Total synthesis of high loading capacity PEG-based supports: Evaluation and improvement of the process by use of ultrafiltration and PEG as a solvent

Article abstract of DOI:10.1039/c3gc37097f

The present work deals with the total synthesis of high loading capacity PEG supports with attention focused on improving the greenness of all the steps. The systematic calculation of green metrics offers an opportunity to evaluate the greenness and then to improve the process. To evidence such an improvement, the evaluation of the optimized processes was compared with that of the classical ones.

Full text of DOI:10.1039/c3gc37097f

Green Chemistry
View Article Online
View Journal | View Issue
PAPER
Total synthesis of high loading capacity PEG-based
supports: evaluation and improvement of the process
by use of ultrafiltration and PEG as a solvent†
Cite this: Green Chem., 2013, 15, 1016
Raphaël Turgis,a Isabelle Billault,a Samir Acherar,a Jacques Augé*b and
Marie-Christine Scherrmann*a
Received 21st December 2012,
Accepted 5th February 2013
The present work deals with the total synthesis of high loading capacity PEG supports with attention
focused on improving the greenness of all the steps. The systematic calculation of green metrics offers an
opportunity to evaluate the greenness and then to improve the process. To evidence such an improve-
ment, the evaluation of the optimized processes was compared with that of the classical ones.
DOI: 10.1039/c3gc37097f
www.rsc.org/greenchem
PEG2000, 0.58 mmol g−1 for PEG3400, and 0.32 mmol g−1 for
PEG6000. The increase of loading capacity of PEGs through
Introduction
Modern chemical syntheses should be based upon green chemical modification to reach values similar to those of the
chemistry principles.1 First, the optimization of atom widely used, commercially available, insoluble Merrifield resin
economy2 has to steer the design of chemical modifications. (1–4 mmol g−1) or OH-functionalized Wang resin (0.4–2 mmol
Second, the reaction conditions have to be optimized in order g−1) has been receiving much attention.14
to strongly decrease the waste, expressed by the environmental
In the present work we describe the synthesis of new high
factor.3 Third, the use of non-toxic reagents and reaction loading capacity branched PEG-based polymers starting from
media has to be preferred.
the commercially available pentaerythritol. Our strategy relies
Solvents constitute the major part of waste, up to 80%,4 on reactions with high or even total atom economy and on the
and are often hazardous and toxic. Although in some cases use of green media, such as water or PEG. The impact of the
solvent-free processes can be developed,5 a strong need for processes was assessed using green metrics:
organic solvent substitutes still remains. Alternatives include
aqueous media,6 PEGs,7 ionic liquids8 or supercritical fluids.9
– The atom economy (AE),2 which allows one to choose a
synthetic pathway that maximizes the incorporation of reagent
Polyethylene glycols (PEGs) are currently employed as and substrate atoms in the product. This metric, however,
organic polymer soluble supports for both synthesis and cata- cannot be used to evaluate the material economy of the
lyst immobilization.10 Their use as drug vectors has been reaction.
receiving growing interest in pharmaceutical and biomedical
– The reaction mass efficiency (RME, eqn (A)),15 which is
areas.11 The main advantages of using PEGs are related to the percentage of the mass of the reactants that remains in the
their non-toxicity and their solubility properties allowing easy product taking into account the experimental conditions
recovery.12 In particular, we have shown that coupling PEG (excess of reagents and yields).
supported synthesis and ultrafiltration allowed the preparation
mass of product
mass of reactants
and purification of various heterocycles without the use of
RME ¼
ðAÞ
organic solvents.13 A major drawback of these soluble poly-
mers is the low loading capacities, i.e. the number of func-
tional groups per gram of polymer: e.g. 1 mmol g−1 for
– The mass intensity (MI),15,16 or its counterpart, the global
material economy (GME, eqn (B)),17 that considers all the
materials used in the process (extraction, washing, separation,
recrystallisation, chromatographic support if not recycled,
etc.).
aUniversité Paris Sud, ICMMO, UMR CNRS 8182, Bâtiment 410, 91405 Orsay,
France. E-mail: marie-christine.scherrmann@u-psud.fr
bUniversité de Cergy-Pontoise, SOSCO, 5 mail Gay-Lussac, Neuville sur Oise, 95031
1
mass of product
MI mass of react: þ auxiliaries
We showed17,18 that, for any synthetic sequence, RME and
GME are directly proportional to the atom economy, which
Cergy-Pontoise, France. E-mail: Jacques.auge@u-cergy.fr
†Electronic supplementary information (ESI) available: Examples of calculation
of green metrics for compounds 1, 19, and 15; 1H, 13C and MALDI TOF
spectra for all compounds; Excel data sheet of the calculations. See DOI:
10.1039/c3gc37097f
GME ¼
¼
ðBÞ
1016 | Green Chem., 2013, 15, 1016–1029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
Scheme 1 Retrosynthesis of the targeted PEG derivatives.
means that the choice of high atom economy reactions is
crucial. However, it is worth noting that also the yields of the
reactions and the excess of the reactants greatly affect RME
and, consequently, GME. Moreover, the amounts of the auxili-
aries, particularly solvents and chromatographic supports, are
very important because they lead to very low GME values.
Therefore, from the above-mentioned definitions, it appears
that GME < RME < AE. The efficiency of a given reaction is
high especially when RME is close or even equal to AE. Simi-
larly, the greenness of a reaction, based on mass economy, is
high especially when GME is close to RME and AE.
Scheme 2 Synthesis of bis-alkynylated PEG 1.
bromide (4) in the presence of tBuOK in anhydrous THF21 or
toluene.22 Alternatively, preparations using water as the solvent
and NaOH as the base in the presence of tetrabutylammonium
hydrogen sulfate were reported.23 In most cases, the dipropar-
gylated polymers were isolated by chromatography. Applying
the anhydrous conditions to PEG6000, we observed the for-
mation of allenes as by-products. Hence, we carried out the
alkylation of PEG6000 under aqueous conditions using NaOH
as the base. At 40 °C, the conversion of PEG was complete
after 12 h, as judged by 1H NMR and MALDI TOF analyses,
and no chromatography was required since dipropargylated
PEG 1 could be isolated using standard precipitation pro-
cedures12 in 96% yield (Scheme 2). However, although the
atom economy of the reaction was high (AE = 0.96) and the
purification of the product required no chromatography, this
efficient preparation using water as the solvent was not fully
satisfactory from the standpoint of green chemistry. Indeed,
organic solvents, e.g. dichloromethane and diethyl ether, were
still required for extraction, precipitation, and washing. There-
fore, we used ultrafiltration, a membrane process that allows
separation of molecules on the basis of their molecular
weight, to isolate PEG 1 in similar yield (95%) by forcing the
aqueous solution through a regenerated cellulose membrane
with a molecular size cutoff of 1000.
Besides the above metrics, in the present work we have
calculated the very popular Sheldon E-factor. There is a simple
relationship between the latter metric and MI (eqn (C)).
mass of waste
mass of products
E ¼
¼ MI ꢀ 1
ðCÞ
Strategy
The design of high loading capacity PEGs was based on the
copper catalysed 1,3-dipolar azide–alkyne cycloaddition
(CuAAC),19 a 100% atom economy reaction occurring with
high yield and selectivity, which are the prerequisites for click
chemistry.20 We chose to prepare dipropargylated PEG 1 from
commercially available PEG6000 and the azide derivatives 2
starting from pentaerythritol 3 (Scheme 1). This approach was
applied to the synthesis of PEGs bearing 6 or 18 functions at
their terminal extremities. In the general formula 2, the R
group could be an allyl substituent that allowed the synthesis
of 6-branched hydroxy PEG derivatives with 100% atom
economy and high yield. On the other hand, for the prep-
aration of 18-branched PEGs, the R group was a three-
branched chain obtained via CuAAC involving a tripropargy-
lated pentaerythritol derivative.
Consequently, the E factor was dramatically reduced from
23.5 to 11.7. Moreover, water is the only solvent used in the
process. If the amount of water used in the work-up is not
included in the calculation of the E-factor, as suggested by
Sheldon,24 then the value of E falls to 1.3. However, for the
ACS Green Chemistry Institute Pharmaceutical Roundtable,
water used in chemical and biosynthetic processes must be
integrated in the green metrics since it could involve signifi-
cant capital, energy, and direct environmental impacts.25
Synthesis of dipropargylated PEGs 1
The synthesis of low molecular weight bis-alkynylated PEG 1
was previously performed by reacting PEG with propargyl
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1017

View Article Online
Paper
Green Chemistry
compound 11 (Fig. 1) was isolated in 4% yield. Under these
conditions RME was greatly improved and consequently the E
Synthesis of PEG6000 with 6 branches
Starting from pentaerythritol 3, we prepared the triallylated factor was largely reduced (Table 1). It is worth noting that
pentaerythritol
6 using aqueous conditions and sodium although the change of base from NaH to NaOH always
hydroxide as a base (Scheme 3).26 Although it is the simplest implies a slight decrease of the atom economy, NaOH is more
way to form the ether bond, the atom economy of the reaction common and cheaper than NaH as a base; moreover, it leads
is only 0.41, since 3 equivalents of NaBr are produced as waste. to water as waste while hydrogen is formed when NaH is used.
