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Unsymmetrical PEG-substituted
tris(triazolyl)amines as bi-functional surfactants
Cite this: New J. Chem., 2022,
46, 6009 for copper-catalyzed aerobic oxidation of
alcohols in water†
Vasut Nakarajouyphon,a Thanthapatra Bunchuay, a Nobuto Yoshinari, b

Takumi Konno b and Preeyanuch Sangtrirutnugul *a

Amphiphilic tris(triazolyl)amines functionalized with poly(ethylene glycol) 1-(1-R-1H-1,2,3-triazol-4-yl)-

Received 8th October 2021,
Accepted 16th February 2022
DOI: 10.1039/d1nj04812k
rsc.li/njc
N,N-bis((1-benzy-1H-1,2,3-triazol-4-yl)methyl)methanamine [R = PEG200 (NBBT200-OH), mPEG550
(NBBT550), and mPEG2000 (NBBT2000)] were investigated as bi-functional surfactants serving as N
donor ligands and surfactants for copper-catalyzed aerobic alcohol oxidation in water. The catalyst
system CuBr/NMI/TEMPO/NBBTn (NMI = N-methylimidazole; TEMPO = 2,2,6,6-tetramethylpiperidine 1-
oxyl, n = 200-OH, 550, 2000) shows oxidation activity toward 4-methoxybenzyl alcohol following the
trend: NBBT550 4 NBBT2000 4 NBBT200-OH. Although UV-Vis spectrophotometric titrations suggest
large binding constants between Cu2+ and NBBT550 in water (K11 = 2.5  104 M1 and K21 = 6.3 
103 M1), flame atomic absorption spectroscopy (FAAS) reveals ca. 35 ppm of Cu ions from the catalyst
system leaching into the EtOAc extract. As a result, in the reusability study, additional 5 mol% CuBr was
added to the reaction mixture before the fourth catalytic run to achieve high conversions to the
oxidized product for at least six catalytic cycles.

Introduction capable of promoting aerobic alcohol oxidation in water have

Copper catalyst systems inspired by copper-containing oxidase
enzymes have been shown to efficiently promote aerobic
alcohol oxidation under mild conditions.1–4 Semmelhack and
co-workers first reported the use of O2 as an oxidant in
the catalyst system CuCl/TEMPO/DMF (TEMPO = 2,2,6,6-
tetramethylpiperidinyl-1-oxyl, DMF = N,N-dimethylformamide)
to oxidize primary alcohols to aldehydes under atmospheric
pressure.5 Subsequently, Sheldon,6 Koskinen,7 and Stahl8
incorporated 2,2 0 -bipyridine as the ligand and bases including
KOtBu, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and NMI
(N-methylimidazole) to improve copper-catalyzed alcohol oxi-
dation under O2 or ambient air in CH3CN. These catalytic
conditions involve organic solvents, which better dissolve
organic substrates and possess higher oxygen solubility than
the more environmentally friendly solvents such as water.9 On
the other hand, only a handful of copper catalyst systems
a
Center of Excellence for Innovation in Chemistry (PERCH-CIC), Department of
Chemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
E-mail: preeyanuch.san@mahidol.edu
b
Department of Chemistry, Graduate School of Science, Osaka University,
Toyonaka, Osaka 560-0043, Japan
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1nj04812k
been reported and they usually require high temperatures and/
or long reaction times to achieve quantitative yields, while
catalyst reuse also poses a challenge (Table 1).2,10–16
A promising strategy to improve catalytic oxidation perfor-
mances and reusability is to employ surfactants, which sponta-
neously self-aggregate in water to provide a micellar
environment where catalytic reactions can take place within
the hydrophobic area.17,18 A notable example includes Lip-
shutz’s surfactant, TPGS-750-M,19 constructed from hydrophi-
lic poly(ethylene glycol) (mPEG-750), a succinic acid linker, and
lipophilic a-tocopherol (i.e., vitamin E), which efficiently facil-
itates copper-catalyzed aerobic alcohol oxidation in water under
mild conditions and can be reused.20 Rodionov and co-workers
also synthesized multifunctional surfactants consisting of TEMPO,
chelate N-based copper binding sites, and a fluorous hydrophobic
‘‘tail’’.21 They have found that, in the presence of catalytic amounts
of CuSO4 and DMAP (4-dimethylaminopyridine) base in air, this
micellar catalyst system oxidized benzyl alcohol to benzaldehyde in
93% yield in water at room temperature after 1 h.21 However, no
catalyst reuse has been reported for this system.
Despite generally strong interactions between metal ions
and nitrogen donors, it is surprising that few examples of
nitrogen-based amphiphiles for metal-catalyzed reactions in
water have been reported.22 Van Hest and colleagues

