A designed bi-functional sugar-based surfactant: Micellar catalysis for C-X coupling reaction in water

Article abstract of DOI:10.1039/c9gc00964g

A bi-functional sugar-based surfactant ALA14 was designed as the ligand and micelle constructor and demonstrated to promote the copper-catalyzed C-X coupling reaction in water. The nature of this micelle, formed by sugar-based surfactants, was investigated with CMC, DLS, and TEM, by which encapsulation and aggregation of the substrates in micelles were verified. Additionally, it was addressed by ¹H-NMR analysis that the enrichment position of the substrates is in the lipophilic alkyl chain. Finally, moderate to excellent yields of the aimed products were obtained in this work. This remarkably simple strategy expanded the scope of C-X coupling reaction in water; most notably, both water and ALA14 can be recycled and reused.

Full text of DOI:10.1039/c9gc00964g

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DOI: 10.1039/C9GC00964G
Journal Name
ARTICLE
A designed bi-functional sugar-based surfactant: micellar catalysis
for C-X coupling reaction in water
Received 00th January 20xx,
Accepted 00th January 20xx
Xin Ge, Shihui Zhang, Xinzhi Chen, Xuemin Liu and Chao Qian b*
a
a
b
a*
DOI: 10.1039/x0xx00000x
A bi-functional sugar-based surfactant ALA14 was designed as the ligand and micelle constructor and demonstrated to
promote the copper-catalyzed C-X coupling reaction in water. The nature of this micelle, formed by sugar-based
surfactants, was investigated with CMC, DLS, and TEM, via which encapsulating and aggregation of the substrates in
www.rsc.org/
1
micelle were verified. Additionally, it was addressed by H-NMR analysis that the enrichment position of the substrates is
in the lipophilic alkyl chain. Finally, moderate to excellent yields of the aimed products were obtained in this work. This
remarkably simple strategy expanded the scope of C-X coupling reaction in water; most notably, both water and ALA14
can
be
recycled
and
reused.
for organic processes is still rather limited due to the
insolubility of organic species in water. To solve this problem,
alternative approaches were developed, e.g. micellar
Introduction
Carbon-heteroatom bonds are important structural motifs1-4 of
various chemicals like natural products, clinically used drugs,
pesticides, and so on. Thus, the cross-coupling reactions to
construct C-X bond, in particular the green processes, continue
to be in the spotlight of chemical research, as for example, Cu-
2
8
29
catalysis , in-water catalysis of homogeneous system , and
1
8
on-water catalysis of heterogeneous system . Micellar
catalysis is an effective strategy to disperse water-insoluble
organic compounds in aqueous system, which depends on the
surfactants to form supramolecular aggregates. Similar to
5
catalyzed Ullmann reaction. Previous studies on Ullmann C-X
reaction focus mainly on ligand effects and are carried out in
3
0
biological enzymes , the amphiphilic structure of micelle
formed by self-aggregation of surfactants in water isolates
species from water and improves the solubility of organic
reactants. Up till now, commercially available surfactants like
6
-16
organic solvents (e.g., DMSO, DMF, THF, dioxane). Although
many efforts have been made to improve the C-X coupling
process with optimized ligands, the use of potentially toxic
organic solvents and unrecyclable ligands violates the 12
Principles of Green Chemistry. In order to make organic
reactions “greener”, water is often employed as reaction
media to reduce or eliminate the use of hazardous organic
solvent, as nature has been doing for billions of years.
3
1, 32
33, 34
35-37
38
39
SDS
, CTAB
, Brij35
, triton X-100 , tween 20/40 ,
4
0
41
and newly designed surfactants such as TPGS-750-M , NOK ,
1
7
4
2
43
PQS , BABTGA , have been developed for efficient promotion
of organic reactions. Especially, the TPGS-750-M series
surfactants established by Lipshutz have been well-studied and
2
0, 21, 40, 44-46
have strong universality
. However, most of the
As the favourite solvent of nature, water is a cheap, safe, non-
toxic, and clean reaction medium. Quite a few reactions have
been proven to proceed successfully in water, e.g. Suzuki-
metal-catalyzed reactions still require the addition of ligands
or promoters even when using surfactants, and the recovery of
surfactants remains challenging. Thus, we envisioned whether
it is possible to combine the functions of surfactants and
ligands. It is always urgent and interesting to explore more
eco-friendly and more simple protocols.