The reaction afforded the tri- and di-allylated products 6 and 7
Various conditions were then tested to prepare the azido
that have to be separated by flash chromatography. We derivative 12 (Scheme 5, Table 2). We first carried out the reac-
improved the total yield of 6 to 75% by reacting 7 with 2 tion under classical conditions with DMF as the solvent. Using
equivalents of allyl bromide (5) under the previously described 1.1 equiv. of NaN3 at 25 °C, we isolated 12 in 91% yield after
conditions.27 The reaction mass efficiency (RME) of the reac- 24 h and in 98% yield at 60 °C after 12 h. As it has been
tion was then raised from 0.18 to 0.22. However, due to the use reported that organic azides could be prepared by microwave-
of an appreciable amount of solvents to convert 7 into 6, the E assisted nucleophilic substitution of halogenated compounds
factor was not greatly affected (without the recovery of com- in water in the absence of any phase-transfer catalyst,28 we
pound 7, E = 289; with the recovery of 7 to prepare 6, E = 285).
tried this protocol to prepare 12. Under these conditions, no
The next step, the reaction of 6 with dibromobutane 8 conversion of 9 was observed. The addition of 10% TBAB
(Scheme 4), was first carried out in DMF using NaH as the under microwave activation allowed us to obtain 12 in 96%
base. An excess of dibromobutane up to 15 equiv. was required yield on a 0.3 mmol scale. Although the yield and RME were
to reach 62% conversion at 60 °C (Table 1, entry 1), but under not improved (Table 2), we prefer the second method, which
these conditions 9 was isolated in only 24% yield and com- uses H2O instead of DMF as the solvent. However, the E-factor
pound 10 was formed (30% isolated yield) as a by-product remained high and a new method had to be investigated.
(Fig. 1). Unfortunately, the use of THF as the solvent gave only Amongst the alternatives to organic solvents, PEG was chosen
19% conversion and 17% isolated yield (Table 1, entry 2). Due because it is known to promote nucleophilic substitution by
to the large excess of dibromobutane, the reaction mass acting as a phase transfer catalyst.7a Therefore, we carried out
efficiency was low (0.065 in the best case, i.e. in DMF). To the reaction in PEG400 (Table 2, entry 5) and after 2 h com-
improve such a metric and to avoid DMF, we investigated pound 12 was isolated in 98% yield by extraction with Et2O.
aqueous conditions in the presence of NaOH and a lower Furthermore, after extraction, PEG400 was recycled 2 more
excess of dibromobutane. We were delighted to observe that times affording 12 in similar high yields. This simple pro-
the addition of TBAB as a phase transfer catalyst enhanced the cedure was successfully scaled up to the transformation of
yield to 73% (Table 1, entry 4). A by-product identified as 200 mmol (80 g) of 9. The E factor was largely reduced
Fig. 1 By-products isolated during the preparation of 9.
Scheme 3 Synthesis of triallylated pentaerythritol 6.
Scheme 5 Preparation of azido derivative 12.
Scheme 4 Preparation of compound 9.
Table 1 Optimization of conditions for the synthesis of compound 9
Entry
Solvent (additive)
Base
8 (equiv.)
Temperature
Time
Conversion (%)
Yield (%)
AE
RME
E
1
2
3
4
DMF
THF
H2O
H2O (TBAB)
NaH
NaH
NaOH
NaOH
15
15
4
60 °C
60 °C
85 °C
85 °C
72 h
48 h
24 h
12 h
62
19
22
80
24
17
20
73
0.79
0.79
0.76
0.76
0.065
818
4
0.31
275
1018 | Green Chem., 2013, 15, 1016–1029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
(Table 2) and could be further reduced by multiple recycling of catalytic activity was already established,30 proved to be very
PEG400 advantageous in providing products containing only traces of
.
Coupling of dipropargylated PEG 1 with a slight excess of the metal.31 Applied to our PEG derivatives that are good
azido derivative 12 was accomplished by the use of CuSO4– ligands for cations, this method allowed us to isolate 13 by
sodium ascorbate in water–THF. The triazole-linked polymer ultrafiltration (95% yield) containing only 220 ppm of copper
13 (Fig. 2) was isolated by extraction with CH2Cl2, washing (ICP MS analysis). Moreover, the copper turnings could be
with an aqueous NH4Cl–NH3 solution, in order to remove the recycled at least 3 times without loss of activity.32
copper salts, and precipitation with Et2O or by ultrafiltration.
Due to a smaller excess of compound 12 (φ1,2 = 1.14 vs. 1.5
Atom economy (100%), yield (96 or 95% recovered yield, in the precedent protocol), RME was enhanced up to 0.936
respectively) and RME (0.91 or 0.90, respectively) were excellent and even 0.942 since a small amount of the excess of 12 could
for that reaction (Table 3). Analysis of 13 by 1H NMR and be recovered. This was interesting because 12 was an advanced
MALDI-TOF MS showed a complete conversion of 1 into the intermediate, though such removal required the use of
1,4-disubstituted triazole derivatives 13.29 The residual copper, dichloromethane as a washing solvent, which led to
a
assayed by atomic absorption, was 835 ppm when 13 was iso- reduction of the global material economy, and consequently
lated by extraction, washing and precipitation, and 1500 ppm an increase of the E-factor from 55 to 60. The copper turnings
when the purification was carried out by ultrafiltration.
protocol had however a great advantage since water was the
The washing steps, necessary to remove most of the copper only solvent used (except for the partial removal of the excess
salts, dramatically increased the E factor, which reached the of one of the reactants).
value of 44. Using an ultrafiltration work-up process not only
reduced this metric to 22, but also allowed one to replace the we chose to exploit another reaction with a total atom
extraction solvents with water.
economy, the thiol–ene addition.33 Hence, 2-mercaptoethanol
In order to install hydroxyl functions on modified PEG 13,
At this stage it was interesting to test the use of copper turn- (14) was photochemically (λ = 254 nm) added to the allyl
ings. Indeed, the protocol using copper turnings, whose groups of 13 in ethanol to give polymer 15 in 94% isolated
yield by precipitation from the crude reaction mixture (Fig. 3).
The moderate RME (0.76) and E-factor (18) were due to a large
excess of 2-mercaptoethanol 14 (4.6 equiv.) used to boost the
yield. Indeed, when 2 or 4 equiv. of 14 were used, the conver-
Table 2 Comparison of solvents in the synthesis of azido derivative 12
sions were 90 and 95% respectively.
Solvent
Entry (additive)
Temp.
(°C)
Time
(h)
Yield
(%)
AE
RME
E
In summary, polymer 15 with 6 connection points was pre-
pared by a convergent synthesis with two parallel sequences
and a point of convergence (see below for the evaluation of
this synthesis by green chemistry metrics). The loading
capacity of 15 is 0.8 mmol per gram of support while that of
PEG6000 is only 0.32 mmol g−1. Then we decided to apply this
strategy to the preparation of a support bearing 18 alcohol
functions.
1
2
3
4
5
6
7
DMF
DMF
H2O
25
60
24
12
1
1
2
2
2
91
98
0
96
98
96
99
0.77 0.75 60.9
0.77 0.69 28.9
120a
H2O (TBAB) 120a
PEG400
PEG400
PEG400
60
60
60
0.77 0.75
7.9
6.3
5.8
b
c
a Microwaves activation. b First recycling. c Second recycling.
Fig. 2 Structure of polymer 13.
Table 3 Comparison of catalyst, solvent and work-up for the synthesis of 13
Entry
12 (equiv.)
1.5
Catalyst (equiv.)
Conditions
Work-up
Yield (%)
AE
1
RME
0.912
0.903
E
1
2
3
CuSO4–NaAsc (0.5 : 1.05)
CuSO4–NaAsc (0.5 : 1.05)
Cu (2.6)a
THF–H2O
4 h, 20 °C
THF–H2O
4 h, 20 °C
H2O
Precipitation
Ultrafiltration
Ultrafiltration
96
95
95
44
22
1.5
1
1.14
1
0.936
55
26 h, 70 °C
0.942b
60b
a Recycled 3 times. b After removal of a part of the excess of 12.