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Table 1 Copper catalyst systems for aerobic oxidation of benzyl alcohol in water
Paper

Catalyst Temp (1C) Time (h) % conversion Reusability study References

5 mol% Cu(OAc)2H2O/5 mol% pytl-b-CD/100 mol% Na2CO3 100 10 94 Yes (6 cycles) 10
5 mol% CuCl/10 mol% DMAP RT 5 499 — 11
5 mol% (m-Cl)2[Cu(bzmd)2Cl]2 RT 10 499 — 12
1 mol% CuCl(tpy)(m-Cl)CuCl/5 mol% DMAP RT 5 499 — 13
5 mol% (m-Cl)2[Cu(Hpyet)Cl]2/Cu0/10 mol% Na2CO3 RT 16 93 — 2
5 mol% CuI/7.9 mol% NH3H2O 100 18 100 — 14
5 mol% Cu(OTf)2/2.5 mol% PEG–PyTa/20 mol% K2CO3 RT 18 99 Yes (7 cycles) 15
2.5 mol% CuSO4/2.5 mol% TEMPO–SO4H/25 mol% DMAP 30 24 100 Yes (22% conv, 2nd cycle) 16

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Fig. 1 Structures of tris(triazolylmethyl)amine (TTA), tris(triazole)–polyethylene glycol (tris-trz–PEG), and unsymmetrical PEG-functionalized
tris(triazolylmethyl)amine.