1
8
1
9-21
22
Miyaura reactions
,
Still reaction , Mizoroki Heck
reactions2
reactions2
3,
24
, Olefin Metathesis reactions , and arylation
. Moreover, the industrial process of water
25
6,
27
recovering has made a significant breakthrough by using
membrane separation and phase separation technology. In
spite of these efforts, the utilization of water as reaction media
As green and biodegradable natural compounds, sugars are
frequently used as ligands in metal-catalyzed coupling
reactions. In 2008, D-glucosamine was reported to efficiently
promote copper-catalyzed Ullmann coupling reaction in
4
7
DMSO. Moreover, it was found that replacing DMSO with the
a. School of Chemical and Material Engineering, Jiangnan University, Wuxi, P.R
China. E-mail: lxm@jiangnan.edu.cn
4
8
mixed water solvent improves this reaction. However, toxic
organic solvent is still required, and the contradiction of water-
soluble catalyst and water-insoluble reactant remains
b.
Zhejiang Provincial Key Laboratory of Advanced Chemical Engineering
Manufacture Technology, College of Chemical and Biological Engineering,
Zhejiang University, Hangzhou, P.R China. E-mail: qianchao@zju.edu.cn
†
Footnotes relating to the title and/or authors should appear here.
unsolved. Thus, following the interests in the fine-tuning and
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
49-56
design of carbohydrate structures
, we attempted to design
a bi-functional sugar-based surfactant, ALA14, which acts as a
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ligand and meanwhile, provides a micellar environment for the nonionic surfactants for this reaction (Table 1, entry 7).
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DOI: 10.1039/C9GC00964G
Increasing the amount of surfactant promotes obviously the
Scheme 1. Synthesis of N-alkyl-glucosamine (AGA12, AGA14,
AGA16)
yield of desired product (Table 1, entries 11-13,5). When only a
little surfactant is added, no aggregates occurred in the system
and the surfactant molecules serves only as ligand. Further,
OH
OH
O
MeOH
r.t.,24h
H
+ H2N
O
N
HO
HO
OH
HO
HO
n
n
OH
OH
Table 1. Optimization of Ullmann C-S coupling in water
n= 5,6,7
O
I
+
-
Surfactant/H2O
O
S
S
Na O
OH
Copper salt, temp, 7h
OH
O
N
HO
HO
n
OH
1a
2a
3a
Scheme 2. Synthesis of N-alkyl-lactosamine (ALA12,
Entry
1
Promoter
AGA12
Copper salt
CuI
Temp/oC
80
Yield/% e
25
ALA14, ALA16)
a
OH
OH
HO
OH
OH
H2O and isopropanol
HO
HO
O
O
H
O
OH + H2N
O
O
N
AGA14 a
AGA16 a
ALA12 a
ALA14 a
ALA16 a
-
HO
O
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
50
30
45
65
58
0
OH HO
OH
n
HO
n
OH
OH
n= 5,6,7
OH
OH
HO
HO
O
OH
OH
O
N
HO
n
OH
aggregation of substrates. Herein, we report a green, simple,
and sustainable micellar protocol for the construction of C-S
and C-N bond via Ullmann reactions.