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1019

View Article Online
Paper
Green Chemistry
Fig. 3 Polymer 15 with 6 connection points having a loading capacity of 0.8 mmol g−1
.
moderate (RME = 0.43) thanks to a total atom economy and a
limited excess of one of the reagents (1.49 equiv.). The high
Synthesis of PEG6000 with 18 branches
For the preparation of PEG with 18 branches we planned to value of the E factor (E = 798) was related to the chromato-
prepare compound 17 (Scheme 6) using the copper(I) catalysed graphy step, which involved solvents and silica gel. This high
cycloaddition between 12 and tripropargylated pentaerythritol value prompted us to change the method or to improve the
16.34 The preparation of the latter compound has been pre- purification step. A first assay to prepare 18 from 17 by
viously described starting from pentaerythritol (3) and propar- addition of dibromobutane in water under the same con-
gyl bromide (4) in H2O–DMSO (71% yield calculated on the ditions developed for the preparation of 9 gave poor results,
basis of propargyl bromide).35 These conditions induce a low since 18 was isolated in only 33% yield due to degradation
value for RME (0.10) due to a high stoichiometric ratio during the purification step. Then, we decided to by-pass the
between pentaerythritol and propargyl bromide (φ1 = 5.01) as preparation of 17 by grafting the spacer earlier in the synthetic
well as a high stoichiometric ratio between sodium hydroxide sequence and we were pleased to obtain 20 in 85% yield
and propargyl bromide (φ2 = 5.68). In order to increase the through the coupling of 16 with dibromobutane in water
mass efficiency of the reaction, we rather choose to work with (Fig. 5). As for the preparation of the allylated derivative 9,
a small excess of propargyl bromide (3.85 mol mol−1 of 3, some elimination occurred, giving rise to 21 in 4% yield.
which corresponds to a stoichiometric ratio of 1.28) and a Dibromobutane was used in excess (4 equiv.), but the recovery
small excess of sodium hydroxide (1.33 equiv.). Under our con- by distillation of a part of this excess allowed us to increase
ditions, the yield based on propargyl bromide is reduced from RME from 0.22 up to 0.36, an acceptable value for a reaction
71% to 35%, whereas the yield based on pentaerythritol is with an atom economy of 0.76.
enhanced from 14 to 45%. Finally, RME was increased by 50%
(RME = 0.15).
The copper-catalysed cycloaddition between 12 and 20 to
form 18 (Fig. 4) proceeded to completion in 1.5 h using a stoi-
Tripropargylated pentaerythritol 16 and the azido derivative chiometric amount of CuSO4–NaAsc (relative to alkyne func-
12 were coupled in the presence of CuSO4–sodium ascorbate tions) in H2O–THF (Table 4, entry 1). Since chromatography
in water–THF affording 17 in 59% yield after chromatography
(Scheme 6). Notwithstanding the yield, RME remained
Fig. 4 Synthesis of 19 from 18.
Scheme 6 Synthesis of compound 17 through CuAAC.
1020 | Green Chem., 2013, 15, 1016–1029
Fig. 5 Structures of compounds 20 and 21.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
Table 4 Optimisation of the synthesis of 18 by CuAAC between 12 and 20
Entry
12 (equiv.)
Catalyst (equiv. per alkyne)
Time (h)
Solvent
Isolated yield (%)
RME
E
1
2
3
4
5
1.3
1
1
1
1
CuSO4–NaAsc (1 : 1)
1.5
5
24
0.5
25
H2O–THF (3 : 1)
H2O–THF (3 : 1)
H2O–THF (1 : 3)
H2O–PEG400 (1 : 7)
H2O–PEG400 (1 : 6)
50
96
96
99
98
CuSO4–NaAsc (0.1 : 0.1)
CuSO4–NaAsc (0.033: 0.033)
CuSO4–NaAsc (0.033: 0.033)
Cu turnings (1.3)
0.99
0.97
9.8
12.5
Table 5 Comparison of solvents for the nucleophilic substitution affording 19
was necessary to remove the excess of azido derivative 12, com-
pound 18 was isolated in only 50% yield due to some
decomposition on silica gel. Hence we tried to reduce the
amount of 12 and copper salts. We found that when the stoi-
chiometric ratio between the reactants was respected and
when 0.1 or even 0.033 equiv. of copper were used, the reaction
was complete in 5 or 24 h, respectively (Table 4, entries 2 and
3). Almost pure 18 (1H NMR analysis) was isolated by simple
extraction and washing with an aqueous NH4Cl–NH3 solution
to remove most of the copper.
Isolated
yield (%)
Entry
Solvent
Time (h)
RME
E
1
2
3
4
5
DMF
PEG400
PEG400 (1st recycling)
PEG400 (2nd recycling)
PEG400 (3rd recycling)
12
93
97
96
99
98
—
—
2.5
2.5
2.5
2.5
0.91
0.91
0.91
0.91
3.8
3.3
3.2
3.1
this technique. The calculation of green metrics gave RME and
E values of 0.66 and 31, respectively. Use of copper turnings as
the catalyst allowed us to carry out the reaction in THF–H2O37
using only 1.25 instead of 2.3 equiv. of azido derivative 19 per
alkyne function. Purification by ultrafiltration allowed recover-
ing 22 in 91% yield containing 1000 ppm of copper (atomic
absorption analysis). These new conditions also led to a high
RME value (0.93) and would lead to an extremely low value of
the E factor (3.0) if H2O was excluded from the calculation.
The actual value of 319, which is high compared to 3, must be
correlated to the fact that water is the major part of the waste.
Finally, the radical addition of an excess of 2-mercapto-
ethanol (φ = 4.97 to reach complete conversion) to 22 was
carried out in ethanol–H2O by irradiating the solution at λ =
254 nm for 14 h to give the polyol 23 (Scheme 7) in 98% iso-
lated yield by precipitation from the reaction mixture. Under
these conditions we found RME = 0.64 and E = 10.8, that are
acceptable values for such a reaction.
Due to the excellent results obtained in reactions carried
out by us (9 → 12) and by others,36 we were encouraged to test
a mild protocol using aqueous PEG400 as the solvent. Using 1
equivalent of 12 and a catalytic amount of copper (0.033 equiv.
per alkyne) allowed us to get a very clean and rapid reaction
with 20 in H2O–PEG400 (1 : 7) (Table 4, entry 4). In order to
avoid the washing step with ammonia, we also tried copper
turnings as the catalyst. The reaction took place in H2O–
PEG400 (1 : 6) and compound 18 was isolated by simple extrac-
tion in almost quantitative yield (Table 4, entry 5), the copper
content in the isolated compound being 910 ppm (atomic
absorption analysis). In reactions performed in H2O–PEG400
,
RME values were excellent (0.97 and 0.99). When using
copper(II), the E factor was reduced to 9.8.
The following nucleophilic substitution step was also per-
formed in PEG400 and a simple extraction allowed us to isolate
19 in 97% yield (Fig. 4, Table 5). For comparison, the reaction
was also conducted in DMF. A yield of 93% was obtained but
the transformation required 12 h while it was complete after
2.5 h in PEG, confirming the efficiency of this solvent for
nucleophilic substitutions.7a PEG400 was recycled 3 times and
similar high yields were obtained. Excellent values of RME
(0.91) and the E-factor (between 3.1 and 3.8 according to the
number of times PEG can be recycled) were obtained for that
reaction with an atom economy of 0.93.
The loading capacity of polymer 23 with 18 connection
points is 1.71 mmol g−1, which corresponds to an increase of
534% compared to PEG6000. It was prepared by a convergent
synthesis with three parallel sequences and two points of
convergence.
The dipropargylated PEG 1 was then reacted with the azido
derivative 19 to obtain 22 (Scheme 7). When CuSO4–sodium
ascorbate was used as the catalyst, the reaction took place in
2 : 1 THF–H2O in 3 h at room temperature. 2.3 equiv. of 19,
with respect to alkyne function, were necessary to reach a total
conversion (1H NMR and MALDI-TOF analyses). PEG 22 was
isolated in 91% yield by extraction with CH2Cl2, washing with
an aqueous NH4Cl–NH3 solution followed by precipitation
with Et2O. The copper content of the polymer was determined
at 240 ppm by atomic absorption. We also tried to purify 22 by
ultrafiltration of the aqueous solution, but we were not able to
remove all the excess of azido derivative 19 from PEG 22 by
Evaluation of the total synthesis of 15
This is a convergent synthesis with two parallel sequences and
one point of convergence (Scheme 8).
Table 6 gathers the green metrics of all the steps. Two of
them gave unsatisfactory E-factors due to a chromatographic
purification in the work-up of these two steps. However, we
succeeded in replacing DMF as a solvent and NaH as a base by
carrying out these transformations under aqueous conditions
using NaOH as a green base. The other steps were optimized
to reduce the impact of the processes. Particularly interesting
was the use of ultrafiltration to purify large molecules and also
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1021

View Article Online
Paper
Green Chemistry
Scheme 7 Synthesis of 23 with 18 connection points having a loading capacity of 1.71 mmol g−1 through thiol–ene addition of 2-mercaptoethanol 14.
We have recently developed a new algorithm to evaluate any
whole synthesis.17 By using this methodology, we found that
the global reaction mass efficiency (GRME) of the total syn-
thesis of 15, starting from PEG6000 and pentaerythritol, was
41% for an overall atom economy of 84%. The overall yield
Scheme 8 Synthesis of 15.
calculated from PEG6000 was equal to 85% (see ESI† for details
of the calculation).
Table 6 Yields and green metrics for each step of the synthesis of 15
Reaction
Yield (%)
AE (%)
RMEa (%)
GME (%)
E
Evaluation of the total synthesis of 23
PEG → 1
3 → 6
6 → 9
9 → 12
1 + 12 → 13
96
75
73
98
95
94
96
41
76
77
100
100
77
22
31
75
94
76
7.88b
0.3
0.4
15
11.72b
285
This is a convergent synthesis with three parallel sequences
and two points of convergence (Scheme 9).