immobilized a chiral Cu(II)–alkynylbis(oxazoline) catalyst to the
hydrophobic portion of the poly(ethylene glycol)-b-poly(styrene-
co-4-vinylbenzyl azide) polymer via copper-catalyzed azide–
alkyne cycloaddition (CuAAC).23 It was found that the resulting
polymeric vesicles containing Cu-bis(oxazoline) catalysts effi-
ciently catalyzed asymmetric cyclopropanation of styrene deri-
vatives and ethyl diazoacetate in water. In another example,
Uozumi and co-workers demonstrated that the amphiphilic
platinum NCN–pincer complex self-assembled in aqueous sol-
vent to produce vesicles capable of catalyzing alkynoic acid
cyclization as well as alkene hydrosilylation in water.24,25
Due to their large copper binding constants,26
tris(triazolylmethyl)amines (TTA; Fig. 1) have widely been
used as ligands in CuAAC27 and copper-catalyzed atom transfer
radical polymerization.28 The related amphiphilic tris(triazole)–
polyethylene glycol (tris-trz–PEG) has been shown to stabilize
metal nanoparticles and facilitate various catalytic reactions
including CuNP-catalyzed azide–alkyne cycloaddition, PdNP-
catalyzed Suzuki–Miyaura cross coupling, and RuNP-catalyzed
transfer hydrogenation of nitrobenzene.29 Based on these cat-
alytic applications, this work reports the synthesis of unsym-
metrical amphiphilic tris(triazolyl)amines featuring varying
PEG chain lengths (Fig. 1). Consequently, their efficiency as
bi-functional surfactants containing N-based binding sites for
copper-catalyzed aerobic oxidation of activated alcohols in
water was investigated and discussed as a function of PEG
chain length.
Experimental section
Materials
Air-sensitive experiments were carried out under a dry N2
atmosphere using standard Schlenk techniques. All chemicals
were used as received from commercial sources. Benzyl azide
was prepared according to the previously reported method,30
while the synthesis of the azido-poly(ethylene) glycol substrates
(i.e., PEG200-N3, mPEG550-N3, and mPEG2000-N3),31 (1-benzyl-
1H-1,2,3-triazol-4-yl)methanol (1),32 1-benzyl-1H-1,2,3-triazole-
4-carbaldehyde (2),33 and N,N-bis((1-benzyl-1H-1,2,3-triazol-4-
yl)methyl)prop-2-yn-1-amine (3)34 followed the literature
methods with slight modifications (see ESI† for details). Unless
otherwise noted, all solvents were of analytical grade. Anhy-
drous CH2Cl2 was purified from INERT PureSolv MD5. Water
was purified by Milli-Q and has a resistivity of 18 MO cm1.
Characterization
Nuclear magnetic resonance spectra were acquired using a
400 MHz Bruker Avance spectrometer for 1H (400 MHz) and
13
C{1H} (100 MHz) nuclei. Chemical shifts are reported in d
units (parts per million) using residual solvent signals as
references. Fourier transform infrared spectroscopy (FTIR)
(400–4000 cm1) was performed on a Bruker Alpha instrument
(Bruker Optics GmbH, Ettlingen, Germany). Percent substrate
conversions obtained from catalytic experiments were analyzed
on a GC6890N Agilent Technology gas chromatograph
equipped with a 5973N mass selective detector. High-
resolution mass spectra were acquired from a Bruker Data
Analysis Esquire-LC mass spectrometer (ESI mode). Matrix-
assisted laser desorption/ionization time-of-flight mass spectra
were recorded on a Bruker autoflex speed MALDI-TOF (Bruker,
Germany) using polymer analysis mode. A Shimadzu UV-2600
UV-Vis spectrophotometer was used to record the absorption
spectra. Fluorescence emission spectra of pyrene probes were
collected on a FluoroMax 4+ Horiba spectrofluorometer at 25 1C
using an excitation wavelength of 333 nm, with the excitation
and emission slit width of 1.5 nm. Dynamic light scattering
(DLS) was measured at 25 1C using the Zetasizer Nanoseries
model S4700 (Malvern Instruments Corporation) laser light
scattering system under the conditions of a He–Ne laser
(l = 632.8 nm). Copper leaching during catalytic alcohol oxida-
tion was determined using flame atomic absorption spectro-
metry (FAAS) (PerkinElmer PinAAcle 900T). TEM images of
negatively stained surfactants were recorded on a JEOL JEM-
ARM200F (JEOL Co., Ltd. Tokyo, Japan) operated at 200 kV
using phosphotungstic acid as a staining agent.
UV-Vis spectrophotometric titration
The 2.0 mL aqueous solution of NBBT550 (1.0  104 M) in a
1 cm quartz cell was directly titrated by successive additions of
aqueous solutions of CuBr2 (1.0  102 M) mixed with
NBBT550 (1.0  104 M). The UV-Vis spectra were recorded at
0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0,