Glucose
Lactose
0
0
1
1
0
1
D-Glucosamine
ALA14 b
20
0
Results and discussion
12
ALA14
c
trace
15
40
40
40
1
1
1
3
4
5
ALA14 d
ALA14 a
ALA14 a
ALA14 a
In general, the condensation of glucose or lactose with long-
chain alkylamine resulted in the formation of nonionic
surfactant. Pure N-alkyl-glucosamine (AGA12, AGA14, AGA16)
and N-alkyl-lactosamine (ALA12, ALA14, ALA16) were obtained
16
3 2
Cu(CH COO)
5
7
in good yields with recrystallization . The anomeric
configurations of these carbohydrate-derived alkylamines
ALA14 a
1
7
CuSO
4
80
40
1
1
8
9
ALA14 a
ALA14 a
CuI
CuI
90
75
90
1
13
were confirmed as β-configuration by the J[ CH(1)] coupling
100
5
8
constants . Notably, the configuration of D-glucose and D-
lactose is in dynamic equilibrium between open chain and ring
structures. After condensation with a long-chain alkylamine,
the open-chain form, in equilibrium with the ring form, is the
structure of a Schiff base, which can effectively anchor the
metal catalyst.
Reaction
conditions:
iodobenzene
(1.0
mmol),
sodium
a
benzenesulfinate (1.2mmol), CuI (0.1 mmol), 0.1mmol surfactant in
10 mL water, 7 h. 0.003mmol surfactant in 10 mL water, 7 h.
b
c
d
0
1
.005mmol surfactant in 10 mL water, 7 h. 0.01mmol surfactant in
0 mL water, 7 h. e Isolated yield.
abundant phenol can be produced by hydrolysis of
With these sugar-based nonionic surfactants in hand, the iodobenzene; however, when sufficient surfactant was present
evaluation of their performances began with the Ullmann C-S in the system to exhibit a micellar environment, the target
coupling of iodobenzene with sodium benzenesulfinate in product yield was significantly improved. The essential role of
various aqueous micellar solution (AGA12, AGA14, AGA16, the micellar environment in such a C-S coupling process is thus
ALA12, ALA14, ALA16); copper salt was employed as the clarified.
catalyst (Table 1, entries 1-6). Since the water-solubility of the Next, various copper sources, i.e. CuI, CuBr, CuCl,
glucosamine part is unsatisfactory, the performance in AGA Cu(CH COO) , and CuSO , were examined regarding this
3
2
4
aqueous micellar solutions is inferior to that in ALA aqueous process (Table 1, entries 5, 14-17). Although all copper salts
micellar solutions. Moreover, the disaccharide part of ALA can can initiate the C-S coupling, obviously CuI outperformed the
effectively enhance its hydrophilicity, resulting in higher others. Finally, different temperatures were examined (Table
reactivity. Most notably, ALA14 showed the highest efficiency 1, entries 5, 18-19). As the reaction temperature increases, the
with a 65% yield, indicating that ALA14 aqueous solution yield is significantly improved. In summary, the optimal
provides the most suitable size of micelles and the best conditions for the C-S coupling can be concluded as: using CuI
hydrophilic-lipophilic balance. Glucose, lactose and D- as the catalyst, the aqueous solution of surfactant ALA14 as
glucosamine were also tested (Table 1, entries 8-10). It turns the solvent, and controlling the temperature at 100 ℃ ;
out that no coupling products were obtained in the presence additional ligand or base is not needed.
of glucose and lactose. When D-glucosamine was used as
ligand, the yield of final product is only 20%. In addition, the
control experiment exhibited the importance of sugar-based
2
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To investigate the nature of micelle upon the dissolution of Figure 2, it was found that the average micelle sVizieew iAnrtcicrleeOansleinde
sugar-based surfactants in water, the critical micelle from 9 nm to 15 nm, indicating that theDmOiI:c1e0ll.1e0s39p/lCa9yGaCc0e0r9t6a4iGn
concentration (CMC) values of employed surfactants must be role in the encapsulating and aggregation of the substrate.