The sequences PEG → 1 and 3 → 12 have been described in
the previous synthesis. We greatly improved the synthesis of 16
in terms of waste production but it still retained a chromato-
275
5.8c
1.7d
5
55b,d
18.7
13 → 15
a RME values were systematically calculated according to (a) the
classical method, i.e. by adding the mass of reactants used, and (b) the graphy step, enhancing dramatically the E-factor. Use of ultra-
method that we have developed recently. Both methods gave strictly
filtration for purification and PEG as the solvent allowed us to
the same results allowing the checking of the data.17 b Purification by
ultrafiltration. c After 2 cycles. d Method with copper turnings.
decrease the environmental impact of the next steps. By using
our methodology, we found that the global reaction mass
efficiency of the total synthesis of 23, starting from PEG6000 and
pentaerythritol, was GRME = 24% for an overall atom economy
of 71% and an overall yield of 86% from PEG6000 (Table 7).
the use of PEG as a solvent both for the substitution reaction
with NaN3 and the copper-catalyzed cycloaddition.
1022 | Green Chem., 2013, 15, 1016–1029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
Spectrométrie de Masse IMAGIF/ICSN – CNRS (Gif-sur-Yvette,
France) with a Perseptive Voyager DE-STR MALDI time-of-
flight mass spectrometer (Perseptive Biosystems) using 2,5-
dihydroxybenzoic acid as the matrix. Spectra of the com-
pounds were compared to commercial PEG6000 (found for the
central peak 6209, HOCH2CH2(OCH2CH2)139OH, [M + Na]).
Copper concentrations were determined at 324.8 nm on a
spectrometer AAS novAA400 with a C2H2–air flame (fuel flow
at 50 L h−1), equipped with a burner of 10 mm and a lamp
M-HCL. A certified solution of Cu in HNO3 (Copper RS
NORMEX, Carlo Erba) was diluted in distillated water to give a
stock solution at 1000 ppm Cu that was used to prepare stan-
dard solutions for calibration. Samples were dissolved in a 1%
aq. solution of HNO3 at 1 mg mL−1. Three replicates were
recorded for each sample (SD for all samples were <4%).
ICP-MS measurements were performed at the Laboratoire
d’Analyses Nucléaires Isotopiques et Elémentaires at CEA-Sa-
clay, France.
Scheme 9 Synthesis of 23.
Table 7 Yields and green metrics for each step of the synthesis of 23
Reaction
Yield (%)
AE (%)
RMEa (%)
GME (%)
E
3 → 16
16 → 20
12 + 20 → 18
18 → 19
1 + 19 → 22
22 → 23
45
85
99
98
91
99
41
76
100
93
100
100
15
36
99
91
86
64
0.2
0.4
9.2
24b
0.3
8.4
409
222
9.8
3.1b
319c
10.8
a RME values were systematically calculated according to (a) the
classical method, i.e. by adding the mass of reactants used, and (b) the
method that we have developed recently. Both methods gave strictly
the same results allowing the checking of the data. b After 3-fold
recycling of PEG. c Most of the waste is water.
Bis propargylated PEG6000 1
To a solution of PEG6000 (40 g; 6.47 mmol) in THF (30 mL) was
added an aqueous solution of sodium hydroxide (5.34 g;
133 mmol in 11 mL of water) under stirring. After 5 min, pro-
pargyl bromide solution 80 wt% in toluene (4.3 mL;
38.6 mmol) was added and the mixture was stirred at 40 °C for
12 h. After cooling to r.t., THF was evaporated.
Purification by extraction and precipitation. The aqueous
solution was extracted with CH2Cl2 (2 × 100 mL). The com-
bined organic layers were washed with an aqueous saturated
solution of KH2PO4 until pH 6 was reached (2 × 40 mL), and
then with water (40 mL), dried over sodium sulfate (10 g), and
filtered. The CH2Cl2 phase was concentrated to 80 mL, cooled
to 0 °C, and dry Et2O (450 mL) was slowly added under vigor-
ous stirring. The precipitate was recovered by filtration and
washed with Et2O (200 mL) affording compound 1 as a white
powder (39.0 g; 96%). 1H NMR (360 MHz, CDCl3): δ 2.44 (t,
2 H, J = 2.5 Hz), 3.43–3.85 (m, 560 H, PEG), 4.20 (d, 4 H, J =
2.5 Hz); 13C NMR (91 MHz, CDCl3). δ 58.5 (OCH2CuCH), 69.2,
70.6 (OCH2, PEG), 76.7 (uCH), 79.8 (CuCH), MALDI-TOF MS:
found for the central peak (n = 139): 6285 [M + Na].
Conclusions
The aim of this work was the synthesis of high loading
capacity polymers by implementing methods of green chem-
istry. The choice of reactions with high atom economy, such as
CuAAC and thiol–ene coupling, and optimization of the reac-
tion conditions to increase the yields and reduce the excess of
reagents allowed us to increase significantly the reaction mass
efficiency (RME) of the different steps. Replacement of sol-
vents, traditionally used in organic synthesis, by recyclable
alternative media such as PEG400 together with the use of puri-
fication methods such as ultrafiltration of aqueous media,
where possible, also contributed to the eco-compatible syn-
thesis. The new polymer featuring 6 connection points has a
loading capacity of 0.80 mmol g−1 whereas that with 18 con-
nection points has a loading capacity of 1.71 mmol g−1, which
correspond to an increase of 250% and 534%, respectively,
with respect to the starting PEG6000. These loading capacities
are comparable to those displayed by most of the commercially
available insoluble resins such as the Merrifield or Wang
resins.
Purification by ultrafiltration. The aqueous solution was
diluted with water (160 mL), filtered on a PVDF membrane
(47 mm, 0.45 μm) and the ultrafiltration was performed in
Amicon 8200 stirred cells fitted with Amicon Ultracell PL Mem-
brane Disks, molecular weight cutoff 1000, under 3.8 bar
pressure. After the first ultrafiltration, the retentate (40 mL)
was diluted with water (120 mL), and the solution was ultrafil-
trated again. The operation was repeated once to afford, after
Experimental
1H NMR and 13C NMR spectra were recorded at room temp- freeze drying, 38.5 g of 1 as a white powder (95%).
erature with Bruker spectrometers (250, 300, or 360 MHz).
Chemical shifts are reported in parts per million (ppm) vs.
Pentaerythritol triallyl ether 6
Me4Si for 1H-NMR and 13C-NMR. Signals were assigned thanks To a solution of pentaerythritol 3 (103.4 g; 0.759 mol) in
to 1H–1H COSY and gradient-HMQC experiments. Mass aqueous sodium hydroxide (122 g; 3.05 mol in 250 mL water)
spectra were recorded in positive mode on a Finnigan MAT 95 was slowly added allyl bromide 5 (368.4 g; 3.04 mol). The
S
spectrometer using electrospray ionization except for mixture was heated at 70 °C for 12 h. After cooling to room
MALDI-TOF which were performed at the Service de temperature, the biphasic mixture was decanted and
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1023

View Article Online
Paper
Green Chemistry
separated. The aqueous layer was extracted with diethyl ether 5.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 4.25 (s, 2 H, OCH2Cq), 5.14
(200 mL). The combined organic layers were washed with a (dq, 3 H, J = 10.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.24 (dq, 3 H,
saturated aqueous solution of sodium hydrogen phosphate J = 17.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.82–5.91 (m, 3 H,
(200 mL), brine (200 mL), dried over sodium sulfate (25 g), fil- OCH2CH:CH2), 8.07 (s, 1 H, CHO). 13C NMR (75 MHz, CDCl3):
tered and concentrated under vacuum. Purification by column
δ
44.4 (Cq), 63.6 (CqCH2O), 68.9 (CqCH2OAll), 72.3
chromatography (petroleum ether–ethyl acetate: 5/1 then 3/1) (OCH2CH:CH2), 116.5 (OCH2CH:CH2), 134.9 (OCH2CH:CH2),
1
afforded first compound 6 as a colorless oil (109 g; 56%). H 161.1 (CHO). IR (NaCl): 3080, 2868, 1725 cm−1. MS: (ES+):
NMR (360 MHz, CDCl3): δ 2.90 (t, 1 H, J = 6.0 Hz, CH2OH), [M + 23]+: 307.1.
3.50 (s, 6 H, CqCH2O), 3.73 (d, 2 H, J = 6.0 Hz, CH2OH), 3.96
Method in water. To a suspension of triallyl pentaerythritol
(dt, 6 H, J = 5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.15 (dq, 3 H, J = 6 (78.0 g; 0.304 mol) in an aqueous solution of sodium hydro-
10.5 Hz, J = 1.5 Hz, CH2CH:CH2), 5.25 (dq, 3 H, J = 17.5 Hz, J = xide (120 g; 3.0 mol in 250 mL water) were added dibromobu-
1.5 Hz, CH2CH:CH2), 5.83–5.92 (m,
3 H, CH2CH:CH2). tane (145 mL, 1.21 mol) and TBAB (9.7 g; 0.03 mol). The
13C NMR (62.5 MHz, CDCl3): δ 44.8 (Cq), 65.9 (CH2OH), 70.8 mixture was heated under stirring at 85 °C for 12 h. After
(CH2OAll), 72.3 (OCH2CH:CH2), 116.5 (OCH2CH:CH2), 134.7 cooling to room temperature, the two layers were separated.