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Paper
6.0, 7.0, 8.0, 9.0, and 10.0 equivalents of Cu ions. Based on the
absorption data at the wavelength 300 nm, binding constants
were determined using the BindFit program.35–37
General procedure for the synthesis of NBBT200-OH, NBBT550,
and NBBT2000
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Under N2, to a 40 mL CH2Cl2 solution of 3 (0.20 g, 0.50 mmol)
and azide-functionalized poly(ethylene glycol) (0.52 mmol) was
added CuI (19 mg, 0.10 mmol) and NEt3 (0.20 mL, 2.5 mmol).
The reaction mixture was refluxed for 2 d, after which 40 mL of
10% NH4OH solution containing ethylenediaminetetraacetic
acid (EDTA, 0.58 g, 2.0 mmol) was added. After 3 h of vigorous
stirring, the aqueous phase was extracted with 3  30 mL of
CH2Cl2. The organic layer was collected and dried with anhy-
drous Na2SO4. Filtration and solvent evaporation followed by
diethyl ether wash afforded the desired product in good yields.
1-(1-PEG200-1H-1,2,3-Triazol-4-yl)-N,N-bis((1-benzy-1H-1,2,3-tri-
azol-4-yl)methyl)methanamine (NBBT200-OH). Yellow oil (0.28 g,
0.45 mmol, 90% yield). 1H NMR (400 MHz, CDCl3) d 8.01 (s, 1H,
H–triazole–PEG200), 7.81 (s, 2H, H–triazole–benzyl), 7.36–7.26
(m, 10H, Ar–H), 5.52 (s, 4H, Ar–CH2–N), 4.54 (t J = 5.1 Hz, 2H,
triazole–CH2–CH2–O), 3.87 (t J = 5.1 Hz, 2H, triazole–CH2–
CH2–O), 3.79 (s, 6H, triazole–CH2–N), 3.71 (m, 2H, triazole–
CH2CH2–O–CH2–), 3.60 (s, 10H, O–CH2–CH2–O). 13C{1H} NMR
(100 MHz, CDCl3) d 134.8, 129.2, 128.8, 128.2, 124,6 72.7, 70.7,
70.6, 70.4, 69.6, 61.7, 54.3, 50.4, 47.4, 47.0. HRMS (m/z): calcd for
C31H40N10O4 [M + Na]+ 639.3132, found 639.3138.
1-(1-mPEG550-1H-1,2,3-Triazol-4-yl)-N,N-bis((1-benzy-1H-1,2,3-
triazol-4-yl)methyl)metha-namine (NBBT550). Yellow oil (0.55 g,
0.50 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) d 7.91
(s, 1H, H–triazole–mPEG550), 7.76 (s, 2H, H–triazole–benzyl),
7.36–7.26 (m, 10H, Ar–H), 5.52 (s, 4H, Ar–CH2–N), 4.52 (t J =
5.2 Hz, 2H, triazole–CH2–CH2–O), 3.86 (t J = 5.2 Hz, 2H, triazole–
CH2–CH2–O), 3.77 (s, 4H, triazole–CH2–N), 3.64 (s, O–CH2–
CH2–O), 3.37 (s, 3H, O–CH3). 13C{1H} NMR (100 MHz, CDCl3)
d 134.7, 129.2, 128.8, 128.1, 126.1, 125.1, 72.0, 70.6, 69.4, 59.1,
54.4, 50.4, 46.9. HRMS (m/z): calcd for C52H82N10O14 [M + Na]+
1093.5910, found 1093.5892.
1-(1-mPEG2000-1H-1,2,3-Triazol-4-yl)-N,N-bis((1-benzy-1H-1,2,3-
triazol-4-yl)methyl)methanamine (NBBT2000). An off-white solid
(1.2 g, 0.47 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) d 7.88
(s, 1H, H–triazole–mPEG2000), 7.73 (s, 2H, H–triazole–benzyl),
7.33–7.24 (m, 10H, Ar–H), 5.50 (s, 4H, Ar–CH2–N), 4.51 (t J =
5.2 Hz, 2H, triazole–CH2–CH2–O), 3.85 (t J = 5.2 Hz, 2H, triazole–
CH2–CH2–O), 3.73 (s, 6H, triazole–CH2–N), 3.62 (m, O–CH2–
CH2–O), 3.36 (s, 3H, O–CH3). 13C{1H} NMR (100 MHz, CDCl3)
d 134.8, 129.2, 128.8, 128.1, 125.2, 124.2, 72.0, 70.6, 69.5, 59.1,
54.2, 50.3, 47.3, 47.1. MALDI-TOF-MS (m/z): calcd for
C112H205N10O45 [NBBT2000 + H2O + H]+ 2410.406, found
2410.229.
General procedure for aerobic alcohol oxidation
To a 10 mL glass vial equipped with a stir bar was added a
surfactant (0.025 mmol) or a ligand (0.025 mmol), followed by
alcohol (0.50 mmol) and CuBr (3.6 mg, 0.025 mmol, 5 mol%).
An aqueous solution of TEMPO (3.9 mg, 0.025 mmol, 5 mol%)
6012 | New J. Chem., 2022, 46, 6009–6017 This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2022
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and NMI (3.98 mL, 0.050 mmol, 10 mol%) in 0.5 mL water was
subsequently added and the reaction mixture was vigorously
stirred. After a given time, 0.050 mmol anisole was added as an
internal standard and the product was extracted using ca. 2 mL
of EtOAc. Then, the filtrate was filtered through a 0.45 mm
nylon membrane syringe filter and was subjected to GC-MS
analysis.
Reusability study
The reaction mixture consisting of NBBT550 (0.050 mmol), 4-
methoxybenzyl alcohol (124 mL, 1.00 mmol), CuBr (7.2 mg,
0.050 mmol), TEMPO (7.8 mg, 0.050 mmol), and NMI (8.0 mL,
0.10 mmol) was left stirring in H2O (1.0 mL) at room tempera-
ture. After 4 h, the product was extracted with 4 mL of EtOAc
and subjected to GC-MS analysis with the anisole standard. The
remaining aqueous solution was bubbled with N2 for 5 min to
remove volatiles, after which the same amounts of 4-
methoxybenzyl alcohol (1.00 mmol), TEMPO (0.050 mmol),
and NMI (0.10 mmol) were added to initiate the subsequent
catalytic run. At the beginning of the fourth catalytic cycle, to
the aqueous solution, CuBr (7.2 mg, 0.050 mmol) was also
added in addition to 4-methoxybenzyl alcohol (1.00 mmol),
TEMPO (0.050 mmol), and NMI (0.10 mmol).
Results and discussion
Unsymmetrical PEG-functionalized tris(triazolylmethyl)amines
A series of chelate amine–triazole ligands containing hydro-
philic poly(ethylene glycol) (PEG) with different chain lengths
was synthesized via multi-step synthesis (Scheme 1). First,
oxidation of (1-benzyl-1H-1,2,3-triazol-4-yl)methanol (1) by
excess MnO2 afforded the aldehyde product 2. Subsequent
reaction between two equiv. of 2 and propargylamine
followed by reduction with Na[BH(OAc)3] in CH2Cl2 produced
the N,N-bis((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)prop-2-yn-1-
amine compound 3 as a white solid in 74% yield. Finally,
CuAAC between the hydrophobic compound 3 and the hydro-
philic azido poly(ethylene glycol) with different chain lengths
(i.e., PEG200-N3, mPEG550-N3, and mPEG2000-N3) using the CuI/
NEt3 catalyst system at room temperature afforded the corres-
ponding amphiphilic tris(triazolylmethyl)amine NBBT200-OH,
NBBT550, and NBBT2000 in high yields after 48 h. It should be
mentioned that the choice of poly(ethylene glycol) substrate was
based on commercial availability and low cost. For the CuAAC
reactions, both the PEG diol and the monomethylated analogues
showed no significant differences in terms of their synthesis and
product yields.
FT-IR spectra of the click products reveal the disappearance
of a strong absorption band at ca. 2100 cm1 of n(N3), suggest-
ing complete CuAAC reactions (Fig. S10–S12, ESI†). Further-
more, 1H NMR spectra of these compounds display two distinct
singlet peaks in the aromatic region (8.0–7.7 ppm) assignable to
trzH containing the PEG and benzyl substituents in a 1 : 2 ratio,
respectively. The mass analysis results are also consistent with
the proposed structures (Fig. S13 and S14, ESI†). Due to a
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Scheme 1 Synthetic pathway for NBBT200-OH, NBBT550, and NBBT2000.

shorter PEG chain and the lower hydrophilic lipophilic balance

(HLB) of 6, NBBT200-OH possesses higher lipophilic component
and, as a result, has low solubility in water compared to NBBT550
and NBBT2000 with the HLB values of 10 and 16, respectively.
To investigate the self-assembly of NBBT550 and NBBT2000
in an aqueous solution, critical micelle concentrations (CMCs)
were determined using fluorescence spectroscopy with pyrene
as an organic probe, resulting in CMC values of 2.16 and
1.28 mM, respectively (Table 2). In an attempt to visualize the
aggregate structures of NBBT550 and NBBT2000, we carried out
transmission electron microscopy (TEM) analysis using negatively Fig. 2 TEM images of negatively stained surfactants by 1% phosphotungs-
stained surfactant samples. TEM images illustrate uniform micelle tic acid. (A) NBBT550, and (B) NBBT2000.
structures with average diameters of ca. 20 nm for both surfactants
(Fig. 2). However, it is important to note that TEM analysis involves
a slow drying step (i.e., water evaporation) of the samples, which data, NBBT2000 features a unimodal distribution of particle
leads to particle shrinkage.38 Thus, the TEM images of NBBT550 sizes while NBBT550 resulted in a bimodal distribution with a
and NBBT2000 shown in Fig. 2 do not reflect the actual size of the major fraction of particles (ca. 70%) having particle sizes in the
self-assembled surfactants in water. range of 300–800 nm (Fig. S15, ESI†). The smaller fraction
Subsequently, the hydrodynamic particle sizes of NBBT550 reveals the average size of 1.8 nm, which can be assigned to
and NBBT2000 in an aqueous solution were obtained using individual molecules. Based on TEM images of negatively stained
dynamic light scattering (DLS) experiments. The results have surfactants which reveal spherical shape morphology (Fig. 2) and
shown that on average 5 mM of NBBT550 and NBBT2000 in large average hydrodynamic sizes (i.e., 480 and 270 nm), we propose
water generate particles with average sizes of ca. 480 nm and that NBBT550 and NBBT2000 self-assemble in water to form large
270 nm, respectively (Table 2). Notably, according to the DLS spherical particles, most likely vesicles with bilayer structures.
Furthermore, our finding that the particle sizes decrease accompa-
nying larger surfactant molecular weights is in line with previous
Table 2 Critical micelle concentration and average diameter of the reports by Lipshutz’s group. In particular, TPGS with longer PEG
surfactants in water chains whose masses were represented by numbers in abbreviations
lead to smaller average surfactant diameters in water, following the
Critical micelle concentrationa Average diameterb
Surfactant (mM) (nm)
trend: TPGS-550-M (65 nm) 4 TPGS-750-M (53 nm) 4 TPGS-1000
(13 nm).19
NBBT550 2.16 480
NBBT2000 1.28 270
TPGS-750-M ca. 0.139 5319
Catalytic study toward Cu-catalyzed aerobic oxidation of
a
Determined by fluorescence spectroscopy using pyrene as an organic alcohol in water
probe. b Determined by dynamic light scattering (DLS) using 5.0 mM
concentration of NBBT-500 and NBBT-2000. The reported diameters are Given that amine–triazole moieties have been efficiently used
the averaged results from three measurements. in various metal-promoted catalyses,27,28 the triazole-based

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compounds NBBT200-OH, NBBT550, and NBBT2000 were Table 3 Control study for aerobic alcohol oxidationa
investigated as bi-functional surfactants and ligands for
copper-catalyzed alcohol oxidation in water. 4-Methoxybenzyl
alcohol was used as a model substrate catalyzed by 5 mol%
CuBr, 5 mol% of surfactants, 5 mol% of TEMPO, and 10 mol%
of NMI in 0.5 mL water at room temperature. The catalyst
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systems containing the surfactants NBBT550 and NBBT2000 Entry Additive Time (h) Conversionb (%)
showed comparable oxidation activities with 37% and 39% 1 — 2 60
conversions to 4-methoxybenzaldehyde, respectively, at 0.5 h. 2 TBTA 2 59
3 bpy 2 90
On the other hand, the ligand NBBT200-OH, afforded a lower 4 bpy/mPEG-550 2 88
conversion of 28% under the same conditions (Fig. 3). After 2 h, 5 NBBT-550 2 94
catalyst systems with NBBT550 gave the highest alcohol con- 6 bpy/TPGS-750-Mc 4 10020
version of 94% followed by NBBT2000 (88%) and NBBT200-OH a
Reaction conditions: 4-methoxybenzyl alcohol (0.5 mmol), CuBr
(84%). Quantitative conversions to 4-methoxybenzaldehyde (0.025 mmol), additive(s) (0.025 mmol), TEMPO (0.025 mmol), NMI
(0.05 mmol) in water (0.5 mL), room temperature with 0.05 mmol
with 100% selectivity were obtained at 3 h for all surfactants. anisole as internal standard. b Calculated from GC results, average of
In a control study, without a surfactant and ligand/additive, two runs (entries 1–5). c 2 wt% TPGS-750-M.
only 60% of 4-methoxybenzyl alcohol was converted to the
oxidized product after 2 h (entry 1, Table 3). The structurally
remaining aqueous solution to initiate the second catalytic
related ligand tris(benzyltriazolylmethyl)amine (TBTA) did not
run. It was found that only the catalyst system featuring the
improve the catalytic activity of copper ions (entry 2) and
bi-functional surfactant NBBT550 provided high conversions
precipitation of the copper complexes as a green solid, probably
(86–100%) for at least six catalytic runs with an addition of
the CuII–TBTA complex, was also observed.40 On the other
5 mol% CuBr to the fourth run (Fig. 4). On the contrary, catalyst
hand, the catalyst systems CuBr/bpy (bpy = 2,2-bipyridine)
systems containing bpy and bpy/mPEG-550 showed an appar-
and CuBr/bpy/mPEG550 afforded high alcohol conversions of
ent decrease in oxidation activity, giving ca. 60–70% conver-
90% and 88%, respectively, comparable to that of CuBr/
sions in the third catalytic cycle. The reduced conversions are
NBBT550 (entries 3–5). Notably, under similar conditions, the
attributed to a loss of Cu species and bpy ligands during the
catalyst system CuBr/TEMPO/NMI with 2 wt% of the surfactant
product extraction step. Thus, the reusability study underlines
TPGS-750-M oxidized 4-methoxybenzyl alcohol to the corres-
the importance of the bi-functional surfactant, which allows
ponding aldehyde in a quantitative yield at 4 h (entry 6).20
the catalytic reactions to take place in the hydrophobic areas of
Based on their high activities (entries 3–5, Table 3), three
vesicles while impeding a catalyst loss during the work-up
catalyst systems CuBr/TEMPO/NMI with the following addi-
tives: NBBT550; bpy; and bpy/mPEG-550 were investigated in
the reusability study. In particular, after 4 h of the first catalytic
reaction, the product was extracted by EtOAc, after which the
alcohol substrate, TEMPO, and NMI were added to the

Fig. 4 Reusability study of the catalyst CuBr/TEMPO/NMI with additive(s).

Fig. 3 Kinetic profiles of NBBT200-OH (’), NBBT550 (K), and
NBBT2000 (E) for Cu-catalyzed aerobic oxidation of 4-methoxybenzyl
alcohol in water. Results were from an average of two runs.
Reaction conditions: 4-methoxybenzyl alcohol (1.0 mmol), CuBr
(0.05 mmol), TEMPO (0.05 mmol), NMI (0.1 mmol) in water (1.0 mL), room
temperature, 4 h, with 0.1 mmol anisole as internal standard. Black: with
NBBT550 (0.05 mmol); grey: with 2,2 0 -bipyridine (0.05 mmol); white: with
2,2 0 -bipyridine (0.05 mmol) and mPEG550 (0.05 mmol). ** Addition of
5 mol% CuBr to the fourth run.

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Table 4 Substrate scope studya
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Entry Aldehyde Time (h) Conversionb (%)
1 4 100
2 4 100
3 4 100
4 4 94
5 4 95
6 4 84
7 4 100
8 4 50
a
Reaction conditions: alcohol substrate (0.5 mmol), CuBr (0.025 mmol),
NBBT550 (0.025 mmol), TEMPO (0.025 mmol), NMI (0.05 mmol) in
water (0.5 mL), room temperature with 0.05 mmol anisole as internal
standard. b % Conversion calculated from GC results.
procedure. To confirm strong binding between Cu ions and the
triazole-based surfactant in water, UV-Vis spectrophotometric
titrations between the water-soluble CuBr2 and NBBT550 were
performed in aqueous solutions. Absorption data collected at
300 nm were analyzed using the BindFit program,35–37 which
suggests a 2 : 1 stoichiometric ratio of NBBT550:CuBr2 with
strong interactions in water, as evidenced by the relatively large
binding constants of K11 = 2.5  104 M1 and K21 = 6.3 
103 M1 (Fig. S2, S3 and Table S2, ESI†). It should be noted that
the binding constant of 5.1  107 M1 was previously reported
for TBTA–Cu2+ in CH3CN.26
However, even in the presence of NBBT550, the loss of Cu
species still affected the catalytic performance of CuBr/TEMPO/
NMI/NBBT550 after three catalytic cycles, at which point an
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addition of 5 mol% CuBr was required to achieve quantitative
conversions in subsequent runs. Consistent with these results,
FAAS reveals 35 ppm of Cu species leached into the EtOAc
extracts on average for each catalytic reaction from the first
three catalytic runs (Table S1, ESI†). In comparison, a similar
loss in activity was also observed with the catalyst system CuBr/
bpy/TEMPO/NMI with 2 wt% TPGS-750-M as 5 mol% of CuBr
must be added to the third catalytic run to maintain efficient
alcohol oxidation.20
Other alcohol substrates were also explored using the
catalyst system CuBr/TEMPO/NMI/NBBT550 in water
(Table 4). It appears that our catalyst system was able to
efficiently catalyze aerobic oxidation of benzyl alcohol deriva-
tives containing both electron-donating (i.e., OMe) and
electron-withdrawing groups (i.e., NO2, Cl, Br), which are often
more difficult to oxidize, as well as cinnamyl and furfuryl
alcohols in water affording high conversions at 4 h. Steric
hindrance at the ortho-position of the phenyl ring (i.e., 2-
methoxy- and 2-nitrobenzyl alcohols) also did not negatively
impact the catalytic activities. The 4-hydroxybenzyl alcohol
substrate, however, resulted in only 50% conversion, possibly
due to a reaction between Cu and phenol or the property of
phenolic compounds as antioxidants.41 Furthermore, the unac-
tivated 11 and 21 aliphatic alcohol substrates including 1-
hexanol, 2-methyl-1-pentanol, and cyclohexanol did not yield
the oxidized products under these catalytic conditions based on
GC-MS. Overall, CuBr/TEMPO/NMI in the presence of the
triazole-based surfactant NBBT550 exhibits higher catalytic
oxidation activities toward activated alcohols in water under
mild conditions with good reusability, compared with those of
previously reported copper catalyst systems (Table 1).
Conclusions
We have demonstrated a new synthetic protocol for unsymme-
trical, amphiphilic PEG-substituted triazole-based compounds
NBBT200-OH, NBBT550, and NBBT2000, which are bifunc-
tional, potentially serving both as chelate ligands for Cu ions
and as surfactants to facilitate copper-catalyzed aerobic alcohol
oxidation in water without the need for additional ligands. Only
the NBBT550 and NBBT2000 surfactants with longer
poly(ethylene glycol) chains and HLB values 4 10 are soluble
in water and form vesicles with average diameters of ca. 480
and 270 nm, respectively, based on DLS and negatively stained
TEM. Among all three surfactants, CuBr/TEMPO/NMI in the
presence of NBBT550 was the most active catalyst system
toward aerobic oxidation of 4-methoxybenzyl alcohol in water.
Although UV-Vis spectrophotometric titrations between CuBr2
and NBBT550 reveal strong Cu2+–surfactant binding, dissocia-
tion of Cu ions from the catalyst system was still evident,
according to FAAS. As a result, addition of 5 mol% CuBr to
the reaction mixture before the fourth catalytic cycle was
needed to achieve high conversions for at least six runs. To
improve the efficiency and reusability for this type of catalyst–
surfactant system, ligand structure modification to enhance
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metal binding in water as well as investigation of other triazole-
containing surfactants such as cationic PEG-substituted tri-
azole–ammonium compounds are ongoing.
Conflicts of interest
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There are no conflicts to declare.
Acknowledgements
Financial support provided by the National Research Council of
Thailand (Grant No. NRCT5-RSA63015-21) and the Royal
Golden Jubilee PhD Programme (Grant No. PHD/0220/2557
for V. N.) is gratefully acknowledged. The authors also appreci-
ate support from Faculty of Science, Mahidol University and
Mahidol University under the National Research Universities
Initiatives; Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Ministry of Higher Education, Science, Research
and Innovation; as well as the CIF Grant.
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