clear. As shown in Figure S1, CMC values of three surfactants,
AGA12, ALA12, and ALA14 were found graphically from
dependence of the surface tension (γ) of their aqueous
1.2
1.0
0.8
0.6
0.4
0.2
0.0
ALA14
ALA14+iodobenzene
-0.2
0.1
1
10
100
1000
10000
Radius [nm]
Figure 2. DLS results for micelle size distribution of 0.1 wt%
ALA14 aqueous solution
In general, micelles are formed to ensure their solubility and
keep the palisade area at the junction between the headgroup
and the alkyl chain by a hydrophobic core and a hydrophilic
surface; around the latter, the hydrophilic groups remain
exposed to water. To elucidate the reaction mechanisms, we
Figure 1. TEM images of 0.1 wt% ALA14 aqueous solution
solutions from their bulk molalities at 40 °C. CMC values of
these surfactants were summarized in Table S1. It was
exhibited that CMC values of ALA series surfactants are
significantly smaller than those of AGA. Moreover, ALA14 has
1
used H NMR spectra at 40 °C to explore the enrichment
the minimum CMC with only 5 × 10― mol·L , which leads to
the highest catalytic activity in Ullmann C-S reaction.
Furthermore, under TEM analysis, the nature of the micelles
formed by ALA14 was found to be spherical in shape and has a
tendency to aggregate (Figure 1). TEM also revealed that
micelle size distribution of ALA14 aqueous solution is in range
of 5-15 nm. The FTIR spectra of ALA14 and ALA14@CuI are
shown in Figure S2. For ALA14, the characteristic absorption
4
-1
position of substrate in surfactant micellar solutions. When
solute molecule interacts with surfactant, the chemical shift of
1
surfactant protons in the H NMR spectra reveals its location.
Figure 3 represents the change of chemical shifts of ALA14 due
to the addition of iodobenzene. The chemical shifts in the
hydrophilic lactose part of ALA14 are strictly identical. But in
the lipophilic part, the upfield shifts of methylene and methyl
groups on the long carbon chain were changed from 1.36ppm
and 0.96ppm to 1.26ppm and 0.88ppm, respectively. It proved
-1
peaks appeared at 3371 cm (O-H stretching vibration), 2917
-
1
-1
-1
cm and 2849 cm (C-H stretching vibration), 1464 cm (C-H
-1
bending vibration of -CH
of -CH
stretching vibration), 1025 cm (C-O stretching vibration).
Compared with the FTIR spectra of ALA14, a wide and high
absorption peak (1567 cm and 1645 cm ) emerged for
ALA14@CuI, which might be due to the C=N stretching
vibration. The new peak implied the stability of Schiff base
structure after ALA14 anchored the metal. The TG curves of
ALA14 was shown in Figure S4. It was obvious that the mass
loss occurred from 150 C to 500 C, which implied the
decomposition of ALA14. Importantly, the surfactant was
stable below 150 C.
2
-), 1375 cm (C-H bending vibration
-
1
-1
3
), 1170 cm (C-N stretching vibration), 1064 cm (C-O-C
-1
-1
-1
o
o
o
The micelle size is an important factor that provides
information about the hydrodynamic radius of the self-
aggregated nanoparticle. ALA14 dissolves in water to form 0.1
wt% ALA14 aqueous solution, which provides micelles with an
average diameter sized of 9nm, as determined by dynamic
light scattering (DLS) measurement in Figure 2. In addition, the
average micelle size, after iodobenzene was dissolved into
ALA14 aqueous solution, was studied by DLS. As shown in
1
Figure 3. Condensed formula of L14 and iodobenzene, H NMR
spectra and peak assignments for the ALA14/D
ALA14+iodobenzene/D O (black line)
2
O (red line) and
2
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that the substrate iodobenzene is mostly wrapped in the withdrawing and donating effects of the group substituted on
View Article Online
DOI: 10.1039/C9GC00964G
aryl ring have much influence on the C-S coupling reaction.
micellar hydrophobic core.
Further, a plausible mechanism of micellar catalysis for C-S When electron-withdrawing groups, e.g. 4-Ac (3e), 4-Cl (3d), 4-
coupling reaction in water is proposed based on the change of NO (3f), 3-NO (3h), and 4-CF (3i) were located in the aryl ring,
2
2
3
the particle size of the micelle after iodobenzene is dissolved the corresponding yields were much lower as compared to
into ALA14 aqueous solution. As shown in Figure 4, initially those with electron donating substituents, e.g., 4-OMe (3b)
ALA14 in water self-assembles to form micelle. In the and 4-Me (3c). In addition, influences of different aryl halides
hydrophilic lactose part, the Schiff base acts as a ligand to were examined. As a result, the activities of different aryl
chelate the copper salts. Moreover, iodobenzene was halides with sodium benzenesulfinate was determined as: PhI
concentrated in the lipophilic part, which is the center of the > PhBr > PhCl. Further, the low yield of 3g revealed that the
micelle. Then, the reaction occurred in the palisade area at the steric hindrance from the ortho-substituents significantly
junction between the headgroup and the alkyl chain. B is hindered the progress of the reaction.