(OCH2CH:CH2).
The aqueous layer was extracted with diethyl ether (200 mL).
Eluted second was compound 7. Colorless oil. (41 g; 25%). The combined organic layers were washed with a saturated
Spectral data were in accordance with those previously aqueous solution of KH2PO4 (100 mL) and water (100 mL),
reported.38 1H NMR (360 MHz, CDCl3): δ 2.65 (br s, 2 H, dried over sodium sulfate (25 g), filtered and concentrated to
CH2OH), 3.50 (s, 4 H, CqCH2O), 3.68 (s, 4 H, CH2OH), 3.96 (dt, give a yellow oil from which 180 g (0.83 mol) of dibromo-
4 H, J = 5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.18 (dq, 2 H, J = butane was recovered by distillation (bp 38 °C at 0.6 mbar).
10.5 Hz, J = 1.5 Hz, CH2CH:CH2), 5.25 (dq, 2 H, J = 17.5 Hz, J = Flash chromatography (petroleum ether–Et2O: 9/1) of the
1.5 Hz, CH2CH:CH2), 5.83–5.92 (m, 2 H, CH2CH:CH2).
residue afforded first compound 11 (3.4 g; 4%). 1H NMR
Following the same procedure, compound 6 was obtained (360 MHz, CDCl3): δ 2.30 (qt, 2 H, J = 6.5 Hz, 1.5 Hz,
from compound 7 (41 g; 0.19 mol) using 2 equivalents of CH2CH2CH:CH2), 3.44 (m, 10 H, OCH2CH2, CqCH2O), 3.93 (dt,
sodium hydroxide (15.2 g; 0.38 mol) in water (30 mL) and allyl 6 H, J = 5.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.00 (dq, 1 H, J =
bromide (46 g; 0.38 mol). Purification by flash chromatography 10.5 Hz, J = 1.5 Hz, CH2CH2CH:CH2), 5.06 (dq, 1 H, J =
(petroleum ether–AcOEt: 5/1) afforded 6 (36.5 g). The two 17.5 Hz, J = 1.5 Hz, CH2CH2CH:CH2), 5.14 (dq, 3 H, J =
batches were brought together to yield 145.5 g (75%).
10.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.24 (dq, 3 H, J = 17.5 Hz,
J = 1.5 Hz, OCH2CH:CH2), 5.76–5.91 (m, 4 H, OCH2CH:CH2).
13C NMR (75 MHz, CDCl3): δ 34.2 (CH2CH2CH:CH2), 45.6 (Cq),
Compound 9
Method in DMF. To a solution of compound 6 (430 mg; 69.5 (CH2OAll), 69.8 (CqCH2O), 70.8 (CqCH2OCH2), 72.4
1.68 mmol) in dry DMF (3.5 mL) was added NaH (60% in (OCH2CH:CH2), 116.1 (CH2CH2CH:CH2), 116.2
mineral paraffin) (135 mg; 3.36 mmol) at 0 °C in three portions (OCH2CH:CH2), 135.4 (OCH2CH:CH2), 135.8 (CH2CH2CH:
over a period of 15 min under stirring. Dibromobutane CH2). MS: (ES+): [M + 23]+: 333.3. Anal. Calcd for C18H30O4: C,
(1.0 mL; 8.4 mmol) was added and the mixture was heated at 69.64; H, 9.74. Found: C, 69.46; H, 9.76.
60 °C for 72 h. After cooling to room temperature, the mixture
was diluted in diethyl ether (10 mL), quenched with water
(3 mL), neutralized with an aqueous saturated solution of
KH2PO4 (5 mL), washed with brine (3 × 5 mL), dried over
Eluted second was compound 9 (86.8 g; 73%).
Compound 12
Method in DMF. To a solution of compound 9 (7.83 g;
Na2SO4 (1.5 g) and concentrated under vacuum. Flash chrom- 20.0 mmol) in DMF (20 mL) was added sodium azide (1.43 g;
atography of the residue (petroleum ether–AcOEt: 95/5) 22.0 mmol). The mixture was stirred and heated at 60 °C for
1
afforded first compound 9 (155 mg; 24%). H NMR (360 MHz, 12 h. After cooling to room temperature, diethyl ether (65 mL)
CDCl3): δ 1.64–1.68 (m, 2 H, Br(CH2)2CH2), 1.90–1.93 (m, 2 H, was added and the organic layer was washed with brine (5 ×
BrCH2CH2), 3.38–3.43 (m, 12 H, BrCH2, OCH2), 3.92 (dt, 6 H, 50 mL) and water (45 mL). The organic layer was dried over
J = 5.0 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.12 (dq, 3 H, J = 10.5 Hz, sodium sulfate (8 g), filtered and concentrated to afford com-
1
J = 1.5 Hz, CH2CH:CH2), 5.26 (dq, 3 H, J = 17.5 Hz, J = 1.5 Hz, pound 12 as a colorless oil (6.95 g; 98%). H NMR (360 MHz,
OCH2CH:CH2), 5.81–5.90 (m, 3 H, OCH2CH:CH2). 13C NMR CDCl3): δ 1.61–1.66 (m, 4 H, N3CH2(CH2)2), 3.27 (t, 2 H, J =
(91 MHz, CDCl3): δ 28.5 (Br(CH2)2CH2), 30.2 (BrCH2CH2), 34.1 6.5 Hz, N3CH2), 3.37–3.48 (m, 10 H, CqCH2O, OCH2CH2), 3.93
(BrCH2), 45.7 (Cq), 69.6 (CqCH2OAll), 70.0 (CqCH2O), 70.6 (dt, 6 H, J = 5.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.11–5.27 (dq,
(OCH2CH2), 72.6 (OCH2CH:CH2), 116.4 (OCH2CH:CH2), 135.5 6 H, J = 10.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.27 (dq, 3 H, J =
(OCH2CH:CH2). IR (NaCl) n: 3079, 2910, 1646, 646 cm−1. MS: 17.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.82–5.91 (m, 3 H,
(ESI
C18H31BrO4Na: 413.1298; Found: 413.1305. Anal. Calcd for 26.9 (OCH2CH2), 45.5 (Cq), 51.4 (N3CH2), 69.5 (CH2OAll), 69.8
+ m/z): [M +
23]+: 415.1. HRMS (ES+) Calcd for OCH2CH:CH2). 13C NMR (91 MHz, CDCl3): δ 26.0 (N3CH2CH2),
C18H31BrO4: C, 55.24; H, 7.98. Found: C, 54.98; H, 7.81.
(CqCH2OCH2), 70.7 (CqCH2O), 72.4 (OCH2CH:CH2), 116.2
Eluted second was compound 7 (142 mg; 30%). 1H NMR (OCH2CH:CH2), 135.4 (OCH2CH:CH2). IR (NaCl): 3079, 2868,
(300 MHz, CDCl3): δ 3.45 (s, 6 H, CH2OAll), 3.93 (dt, 6 H, J = 2096, 1646 cm−1. MS: (ES+): [M + 23]+: 376.2. HRMS (ES+):
1024 | Green Chem., 2013, 15, 1016–1029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
Calcd for C18H31N3O4Na: 376.2207. Found: 376.2218. Anal. pressure. After the first ultrafiltration, the retentate (10 mL)
Calcd for C18H31N3O4: C, 61.17; H, 8.84; N, 11.89; O, 18.11. was diluted with water (30 mL), and the solution was ultra-
Found: C, 61.12; H, 8.62; N, 11.71; O, 18.11.
filtrated again to afford, after freeze drying, 3.17 g of 13 as a
Method in PEG400. To a solution of compound 9 (80 g; powder (95%).
204.4 mmol) in PEG400 (200 mL) was added sodium azide
Method with copper turnings. A mixture of bispropargy-
(14.6 g; 224.4 mmol). The mixture was stirred and heated at lated PEG 1 (715 mg; 0.11 mmol), azido derivative 12 (92 mg;
60 °C for 2 h. After cooling to room temperature, compound 0.26 mmol), copper turnings (38 mg; 0.60 mmol), and water
12 was extracted with diethyl ether (200 mL). The organic layer (1.4 mL) was stirred at 70 °C for 26 h. The copper turnings
was washed with water (150 mL), dried over sodium sulfate were removed and the aqueous solution was diluted with water
(25 g), filtered and concentrated to afford compound 12 as a (20 mL), filtered on a PVDF membrane (47 mm, 0.45 μm) and
colorless oil (71.1 g; 98%). An analytical sample was obtained the ultrafiltration was performed in Amicon 8050 stirred cells
by flash chromatography (petroleum ether–Et2O: 9/1).
fitted with Amicon Ultracell PL Membrane Disks, molecular
Method in water under microwave activation. Compound 9 weight cutoff 1000, under 3.8 bar pressure. After the first ultra-
(177 mg; 0.45 mmol), TBAB (14 mg; 0.04 mmol), sodium azide filtration, the retentate (5 mL) was diluted with water (20 mL),
(44 mg; 0.677 mmol) and water (1 mL) were placed in a micro- and the solution was ultrafiltrated again to afford, after freeze
wave reactor (CEM discovery). The reactor was then sealed and drying of the retentate, 0.755 g of 13 as a white powder (95%).
irradiated at 120 °C for 1 h (power 100 watt). After cooling to The PVDF membrane was washed with CH2Cl2 (3 mL). Concen-
room temperature, compound 12 was extracted with diethyl tration of the solution allowed recovering 3.5 mg of the azido
ether (2 × 2 mL). The organic layer was dried over sodium derivative 12. Concentration of the ultrafiltration filtrate
sulfate (0.5 g), filtered and concentrated to afford compound allowed recovering 2 mg of the azido derivative 12.
12 as a slightly yellow oil (153 mg; 96%).
PEG6000 with 6 alcohol functions (15)
PEG6000 with 6 allyl functions (13)
Polymer 13 (0.34 g; 0.049 mmol) was dissolved in ethanol
Method with CuSO4–AscNa. To a solution of bispropargy- (0.5 mL) by heating at 60 °C in a quartz tube equipped with
lated PEG 1 (3.00 g; 0.48 mmol) and azido derivative 12 a stirring bar. After cooling to room temperature, mercapto-
(508 mg; 1.4 mmol) in a mixture of THF–H2O (6 mL/4.5 mL) ethanol (96 μL; 1.37 mmol) was added. The mixture was sub-
were successively added
CuSO4·5H2O (500 μL) and a 1 M aqueous solution of sodium diluted with 2 mL of ethanol, placed at −14 °C for 30 min. The
ascorbate (1 mL). After 4 h, THF was removed under vacuum. white solid was then filtered and washed with diethyl ether
a 1 M aqueous solution of mitted to UV irradiation (254 nm) under stirring for 14 h then
Purification by extraction/precipitation. The aqueous solu- (2 × 3 mL) affording compound 15 as a white solid (0.34 g;
tion was extracted with dichloromethane (3 × 10 mL). The 94%). 1H NMR (360 MHz, CDCl3): δ 1.54–1.63 (m, 4 H,
combined organic layers were washed twice with a mixture of a OCH2CH2(CH2)2), 1.77–1.85 (m, 12 H, SCH2CH2CH2),
saturated aqueous solution of ammonium chloride (10 mL) 1.94–2.02 (m, 4 H, NCH2CH2), 2.58 (t, 12 H, J = 7.0 Hz,
and a 28% aqueous solution of ammonia (3 mL) for 30 min, SCH2CH2CH2), 2.70 (t, 12 H, J = 6.0 Hz, SCH2CH2OH), 3.34
water (20 mL), dried over sodium sulfate (4 g) and filtered. The (s, 16 H, CqCH2O), 3.40–3.46 (m, 28 H, OCH2CH2, CH2OH),
CH2Cl2 phase was concentrated to 5 mL and Et2O (40 mL) was 3.63–3.71 (m, 560 H, PEG), 4.37 (t, 4 H, J = 7.0 Hz, NCH2), 4.54
added over 30 min under vigorous stirring at 0 °C and polymer (s, 4 H, O-CH2-Cq:CH), 7.61 (s, 2 H, O-CH2-Cq:CH). 13C NMR
13 was filtered. The white powder was washed with Et2O (91 MHz, CDCl3): δ 26.2 (OCH2CH2(CH2)2), 27.2 (NCH2CH2),
1
(20 mL) to afford 13 (3.20 g; 96%). H NMR (360 MHz, CDCl3): 28.4 (SCH2CH2CH2), 29.6 (SCH2CH2CH2), 34.6 (SCH2CH2OH),
δ 1.53–1.60 (m, 4 H, OCH2CH2), 1.92–2.01 (m, 4 H, NCH2CH2), 45.1 (Cq), 49.8 (NCH2), 60.6 (CH2OH), 64.4 (O-CH2-Cq:CH),
3.40–3.44 (m, 20H, CqCH2O, OCH2CH2), 3.57–3.75 (m, 560 H, 69.3 (CqCH2O), 70.2 (OCH2, PEG), 122.4 (O-CH2-Cq:CH), 144.7
PEG), 3.93 (dt, 12 H, J = 5.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 4.37 (O-CH2-Cq:CH). MALDI-TOF MS: found for the central peak:
(t, 4 H, J = 7.5 Hz, NCH2), 4.68 (s, 4 H, O-CH2-Cq:CH), 5.12 (dq, 7458 [M + Na].
6 H, J = 10.5 Hz, 1.5 Hz, OCH2CH:CH2), 5.23 (dq, 6 H, J =
17.5 Hz, 1.5 Hz, OCH2CH:CH2), 5.81–5.92 (m, 6 H, OCH2CH:
2,2-Bis(prop-2-ynyloxy)propan-1-ol (16)
CH2), 7.55 (s, 2 H, O-CH2-Cq:CH). 13C NMR (63 MHz, CDCl3): To a solution of pentaerythritol (100 g; 0.73 mmol) in DMSO
δ 26.4 (OCH2CH2), 27.4 (NCH2CH2), 45.5 (Cq), 50.1 (NCH2), (250 mL) was added, under stirring, sodium hydroxide (117 g;
65.2 (O-CH2-Cq:CH), 69.3 (Cd), 69.6 (CqCH2OAll), 70.7 (OCH2, 2.92 mol) in water (250 mL). The mixture was cooled to 0 °C
PEG), 72.2 (OCH2CH:CH2), 116.0 (OCH2CH:CH2), 122.3 and propargyl bromide (315 mL; 2.82 mol; 80% in toluene)
(O-CH2-Cq:CH), 135.3 (OCH2CH:CH2), 145.3 (O-CH2-Cq:CH). was slowly added. The mixture was then stirred at room temp-
MALDI-TOF MS: found for the central peak: 6990 [M + Na].
erature for 24 h. The mixture was extracted with diethyl ether
Purification by ultrafiltration. The aqueous solution was (3 × 300 mL). The combined organic layers were washed with a
diluted with water (30 mL), filtered on a PVDF membrane saturated aqueous solution of sodium hydrogen phosphate
(47 mm, 0.45 μm) and the ultrafiltration was performed in (200 mL), brine (200 mL), dried over sodium sulfate (100 g), fil-
Amicon 8050 stirred cells fitted with Amicon Ultracell PL Mem- tered and concentrated under vacuum. Purification by flash
brane Disks, molecular weight cutoff 1000, under 3.8 bar chromatography (petroleum ether–AcOEt: 3/2) afforded
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1025

View Article Online
Paper
Green Chemistry
compound 16 as a colorless oil (82.7 g; 45%). Spectral data (ES+): [M + 23]+: 327.3. Anal. Calcd for C18H26BrO4: C, 71.03;
were in accordance with those previously reported.30
H, 7.95; O, 21.03. Found: C, 70.98; H, 8.07; O, 21.01.
Eluted second was compound 20 as a colorless oil (107.7 g;
85%). 1H NMR (360 MHz, CDCl3): δ 1.67–1.71 (m, 2 H,
OCH2CH2), 1.92–1.97 (m, 2 H, BrCH2CH2), 2.40 (t, 2 H, J =
2.5 Hz, uCH), 3.39 (s, 2 H, CqCH2O), 3.41–3.47 (m, 4 H,
BrCH2CH2, OCH2CH2), 3.51 (s, 6 H, CqCH2O), 4.12 (d, 6 H, J =
2.5 Hz, OCH2CuCH). 13C NMR (91 MHz, CDCl3): δ 28.3
(OCH2CH2), 30.0 (BrCH2CH2), 34.0 (BrCH2CH2), 45.0 (Cq), 58.8
(OCH2CuCH), 69.2 (CqCH2O), 69.4 (CqCH2O), 70.4
(OCH2CH2), 74.2 (uCH), 80.4 (CuCH). IR (NaCl): 3292, 2876,
2116, 1091, 642 cm−1. MS (ES+): 409.4. HRMS (ES+): Calcd for
C18H25BrO4Na: 407.0828. Found: 407.0832. Anal. Calcd for
C18H25BrO4: C, 56.11; H, 6.54. Found: C, 56.33; H, 6.31.
Compound 17
To a solution of 16 (116 mg; 0.46 mmol) and 12 (732 mg;
2.07 mmol) in THF (5 mL) were successively added under stir-
ring a 1 M aqueous solution of CuSO4·5H2O (1.2 mL) and a
1 M aqueous solution of sodium ascorbate (2.8 mL). After 20 h
compound 17 was extracted with diethyl ether (3 × 10 mL). The
combined organic layer was washed three times with a mixture
of a saturated aqueous solution of ammonium chloride
(10 mL) and a 28% aqueous solution of ammonia (3 mL) for
30 min, water (10 mL) and brine (10 mL), dried over sodium
sulfate (4 g), filtered and concentrated. Compound 17 was
obtained as a colorless oil (361 mg; 60%) after flash chromato-
graphy (CH2Cl2–MeOH: 95/5). 1H NMR (360 MHz, CDCl3):
δ 1.41–1.60 (m, 6 H, OCH2CH2), 1.91–2.00 (m, 6 H, NCH2CH2),
3.34–3.40 (m, 30 H, CqCH2O), 3.51 (s, 6 H, OCH2CH2), 3.62 (s,
2 H, CH2OH), 3.91 (dt, 18 H, J = 5.5 Hz, J = 1.5 Hz, OCH2CH:
CH2), 4.36 (t, 6 H, J = 7.5 Hz, CH2N), 4.56 (s, 6 H, OCH2Cq:CH),
5.08–5.13 (dq, 9 H, J = 10.5 Hz, J = 1.5 Hz, OCH2CH:CH2),
5.18–5.26 (dq, 9 H, J = 17.5 Hz, J = 1.5 Hz, OCH2CH:CH2),
5.78–5.91 (m = 9 H, OCH2CH:CH2), 7.53 (s, 3 H, OCH2Cq:CH).
Compound 18
Method with CuSO4–AscNa. To a solution of compound 20
(23.4 g; 60.7 mmol) and compound 12 (64.4 g; 182.2 mmol) in
PEG400 (130 mL) at 0 °C were successively added, under stir-
ring, a 1 M aqueous solution of CuSO4·5H2O (1.51 g;
6.07 mmol) and a 1 M aqueous solution of sodium ascorbate
(2.41 g; 12.1 mmol). After 30 min, compound 18 was extracted
with diethyl ether (2 × 200 mL). The organic layer was washed
twice with a mixture of a saturated aqueous solution of
ammonium chloride (50 mL) and a 28% aqueous solution of
ammonia (15 mL) for 30 min, water (100 mL) and brine
(100 mL), dried over sodium sulfate (50 g) and filtered. Evapor-
ation of the solvent afforded compound 18 as a slightly orange
oil (87.3 g; 99%) that was used in the next step without further
purification. An analytical sample was obtained by flash
chromatography (petroleum ether–AcOEt: 3/7). 1H NMR
(360 MHz, CDCl3): δ 1.53–1.68 (m, 8 H, OCH2CH2(CH2)2),
1.83–2.03 (m, 8 H, BrCH2CH2, NCH2CH2), 3.34–3.47 (m, 42 H,
BrCH2, OCH2CH2, CqCH2O), 3.92 (dt, 18 H, J = 5.5 Hz, J =
1.5 Hz, OCH2CH:CH2), 4.36 (t, 6 H, J = 7.5 Hz, NCH2), 4.56 (s,
13C NMR (91 MHz, CDCl3):
δ 26.6 (OCH2CH2), 27.5
(NCH2CH2), 45.3 (Cq), 45.5 (Cq), 50.3 (CH2N), 64.7 (CH2OH),
65.2 (OCH2Cq:CH), 69.5 (CqCH2O), 70.0 (CqCH2O), 70.6
(OCH2CH2), 72.4 (OCH2CH:CH2), 116.2 (OCH2CH:CH2), 122.6
(OCH2Cq:CH), 135.3 (OCH2CH:CH2), 145.3 (OCH2Cq:CH). IR
(NaCl): 3400, 3079, 3012, 2868, 1645, 1094 cm−1. MS: (ES+):
[M + 23]+: 1333.6, [M/2 + 23]+: 666.9. Anal. Calcd for
C68H111N9O16: C, 62.31; H, 8.54; N, 9.62; O, 19.53. Found: C,
61.91; H, 8.46; N, 9.51; O, 19.35.
Compound 20
To a suspension of tripropargylated pentaerythritol 16 (82.0 g; 6 H, OCH2Cq:CH), 5.11–5.27 (dq, 9 H, J = 10.5 Hz, J = 1.5 Hz,
0.328 mol) in aqueous sodium hydroxide (131 g; 3.28 mol in OCH2CH:CH2), 5.27 (dq, 9 H, J = 17.5 Hz, J = 1.5 Hz,
250 mL of water) were added dibromobutane (155 mL; OCH2CH:CH2), 5.82–5.93 (m = 9 H, OCH2CH:CH2), 7.56 (s, 3 H,
1.30 mol) and TBAB (10.0 g; 0.03 mol). The mixture was OCH2Cq:CH). 13C NMR (91 MHz, CDCl3): δ 26.4 (OCH2CH2), 27.3
heated at 85 °C under stirring for 12 h. After cooling to room (NCH2CH2), 28.0 (OCH2CH2), 29.7 (BrCH2CH2), 33.8 (BrCH2),
temperature, the two layers were separated. The aqueous layer 45.2 (Cq), 50.0 (NCH2), 65.0 (OCH2Cq:CH), 69.2 (CqCH2O), 69.7
was extracted once with diethyl ether (200 mL). The organic (CqCH2O), 70.3 (OCH2CH2), 72.3 (OCH2CH:CH2), 116.2
layer was washed with a saturated aqueous solution of KH2PO4 (OCH2CH:CH2), 122.6 (OCH2Cq:CH), 135.3 (OCH2CH:CH2), 145.3
(100 mL) and water (100 mL), dried over sodium sulfate (25 g), (OCH2Cq:CH). IR (NaCl): 3400, 3079, 3012, 2868, 1645,
filtered and concentrated to give a yellow oil from which 1094 cm−1. MS: (ES+): [M + 23]+: 1468.8, [M/2 + 23]+: 745.9.
dibromobutane (190 g) was recovered by distillation (bp 38 °C at HRMS (ES+): Calcd for C72H118BrN9O16Na2: 744.8832. Found:
0.6 mbar). Flash chromatography (petroleum ether–Et2O: 9/1) of 744.8823. Anal. Calcd for C72H118BrN9O16: C, 59.82; H, 8.23; N,
the residue afforded first compound 21 (4.0 g; 4%). 1H NMR 8.72; O, 17.71. Found: C, 59.79; H, 7.99; N, 8.77; O, 17.47.
(360 MHz, CDCl3): δ 2.30 (qt, 2 H, J = 6.5 Hz, 1.5 Hz, CH2CH:
Method with copper turnings. A mixture of compound 20
CH2), 2.40 (t, 2 H, J = 2.5 Hz, uCH), 3.41 (s, 2 H, CqCH2O), (0.77 g–2.00 mmol) and compound 12 (2.13 g–6.03 mmol),
3.45 (t, 2 H, J = 6.5 Hz, OCH2CH2), 3.52 (s, 6 H, CqCH2O), 4.12 copper turnings (0.5 g–7.86 mmol), water (1.2 mL), and PEG400
(d, 6 H, J = 2.5 Hz, OCH2CuCH), 4.98–5.10 (m, 2 H, CH2CH: (8.4 g) was stirred at r.t. for 17 h and then at 60 °C for 8 h. The
CH2), 5.75–5.89 (m, 1 H, CH2CH:CH2). 13C NMR (75 MHz, copper turnings were removed and the solution was extracted
CDCl3): δ 34.2 (CH2CH:CH2), 45.1 (Cq), 58.8 (OCH2CuCH), with Et2O (2 × 12.5 mL), washed with water (5 mL) and brine
69.2 (CqCH2O), 69.3 (CqCH2O), 70.8 (OCH2CH2), 74.1 (uCH), (1 mL), dried over sodium sulfate (1 g), filtered and concen-
80.2 (CuCH) 116.2 (CH2CH:CH2), 135.7 (CH2CH:CH2). MS: trated. Compound 18 was obtained as an oil (2.82 g – 97%).
1026 | Green Chem., 2013, 15, 1016–1029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
Compound 19
6 H, OCH2Cq:CH), 7.60 (s, 2 H, OCH2Cq:CH). 13C NMR
(91 MHz, CDCl3): δ 26.7 (OCH2CH2), 27.6 (NCH2CH2), 45.5
(Cq), 50.2 (NCH2CH2), 64.8 (OCH2Cq:CH), 65.2 (OCH2Cq:CH),
69.5 (CqCH2O), 70.0 (PEG-CH2-O), 70.7 (OCH2, PEG), 72.4
(OCH2CH:CH2), 116.2 (OCH2CH:CH2), 122.5 (OCH2Cq:CH),
122.7 (OCH2Cq:CH), 135.3 (OCH2CH:CH2), 145.3 (OCH2Cq:
CH). MALDI-TOF MS: found for the central peak: 9097
[M + Na].
Method with copper turnings. A mixture of bispropargy-
lated PEG 1 (324 mg; 51.7 μmol), azido derivative 12 (176 mg;
125 μmol), copper turnings (233 mg; 3.6 mmol), water
(0.5 mL), and THF (1 mL) was stirred at r.t. for 22 h and then
at 60 °C for 2.5 h. The copper turnings were removed and the
aqueous solution was diluted with water (20 mL), filtered on a
PVDF membrane (47 mm, 0.45 μm) and the ultrafiltration was
performed in Amicon 8050 stirred cells fitted with Amicon
Ultracell PL Membrane Disks, molecular weight cutoff 1000,
under 3.8 bar pressure. After the first ultrafiltration, the reten-
tate (5 mL) was diluted with water (20 mL), and the solution
was ultrafiltrated again to afford, after freeze drying, 430 mg of
22 as a white powder (91%).
To a solution of compound 18 (20.0 g; 13.8 mmol) in PEG400
(16 mL) was added sodium azide (0.99 g; 15.2 mmol). The
mixture was heated at 60 °C under stirring for 2.5 h and then
cooled to room temperature. Compound 19 was extracted with
diethyl ether (2 × 20 mL). The organic layer was washed once
with water (20 mL), dried over sodium sulfate (5 g) and fil-
tered. Evaporation of diethyl ether afforded compound 19 as a
slightly orange viscous oil (19.1 g; 98%) that was used in the
next step without further purification. An analytical sample
was obtained by flash chromatography (petroleum ether–
1
AcOEt: 3/7). H NMR (360 MHz, CDCl3): δ 1.52–1.67 (m, 10 H,
OCH2CH2, N3CH2CH2), 1.91–2.03 (m, 6 H, NCH2CH2), 3.27 (t,
2 H, J = 6.5 Hz, N3CH2), 3.32–3.52 (m, 40 H, OCH2CH2), 3.92
(dt, 18 H, J = 5.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 4.36 (t, 6 H, J =
7.5 Hz, NCH2CH2), 4.56 (s, 6 H, OCH2Cq:CH), 5.11–5.27 (dq,
9 H, J = 10.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.11 (dq, 9 H, J =
10.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 5.24 (dq, 9 H, J = 17.5 Hz,
J = 1.5 Hz, OCH2CH:CH2), 5.79–5.92 (m = 9 H, OCH2CH:CH2),
7.56 (s, 3 H, OCH2Cq:CH). 13C NMR (91 MHz, CDCl3): δ 26.0
(OCH2CH2), 26.5 (OCH2CH2), 26.7 (N3CH2CH2), 27.4
(NCH2CH2), 45.4 (Cq), 50.1 (NCH2CH2), 51.2 (N3CH2CH2), 65.1
(OCH2Cq:CH), 69.3 (CqCH2O), 69.8 (CqCH2O), 70.4 (OCH2CH2),
72.3 (OCH2CH:CH2), 116.2 (OCH2CH:CH2), 122.6 (OCH2Cq:
CH), 135.3 (OCH2CH:CH2), 145.3 (OCH2Cq:CH). IR (NaCl):
3400, 3079, 2096, 1645, 1094 cm−1. MS: (ES+): [M + 23]+:
Compound 23
Compound 22 (0.50 g; 0.056 mmol) was dissolved in ethanol
(1 mL) by heating at 60 °C in a quartz tube equipped with a
magnetic stirrer. After cooling to room temperature, mercapto-
ethanol 14 (0.35 mL; 5 mmol) was added. The mixture was
submitted to UV irradiation at 254 nm under stirring for 14 h
then diluted with 1 mL of ethanol, placed at −14 °C for
30 min. The white solid was then filtered and washed with
diethyl ether (2 × 3 mL) affording compound 23 as a white
1429.8, [M/2
+
23]+: 726.4. HRMS (ES+): Calcd for
C72H118N12O16Na2: 726.4287. Found: 726.4291. Anal. Calcd for
C72H118N12O16: C, 61.43; H, 8.45; N, 11.94; O, 18.18. Found: C,
61.31; H, 8.41; N, 11.68; O, 18.15.
Compound 22
1
powder (0.57 g; 99%). H NMR (360 MHz, CDCl3): δ 1.50–1.63
Method with CuSO4/AscNa. To a solution of propargylated
PEG 1 (20.0 g; 3.2 mmol) and compound 19 (20.0 g;
14.2 mmol) in THF (35 mL) and water (35 mL) were succes-
sively added, under stirring, CuSO4·5H2O (0.80 g; 3.2 mmol)
and sodium ascorbate (1.27 g; 6.4 mmol). After 3 h, THF was
evaporated and the aqueous phase was extracted with dichloro-
methane (3 × 60 mL). The combined organic layers were
washed twice with a mixture of a saturated aqueous solution of
ammonium chloride (50 mL) and a 28% aqueous solution of
ammonia (15 mL) for 30 min, water (100 mL), dried over
sodium sulfate (20 g), and filtered. The volume of the organic
phase was reduced to 40 mL and compound 22 was precipi-
tated under vigorous stirring at 0 °C by addition of Et2O
(250 mL). The precipitate was recovered by filtration and
washed with Et2O (100 mL) affording compound 22 as a white
(m, 16 H, OCH2CH2), 1.75–1.85 (m, 36 H, SCH2CH2CH2),
1.92–2.00 (m, 16 H, NCH2CH2), 2.58 (t, 36 H, J = 7.0 Hz,
SCH2CH2CH2), 2.70 (t, 36 H, J = 5.5 Hz, SCH2CH2OH), 3.34 (s,
64 H, CqCH2O), 3.40–3.46 (m, 52 H, OCH2CH2), 3.63–3.71 (m,
590 H,(OCH2CH2)140O, PEG, CH2OH), 4.37 (t, 16 H, J = 7.0 Hz,
NCH2CH2), 4.54 (s, 12 H, OCH2Cq:CH), 4.66 (s, 4 H, OCH2Cq:
CH), 7.61 (s, 8 H, OCH2Cq:CH). 13C NMR (91 MHz, CDCl3):
δ 26.9 (OCH2CH2), 27.7 (NCH2CH2), 28.9 (SCH2CH2CH2), 30.2
(SCH2CH2CH2), 35.4 (SCH2CH2OH), 45.7 (Cq), 50.4
(NCH2CH2), 61.0 (SCH2CH2OH), 65.3 (OCH2Cq:CH), 69.7–69.9
(OCH2CH2), 70.8 (OCH2, PEG), 122.9 (OCH2Cq:CH), 145.4
(OCH2Cq:CH). MALDI-TOF MS: found for the central peak:
10 503 [M + Na].
1
powder (26.4 g; 91%). H NMR (360 MHz, CDCl3): δ 1.51–1.61
(m, 16 H, OCH2CH2), 1.92–2.01 (m, 16 H, NCH2CH2), 3.36–3.46
(m, 80 H, OCH2CH2), 3.57–3.75 (m, 560 H, PEG), 3.93 (dt,
Acknowledgements
36 H, J = 5.5 Hz, J = 1.5 Hz, OCH2CH:CH2), 4.35 (t, 16 H, J = 7.0 We thank the Ministère de l’Enseignement Supérieur et de la
Hz, NCH2CH2), 4.54 (s, 12 H, OCH2Cq:CH), 4.67 (s, 4 H, Recherche, the Centre National de la Recherche Scientifique,
OCH2Cq:CH′), 5.10 (dq, 18 H,
OCH2CH:CH2), 5.23 (dq, 18 H,
J
J
=
10.5 Hz, 1.5 Hz, the Université Paris-Sud and the Université of Cergy-Pontoise
= 17.5 Hz, 1.5 Hz, for financial support. We are grateful to René Brennetot from
OCH2CH:CH2), 5.81–5.91 (m = 18 H, OCH2CH:CH2), 7.56 (s, CEA-Saclay for ICP-MS analysis.
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1027

View Article Online
Paper
Green Chemistry
(d) A. Malleron and C. Le Narvor, Carbohydr. Res., 2008,
343, 970–976; (e) M. Zacchigna, F. Cateni, S. Drioli and
G. M. Bonora, Polymers, 2011, 3, 1076–1090 and references
cited herein.
Notes and references
1 (a) F. Garcia Calvo-Flores, ChemSusChem, 2009, 2, 905–919;
(b) P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39,
301–312.
2 B. M. Trost, Science, 1991, 254, 1471–1477.
3 R. A. Sheldon, ChemTech, 1994, 24, 38–47.
4 (a) C. Jiménez-González, A. D. Curzons, D. J. C. Constable
15 (a) A. D. Curzons, D. J. C. Constable, D. N. Mortimer and
V. L. Cunningham, Green Chem., 2001, 3, 1–6;
(b) D. J. C. Constable, A. D. Curzons and
V. L. Cunningham, Green Chem., 2002, 4, 521–527.
and V. L. Cunningham, Int. J. Life Cycle Assess., 2004, 9, 16 M. Eissen and J. O. Metzger, Chem.–Eur. J., 2002, 8,
114–121; (b) D. J. C. Constable, C. Jimenez-Gonzalez and
R. K. Henderson, Org. Process Res. Dev., 2007, 11, 133–137.
5 (a) G. W. V. Cave, C. L. Raston and J. L. Scott, Chem.
3580–3585.
17 J. Augé and M.-C. Scherrmann, New J. Chem., 2012, 36,
1091–1098.
Commun., 2001, 2159–2169; (b) K. Tanaka, Solvent-free 18 J. Augé, Green Chem., 2008, 10, 225–231.
Organic Synthesis, Wiley-VCH, 2003; (c) R. S. Varma and 19 (a) M. Meldal and W. Tornøe, Chem. Rev., 2008, 108,
Y. Ju, in Green Separation Processes, ed. C. A. M. Afonso and
J. G. Crespo, Wiley-VCH, 2005, pp. 53–87; (d) F. M. Kerton,
2952–3015; (b) J. E. Hein and V. V. Fokin, Chem. Soc. