo-
catalyst, in a direct aldol reaction18 and Michael addition.19 The
striking effects of the nanobrillation and crystallinity of
nanocellulose on catalytic performance have clearly indicated
that this unique interfacial nanoarchitecture plays an indis-
pensable role in catalytic enhancement.
Some studies have reported that nanosized cellulose mate-
rials affect enantioselectivity in catalytic processes. Serizawa
and coworkers reported that the hydrolysis of chiral peptides for
several days showed different reaction rates for each enan-
tiomer when the hydrolytic reaction was directly catalysed by
cellulose nanowhiskers.20 Furthermore, Kaushik and coworkers
showed that the hydrogenation of ketones catalyzed by palla-
dium nanoparticles supported on cellulose nanowhiskers
afforded the products with some enantioselectivity.21 Although
the reaction selectivities were insufficient from the viewpoint of
asymmetric synthesis, these two reports clearly indicated that
Nanocellulose has emerged as a cutting-edge sustainable
nanomaterial in the last two decades.1–3 Native cellulose, found
mainly in phytomass such as trees and plants, is a homopol-
ymer of b-1,4-linked D-glucopyranose.4 Biologically synthesized
cellulose molecules assemble and then crystallize into
nanometer-width bers during biosynthesis, in which dozens of
cellulose chains are regularly packed in parallel.3 Various
methods to isolate this naturally occurring nanober, known as
nanocellulose, have been developed to date, including
mechanical, chemical, and enzymatic treatments.5–7 The highly
crystalline nature of thin nanocellulose provides steel-level
mechanical strength, quartz-level thermal stability, and glass-
level transparency. Owing to its superior physicochemical
properties, accompanied by huge abundance and carbon-
neutral renewability, a wide range of studies are currently
underway to develop composite llers,8 gas-barrier lms,9 heat
insulators,10 and solid emulsiers for foods and cosmetics.11,12
Despite being a developing eld, the use of nanocellulose in
catalysis is among its most fascinating applications owing to the
high demand for green molecular transformations in ne
chemical industries. Metal nanoparticle catalysts immobilized
aDepartment of Agro-Environmental Sciences, Graduate School of Bioresource and
Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan. E-mail:
tkitaoka@agr.kyushu-u.ac.jp
bOrganization for Promotion of Tenure Track, University of Miyazaki, Miyazaki 889-
2192, Japan
cDepartment of Applied Chemistry, Faculty of Engineering, University of Miyazaki,
Miyazaki 889-2192, Japan
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra07412h
‡ Both authors contributed equally to this work.
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nanocellulose has the potential to induce enantioselectivity, a greater effect at lower temperatures, the reaction solvent was
possibly owing to its inherent chiral nanoarchitecture.22–25 As changed to DMF (entries 4 and 5). The reaction without TOCNFs
tremendous research effort has been focused on developing gave a low yield and ee (entry 4), while the product was formed
enantioselective catalysis, enantiodiscrimination based on almost quantitatively in the presence of TOCNFs (entry 5). As
naturally-occurring and renewable nanocellulose would be expected, the ee was improved accordingly (from 84%/71% to
a promising development for a greener ne chemical industry. 89%/87% for syn/anti). In our previous studies, TOCNF precip-
Herein, we report for the rst time that nanocellulose signi- itates in the sodium form were sensitive to aggregation in the
cantly enhanced enantioselectivity and catalytic efficiency in reaction media without noticeably inuencing the selectivity of
proline-catalyzed aldol reactions, as shown in Fig. 1. This the aldol reaction.18 To prevent this, standing organogels were
method for synthesizing aldol adducts with up to 89% enan- used, which enabled superior dispersion in the reaction media
tiopurity in the presence of catalytically inactive nanocellulose, compared with that obtained by simple solvent exchange and
TOCNFs, provides an entirely new approach to the development centrifugation. Using the organogels, the reaction reached
of high-performance proline-based organocatalytic systems completion within 24 h (entry 6). No traces of 4-nitro-
among extensive research efforts.26–29 The present conditions benzaldehyde could be detected on stained TLC plates, nor of
afford highly enantioenriched syn-products from cyclic ketones. byproducts. However, the product could not be fully isolated
(86% yield), probably owing to its strong adhesion to TOCNF
surfaces.
Results and discussion
Optimization of reaction conditions
The obtained diastereoselectivity and enantioselectivity were
comparable with the reaction using precipitated TOCNFs. The
This study was initiated by determining the best conditions for improved enantioselectivity was not solely attributed to the
the reaction between 4-nitrobenzaldehyde (1) and cyclo- reaction solvent or temperature, as the reaction with TOCNFs at
pentanone (2) (Table 1) using TOCNFs (Fig. S1–S3†). The room temperature delivered values comparable to that with
ꢀ
amount of proline subjected to the reaction system was set at proline alone at 0 C in DMF (entries 4 and 7). Therefore, the
10 mol% against 1 instead of the 20 mol% load used in the stereoselectivity of the reaction with aromatic aldehydes was
literature,30 to emphasize the effect of TOCNFs on the reaction presumably improved via the TOCNFs, with (R,R)- and (R,S)-
outcome and to prevent proline-only catalyzed reactions, which formation increasing and (S,S)-formation decreasing. This was
may occur apart from nanocellulose suspended in the reaction possibly due to the aromatic aldehydes being restricted to
medium. The reaction catalyzed by (S)-proline alone resulted in adsorption to the TOCNF solid surfaces bearing regularly
a low yield aer 24 h in DMSO at room temperature (entry 1). aligned chiral carbons on crystalline facets where hydrophobic
The major product had a syn-conguration with poor enantio- and hydrophilic faces are separately located on the nanober
selectivity. TOCNFs alone did not catalyze the aldol reaction surfaces.33,34 Cyclohexanone as the ketone substrate also
(entry 2), indicating that TOCNFs were catalytically inactive in beneted the enhancement via the TOCNFs, from 18% to at
this reaction. However, adding precipitated TOCNFs to (S)- least 51% in rough yield, but due to the difficulty in quantitative
proline in the reaction medium markedly increased the yield product extraction, this study focused on cyclopentanone.
from 9% to 55% (entry 3). Water is known to increase the rate of
Solvent screening indicated that protic solvents (methanol
aldol reactions by inhibiting byproduct formation, but also to and ethanol) and aprotic solvents (DMAc and dioxane) in which
adversely inhibit the reaction step of the enamine formation TOCNFs aggregated were unsuitable for delivering the aldol
from proline and ketone substrates.31,32 Additionally, more than adducts. DMF, which gave the most stable TOCNF dispersion,
5 vol% of water resulted in fatal reduction of the ee of the was the best solvent for the direct aldol reactions. Unless
products.30 In the present work, although the TOCNFs used otherwise stated, precipitated TOCNFs in DMF were used in the
contained the trace amount of residual water (1.2 vol%), the subsequent experiments.
overall activity and enantioselectivity was drastically improved
compared with the reaction using (S)-proline alone. To obtain
Investigation of catalytic efficiency
Proline is known to form an oxazolidinone with aldehyde
substrates to a certain extent during reactions, which can lead
to fatal catalyst deactivation. The proton signals for the deac-
tivated form were clearly detected by 1H-NMR for the reaction in
the absence of TOCNFs (Fig. S4†).28,31 Pleasingly, conducting the
reaction in the presence of TOCNFs drastically suppressed
oxazolidinone formation, indicating effective prevention of
proline decarboxylation in the reaction media. Furthermore,
the baseline of the NMR spectra was distorted for reactions
without TOCNFs, which indicated side polymerization reac-
tions occurring among substrates and/or products (Fig. S5†).
Conversely, TOCNFs provided the target product with high
Fig. 1 Schematic illustration of the research strategy in this work.
purity (Fig. S6†).
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Table 1 Optimization of reaction conditionsa
Entry
Solvent
Temperature
TOCNFs
Yieldb (%)
syn/antic
eed (% syn/anti)
1
2e
3
4
5
6
7
DMSO
DMSO
DMSO
DMF
DMF
DMF
rt
rt
rt
0
0
0
rt
—
9
77 : 23
—
39/54
—
Precipitate
Precipitate
—
Precipitate
Gel
—
55
18
>99
86
85
65 : 35
80 : 20
78 : 22
78 : 22
71 : 29
84/71
64/68
89/87
90/86
60/79
ꢀC
ꢀC
ꢀC
DMF
Gel
a
Conditions: 1 (2 mmol), 2 (10 mL), (S)-proline (0.2 mmol), TOCNFs (300 mg, when used), solvent (40 mL). b Isolated yield. c Determined by 1H-
NMR (400 MHz, CDCl3). d Determined by chiral-phase SFC. e Without (S)-proline.
Several reports on proline-catalyzed aldol reactions showed (S)-proline, no reaction occurred during the screening time
that despite having complex kinetics, the reaction is oen period when using amino acids alone. However, when paired
reversible, especially at high catalyst concentrations (>30 mol%) with TOCNFs, an appreciable amount of product was formed
and long reaction times (several days). Albeit the reversibility, within 24 h (entries 2, 4, and 6). In general, the ee of the anti-
a critical control on the transition states can grant higher product was high, similar to the case of TOCNFs combined with
enantioselectivity within relatively short reaction time.35,36 proline (Table 2). Aliphatic amino acids proved to be a good
Fortunately, TOCNFs enabled faster reaction completion and match with TOCNFs (entries 1–6), while aromatic (S)-phenylal-
the use of a lower concentration of (S)-proline. Furthermore, anine and (S)-tyrosine failed to catalyze the reaction (entries 7–
upon following the diastereoselectivity determined by SFC 10). This was probably due to both hydrophobic catalysts and
analysis until full conversion, no epimerization was detected as substrates being competitively adsorbed on the hydrophobic
the dr stayed constant throughout the reaction (Fig. S15†). As facets of the TOCNF crystals.
the same was applied to the enantioselectivity, there was no
erosion of the ee. Therefore, although there is a possibility for
numerous hydroxy and carboxylic acid groups to potentially
Molecular dynamics simulation
The adsorption of substrates and intermediates onto TOCNFs
was probably a key step in these asymmetric aldol reactions.
The three-dimensional structure of the product was speculated
to be determined by the enantioselective mechanism occurring
on the TOCNF surface, rather than asymmetric induction by the
interact with reaction species, the planar rigid TOCNFs surface
probably allowed the stabilization of key transition states as the
reaction is kinetically controlled in the presence of the nano-
ꢀ
cellulose in DMF at 0 C.
Substrate scope
Table 2 Stereoselective aldol reaction in the presence of protonated
TOCNFs as a matrix using (S)-proline as organocatalysta
Different aldehyde substrates were tested in the TOCNF/(S)-
proline catalyzed aldol reaction (Table 2). The main diaste-
reomer had a syn-conguration (Fig. S7–S14†). Surprisingly, all
substrates resulted in enhanced enantioselectivity in the anti-
product. The reaction yields gradually decreased with
increasing strength of the electron-withdrawing groups on the
aldehyde (entries 1 to 3). The bulky naphthaldehyde yielded the
anti-product in a low yield with high enantiopurity (entry 4).
This effect might be attributed to both electrophilic interaction
and steric hindrance between the substrates and the TOCNF
solid surface bearing carboxylate groups,39 although a detailed
mechanism remains to be determined.
Entry
R
Yieldb (%) syn/antic syn eed (%) anti eed (%)
1
2
3
4
4-NO2–C6H4 >99
78 : 22
63 : 37
64 : 36
64 : 36
89
53
55
51
87
88
88
87
4-Br–C6H4
4-Cl–C6H4
2-Naphthyl
60
55
24
a
Conditions: arylaldehyde (2 mmol), cyclopentanone (10 mL), (S)-
proline (0.2 mmol), precipitated TOCNFs (300 mg), DMF (40 mL).
b
Each product structure conformed to previous reports.37,38 Isolated
Amino acid scope
c
d
yield. Determined by 1H-NMR (400 MHz, CDCl3). Determined by
Several amino acids were also tested to determine whether they
chiral-phase SFC.
benetted from the assistance of TOCNFs (Table 3). Excluding
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Table 3 Scope of amino acids for cooperative catalysis in aldol reactiona
Entry
Amino acid
(S)-Alanine
(S)-Valine
TOCNFs
Yieldb (%)
syn/antic
eed (% syn/anti)
1
2
3
4
5
6
7
8
9
10
ꢁ
+
Trace
60
Trace
65
Trace
54
Trace
Trace
Trace
Trace
—
51 : 49
—
49 : 51
—
69 : 31
—
—
—
—
—
48/89
—
40/91
—
36/82
—
—
—
—
ꢁ
+
(S)-Lysine
ꢁ
+
(S)-Phenylalanine
(S)-Tyrosine
ꢁ
+
ꢁ
+
a
Conditions: 1 (2 mmol), 2 (10 mL), (S)-proline (0.2 mmol), TOCNFs (300 mg, when used), DMF (40 mL). b Isolated yield. c Determined by 1H-NMR
d
(400 MHz, CDCl3). Determined by chiral-phase SFC.
catalyst molecule as a unique chiral source. Attempts on the surface was especially constrained by carbohydrate–aromatic
modelization of hexagonal crystals of TOCNFs for the QM/MM- CH/p and hydrophobic interactions, which possibly led to
SMD were unfruitful, probably due to the electronegative nucleophilic attack by the enamine intermediate at the alde-
carboxylate moiety at the C6 position, which may cause the hyde group of the adsorbed substrate from a specic direction.
unstable architecture of cellulose chain assembly. On the other
This MD simulation successfully provided pictorial elucida-
hand, the (100)/(200) planes of TOCNF and CNF crystals are tion of the enantioselectivity in the presence of CNF observed in
regarded as being both hydrophobic.40,41 The adsorption of key the present aldol reaction. Our next target was to verify whether
intermediates in the TOCNFs-enhanced aldol reaction is ex- the asymmetric aldol reaction proceeded on the substrate
pected to occur on the same lattice plane. Despite being less adsorbed on the CNF surface in the manner proposed by the
selective, precipitated CNFs devoid of carboxylate groups on MD simulation.
A quantum mechanics (QM)/molecular
their surface also improved the outcome of the reaction with the mechanics (MM)-steered molecular dynamics (SMD) simula-
same conditions as precipitated TOCNFs (90% yield, 54 : 46 dr, tion was conducted to evaluate the aldol reaction on the CNF
76/68 ee). Therefore, the adsorption behavior of the substrate
and enamine intermediate was evaluated on the CNF surface in
DMF solution using conventional molecular dynamics (MD)
calculations. The substrate (4-nitrobenzaldehyde) was reversibly
adsorbed on the hydrophobic surface of CNF of the (100)/(200)
lattice planes of cellulose Ib (Movie 1†). In particular, the
molecular axis of 4-nitrobenzaldehyde preferred being perpen-
dicular to the ber axis of the cellulose chains, with the
aromatic plane of the substrate parallel to the pyranose plane.
Fig. 2 shows the distribution of substrate and intermediate on
the surface of the CNF model for 2 ms, with the clear distribution
of 4-nitrobenzaldehyde obtained by reecting the aromatic ring.
The regular and homogeneous high-density distribution of
the substrate exclusively appeared over the cellobiose unit,
reecting the two-fold helical symmetry of a cellulose chain,
which suggested that the orientation of the substrate was
Fig. 2 Isocounter surfaces of the substrate and intermediate density
relative to the structures of the CNF model calculated from the MD
trajectories. Red and blue surfaces indicate 0.38 mol Lꢁ1 (corre-
sponding to twice the bulk density) for 4-nitrobenzaldehyde and the
enamine intermediate, respectively. The density was calculated for
a 0.5 ꢂ 0.5 ꢂ 0.5 A˚ grid as the number of hits in 2 000 000 frames.
Molecular graphics with isocontour map were analyzed and drawn
using PyMOL 1.7.1 (http://www.pymol.org).
restricted by the surface topology of the CNF. Conversely, the
enamine intermediate showed an obscure distribution, indi-
cating less specic adsorption behavior, albeit with a tendency
to be located around the substituted groups of the adsorbed
substrate. Therefore, substrate 4-nitrobenzaldehyde on the CNF
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enantioselectivity, such that the enamine intermediate carbon
(Ca) was pulled toward the carbonyl carbon (Cd) of the substrate,
giving the (R,R)-product. As shown in Fig. 3 and Movie 2† (2a
and 2b are the same in different drawings), proton transfer
occurred from the carboxy group of the enamine intermediate
to the carbonyl oxygen of the substrate, accompanied by Ca–Cd
bond formation. Fig. 4 shows the nonequilibrium work and
potential of mean force (PMF) for the reaction coordinate of the
Ca–Cd distance. The C–C bond forming reaction pathway of the
present aldol reaction was exothermic (DGr ¼ ꢁ10.0 kcal molꢁ1
)
Fig. 3 Ca–Cd bond forming reaction progression on CNF surface
observed by QM/MM-SMD simulation. All structure diagrams were
generated using PyMOL 1.7.1 (http://www.pymol.org).
and involved the transition state at a Ca–Cd distance of 1.95–
˚
2.00 A, in which the eight-membered ring structure with half-
chair form contributed to stabilizing the transition state struc-
ture.42–44 The activation energy (DG‡) was estimated to be
3.7 kcal molꢁ1. Therefore, the asymmetric aldol reaction was
reasonably concluded to proceed on the CNF surface. Subse-
quent hydrolysis provided the reaction products, accompanied
by recovery of the (S)-proline catalyst (Fig. 5).
Conclusions
In conclusion, green natural nanobers obtained from wood
pulp by aqueous TEMPO-mediated oxidation substantially
enriched enantiomers and enhanced catalytic efficiency in
direct asymmetric aldol reactions. The proposed catalytic
pathway for enantioselective asymmetric aldol reactions
occurring on nanocellulose surfaces is shown in Fig. 5. TOCNFs
drastically suppressed oxazolidinone formation, which indi-
cates effective prevention of proline decarboxylation in the
reaction media and avoidance of undesirable side polymeriza-
tion reactions among substrates and/or products. MD calcula-
tions proved that the aldehyde substrate orientation was
controlled by carbohydrate–aromatic CH/p and hydrophobic
interactions on the CNF surfaces. The interfacial interaction
was assumed to exert considerable enantiocontrol on the aldol
reaction. Furthermore, the reaction proceeded in the direct
vicinity of the cellulose surface, as suggested by QM/MM-SMD
Fig. 4 Work distribution and potential mean force (PMF) obtained for
the forced approach between the substrate (Cd) and enamine inter-
mediate (Ca) in DMF solvents, displayed for 0.01 A˚ psꢁ1 for 1000
trajectories in an SMD pulling simulation.
surface in a DMF solution. The QM region consisted of the
aldehyde substrate and the enamine intermediate involved in
the reaction. The MM region included the CNF model, DMF
solvent and the surrounding substrates/intermediates that are
not directly taking part in the new bond formation (Fig. S25†).
The QM/MM-SMD method showed that C–C bond formation
was selected as the reaction coordinate leading to
Fig. 5 Proposed catalytic pathway for enantioselective asymmetric aldol reactions occurring on nanocellulose surfaces in this study.
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calculation results and proposed in Fig. 1. This extraordinary mesh). A 0.1 M aqueous HCl solution (10 mL) was spread over
development of highly efficient, enantioselective, and stereo- the nylon sheet and the mold was allowed to stand overnight.
regulated organocatalysis via nanocellulose provides a new The resulting stiff gel was cut into cubes (1 cm ꢂ 1 cm ꢂ 1 cm)
direction for green sustainable chemistry and industry.
and shaken gently in 0.01 M aqueous HCl overnight (30 mL).
The as-prepared hydrogel cubes were immersed in DMF (30 mL)
and shaken gently, renewing the solvent every 8 h (ve times), to
afford the TOCNF organogel of DMF with less than 1.2 wt%
water content (15 eq. of aldehyde 1). Organogel samples of other
solvents were prepared using the same procedure.45,46
Experimental
Materials
TEMPO-oxidized cellulose nanober (TOCNFs; crystallinity
index 72%, crystallite size 2.6 nm, carboxylate content ¼
1.45 mmol gꢁ1) was kindly supplied by Nippon Paper Industries
Co., Ltd. (Tokyo, Japan). 4-Nitrobenzaldehyde and (S)-proline
were purchased from Sigma-Aldrich Japan Ltd. (Tokyo, Japan)
and used as received. Other chemicals and organic solvents
were purchased from Sigma-Aldrich Japan Ltd. (Tokyo, Japan),
Wako Pure Chemical Industries, Ltd. (Osaka, Japan), and Tokyo
Chemical Industry Co., Ltd. (Tokyo, Japan), and used as
received. Water used in this study was puried using an Arium
Ultrapure Water System (Sartorius Co., Ltd., Tokyo, Japan). The
water content of the precipitated TOCNFs was measured by Karl
Fischer titration method on an MKH-700 titrator (Kyoto Elec-
tronics Manufacturing Co., Ltd., Kyoto, Japan). Reaction prog-
ress was monitored by thin-layer chromatography (TLC) on
glass-backed plates precoated with silica gel (silica gel 60
GF254, 0.25 mm Merck, Tokyo, Japan). Purication by column
chromatography was performed using an automated ash
chromatography system (Smart Flash EPCLC-AI-580S, Yamazen,
Osaka, Japan). All product structures were in agreement with
previously reported data from nuclear magnetic resonance
(NMR) analysis.37,38 1H-NMR spectra were recorded on a JNM-
ECZ400 spectrometer (JEOL, Tokyo, Japan) at the Center of
Advanced Instrumental Analysis, Kyushu University. The
enantioselectivity and diastereomeric ratios of products were
measured by supercritical uid chromatography (SFC; ACQ-
UITY UPC2, Waters, Tokyo, Japan) using chiral stationary
phases.
Representative aldol reaction procedure. Cubes of the
TOCNF organogel of DMF or precipitates (300 mg) were
dispersed in DMF (40 mL) using a double-cylinder-type
homogenizer. To the suspension were added 4-nitro-
benzaldehyde (300 mg, 2 mmol), cyclopentanone (10 mL), and
(Sꢀ)-proline (0.2 mmol), and the resultant mixture was stirred at
0 C for 24 h. The reaction was then quenched with water and
extracted with CH2Cl2. Aer drying over MgSO4 and concen-
trating, the residue was puried by silica gel column chroma-
tography to afford the product as
a colorless oil. The
diastereomeric ratio and enantioselectivity were determined
ꢀ
using SFC (Chiralpak IB-3; IPA/CO2, 95 : 5; 40 C; 264 nm).
Molecular dynamics simulation. A CNF model with a hexag-
onal shape consisting of 19 chains of 10-mers in a 3 ꢂ 4 ꢂ 5 ꢂ 4
ꢂ 3 cellulose chain arrangement was built based on the crys-
tallographic structural data of cellulose Ib (Fig. S24†).47 The
DMF suspension system around the CNF model was con-
structed, including 50 molecules of either 4-nitrobenzaldehyde
or the enamine intermediate equivalent to a concentration of
0.19 mol Lꢁ1. The latter was an intermediate of the reaction of
cyclopentanone with (S)-proline in DMF solution (Fig. 5).
Conventional molecular dynamics (MD) calculations were per-
formed for the system at constant temperature (300 K) and
pressure (1 bar) for 2 ms. The adsorption distribution of 4-
nitrobenzaldehyde and the enamine intermediate on the CNF
surface was evaluated by analyzing the obtained MD trajectory.
Furthermore, a multiscale simulation combining quantum
mechanics (QM) and molecular mechanics (MM) was con-
ducted to reproduce the aldol reaction on the CNF surface. The
substrate was appropriately arranged on the CNF model based
Methods
Preparation of TOCNF precipitate. A water suspension of on the results obtained by MD calculation. The substrate and
TOCNFs in the sodium carboxylate form (2.01 wt%, 300 mg of enamine intermediate involved in the aldol reaction were
dried cellulose) was mixed with 0.1 M aqueous HCl solution (25 included as the QM region, and the rest of the system was
mL), shaken several times, and then centrifuged (12 000 ꢂ g, 10 treated as the MM region (Fig. S25†). The enamine intermediate
min). The supernatant was then renewed with deionized water was pulled toward 4-nitrobenzaldehyde arranged on ꢁth2 e CNF
(25 mL) and the mixture was centrifuged again. This washing model by an external force of 1000 kcal molꢁ1
using
˚
A
cycle was repeated until the supernatant pH reached 4.5 (3 a steered molecular dynamics (SMD) method.48 The potential of
times). To remove water, the protonated TOCNFs were washed mean force (PMF) of the reaction process was estimated from
with the type of solvent to be used in the respective aldol reac- the exponential Boltzmann-weighted ensemble average of
tion using the same centrifugation procedure (12 000 ꢂ g, nonequilibrium works obtained from 1000 SMD runs under
10 min, 7 cycles). Aer the last cycle, the solvent was removed, ambient conditions (300 K and 1 bar) for 100 ps.