formed via nucleophilic reaction of A with benzenesulfonate. The ALA14 micellar-catalyzed protocol was further expanded
The oxidation addition of complex B with iodobenzene to the Ullmann C-N coupling reaction of aryl halides with
generates complex D. Finally, the target product was obtained nucleophiles, and the results are shown in Table 3. To our
by reductive elimination and the micellar catalyst was delight, nucleophiles coupled smoothly with aryl halides. It was
regenerated.
shown that the electron withdrawing and donating effect of
the groups substituted at the aryl halide, exerted no obvious
influence on the C-N coupling with imidazole. The aryl halides
with electron-donating groups, e.g., 4-OMe (5b), 4-Me (5c), 4-
OEt (5d) gave the corresponding products in good yields.
When electron-withdrawing groups, e.g., 4-Cl (5e), 4-F (5f), 4-
Ac (5h), were located in the aryl ring, the corresponding yields
did not drop significantly (64%-86%). Because of the steric
hindrance, the ortho-substituents such as 2-OMe (5j), 2-Me
(
5k), led to poor yields. Moreover, the coupling with various
nucleophiles including several heterocycles, e.g. pyrrolidine
5l), n-butylamine (5m), 2-pyrrolidinone (5n), 4-methyl-1H-
(
imidazole (5o), and 1H-benzoimidazole (5p) proceeded
successfully, with moderate to good yields. Finally, to test the
Figure 4. Proposed reaction mechanism.
Further study focused on expanding the substrate scope to
reveal the generality of this protocol. More attention was paid
on different functional groups, steric and electronic effects.
Associated details are summarized in Table 2. Electron
Table 3. Substrate scope of Ullman C-N couplings in ALA14
a
aqueous solution
R1
R2
Surfactant/H2O(0.01M)
R1
R2
Ar
X
+
HN
Ar
N
CuI, Cs2CO3
Air,100 oC,12h
1
4
5
Table 2. Substrate scope of Ullman C-S couplings in ALA14
aqueous solution
a
N
N
N
N
N
N
N
N
N
N
O
X
+
-
O
S
MeO
EtO
Cl
S
Surfactant/H2O (0.01M)
R2 CuI,100 oC, air,12 h
Me
R1
Na O
5a,
X=I, 90%
R1
R2
5b, X=I, 80%
b, X=Br, 56%
5c, X=I, 88%
5d, X=I, 65%
5e, X=I, 85%
O
5a, X=Br, 88%
a, X=Cl, 0%
5
5
1
2
3
N
N
N
N
N
N
N
OMe
N
N
N
O
O
O
O
O
O
S
S
S
F
F3CO
Ac
O2N
5h, X=I, 64%
5i, X=I, 15%
5j, X=I, 10%
MeO
Me
5f, X=I, 86%
5g, X=I, 40%
3
3
3
a, X=I, 90%
a, X=Br, 85%
a, X=Cl, 0%
3c, R1=4-Me, X=I, 95%
3
b, R1=4-OMe, X=I, 85%
3c, R =4-Me, X=I, 85%
2
N
O
N
3b, R1=4-OMe, X=Br, 80%
N
H
N
3c, R =4-Me, X=Br, 70%
2
Me
N
N
N
n-Butyl
O
O
O
O
S
O
O
MeO
5l, X=I, 74%
MeO
MeO
5o, X=I, 80%
S
MeO
S
5
m, X=I, 31%
5n, X=I, 48%
5k, X=I, trace
Cl
O2N
3f, R1=4-NO2, X=I, 30%
Ac
3
3
3
d, R1=4-Cl, X=I, 78%
d, R2=4-Cl, X=I, 60%
d, R2=4-Cl, X=Br, 75%
N
3e, R1=4-Ac, X=I, 40%
Cl
N
N
N
O2N
NC
N
MeO
O
O
O
O
O
O
O
Me
O
S
O
2
O N
S
S
5p, X=I, 85%
5q, X=I, 75%
5r, X=I, 64%
5s, X=I, 40%
F3C
3i, R1=4-CF3, X=I, 20%
N
N
N
3g, R1=2-Me, X=I, 55%
3h, R1=3-NO2, X=I, 45%
Br
N
O
O
O
O
a
5t, X=I, 70%
5u, X=I, 35%
5v, X=I, 31%
5w, X=I, 30%
Reaction conditions: 1 (1.0mmol), 2 (1.2 mmol), CuI (0.1 mmol) and
o
surfactant ALA14 (0.1 mmol) in water (10 ml) under air at 100 C for
2 h.
a
1
Reaction conditions: 1 (1.0 mmol), 4 (1.2 mmol), CuI (0.1 mmol),
Cs CO (2.0 mmol), surfactant ALA14 (0.1 mmol), water (10 ml), 100
C, 12 h.
2
3
o
4
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scope of this procedure, this in-water catalytic system was assembles to form a micellar nanoreactor wVitiehw AdrtiicflfeeOrnelinnet
applied to various indole derivatives. Interestingly, the C-N binding sites, i.e., (i) hydrophilic lactoseDpOaI:rt10i.s10r3e9s/pCo9nGsCi0b0le96f4oGr
reaction of 4-methoxyiodobenzene with unsubstituted indole chelating the copper catalyst, acting as a ligand, (ii) the
only gave 35% yield. Notably, when indoles possess electron- lipophilic part traps the oil-soluble substrate to concentrate it
2
withdrawing groups including NO (5q), CN (5r), Cl (5s) and Br in the center of the micelle. It can successfully promote the
(5t), the yields were obviously higher than the unsubstituted Ullmann C-X coupling reaction in water. The substrate
indoles. In contrast, indoles with electron-donating applicability of the micellar catalysis in water is expanded and
substituents 3-methylindole (5v) and 4-methylindole (5w) a moderate to excellent yields of C-X coupling reaction were
afforded the coupling products in low yields.
obtained. The nature of micelle formed by sugar-based
Finally, as a further advantage of ALA14 micellar catalysis, surfactant was investigated by CMC, DLS, and TEM. The
ALA/water system can be easily reused. Thus, during the encapsulating and aggregation of the substrate in micelle were
reaction, the mixtures in ALA14/water formed a stable and clarified and the enrichment position of the substrate was
1
slight yellow dispersion (Figure 5a). Once the reaction was revealed by HNMR to be in the lipophilic alkyl chain. The
finished and cooled down, the ALA began to precipitate as possible micellar catalytic reaction mechanism was deduced.
Most notably, the water and ALA14 are able to be recycled.
This strategy is proven to be green, simple, and sustainable.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are grateful for the financial support from the
Natural Science Foundation of China (21606104) and the
National Key Research and Development Program of China
(2016YFB0301800).
Notes and references
1
6
2
1
3
9
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Figure 5. Appearance of C-S coupling reaction in ALA14/water
a) during the reaction and (b) after cooling and extracting with
ethyl acetate, (c) Recycling and reuse of ALA14/water.
(
22.
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ALA/water was studied in the above Ullmann C-S reaction. The
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Figure 5c. It was obvious that the ALA/water still had excellent
performance for C-S coupling reaction after being reused for
five times.
8
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1
In summary, a newly bi-functional sugar-based surfactant,
ALA14, was designed to act as a ligand and provide a micellar
environment for aggregation of substrates. The alkyl
lactosamine ALA14 is easily synthesized and naturally
degradable, which is made up of the hydrophobic part of the
molecule based on long-chain alkyl and the hydrophilic portion
based on lactose. The nonionic surfactant ALA14 self-
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DOI: 10.1039/C9GC00964G
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