and the TOCNF precipitate was recovered and used in reactions.
The CNF model was described by the GLYCAM06 force
Each sample had less than 1.2 wt% (15 eq. of aldehyde 1) water eld.49 4-Nitrobenzaldehyde, the enamine intermediate, and
content upon Karl Fischer titration of the dispersed nano- DMF solvent were modeled using the GAFF force eld.50 The
material as a reaction solvent.
QM/MM simulation was conducted using the SCC-DFTB-PA
Preparation of TOCNF organogel. TOCNFs dispersion (0.5% method with mio-1-1 parameters (Fig. S26†).51,52 The particle
w/v, 100 mg of dried cellulose) was poured into a mold (6 cm ꢂ mesh Ewald algorithm was adopted for long-range interactions,
5 cm ꢂ 1 cm in size) and covered with a nylon sheet (20 mm and the cutoff for nonbonding interactions in the coordinate
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space was xed at 12 A. All MD and DFTB/MM-MD calculations 13 M. Kaushik and A. Moores, Green Chem., 2016, 18, 622–637.
were conducted using the SANDER and PMEMD. CUDA 14 M. Matsumoto and T. Kitaoka, Adv. Mater., 2016, 28, 1765–
modules of the Amber 18 package with the NVIDIA Kepler GPU
1769.
system.53–55 MD trajectory analysis was performed using the 15 H. Koga, E. Tokunaga, M. Hidaka, Y. Umemura, T. Saito,
CPPTRAJ module of AmberTools 19.56
A. Isogai and T. Kitaoka, Chem. Commun., 2010, 46, 8567–
8569.
16 Y. Tamura, K. Kanomata and T. Kitaoka, Sci. Rep., 2018, 8,
Conflicts of interest
5021.
There are no conicts to declare.
17 A. Isogai, T. Saito and H. Fukuzumi, Nanoscale, 2011, 3, 71–
85.
18 K. Kanomata, N. Tatebayashi, X. Habaki and T. Kitaoka, Sci.
Rep., 2018, 8, 4098.
Acknowledgements
This research was supported by an Advanced Low Carbon 19 N. Ranaivoarimanana, K. Kanomata and T. Kitaoka,
Technology Research and Development Program (Grant No. Molecules, 2019, 24, 1231.
JPMJAL1505 to T. K.) from Japan Science and Technology 20 T. Serizawa, T. Sawada and M. Wada, Chem. Commun., 2013,
Agency, and a Grant-in-Aid (KAKENHI) for Challenging Explor- 49, 8827–8829.
atory Research (Grant No.: JP18K19233 to T. K.) from Japan 21 M. Kaushik, K. Basu, C. Benoit, C. M. Cirtiu, H. Vali and
Society for the Promotion of Science. The theoretical calcula-
A. Moores, J. Am. Chem. Soc., 2015, 137, 6124–6127.
tions were partly performed using Research Center for 22 S. J. Hanley, J. F. Revol, L. Godbout and D. G. Gray, Cellulose,
Computational Science, Okazaki Research Facilities, National 1997, 4, 209–220.
Institutes of Natural Sciences (NINS), Japan. We thank Simon 23 I. Usov, G. Nystrom, J. Adamcik, S. Handschin, C. Schutz,
¨
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Partridge, PhD, from Edanz Group (www.edanzediting.com/ac)
A. Fall, L. Bergstrom and R. Mezzenga, Nat. Commun.,
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24 H. Goto, J. Jwa, K. Nakajima and A. Wang, J. Appl. Polym. Sci.,
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25 H. Yu and J. Deng, Macromolecules, 2016, 49, 7728–7736.
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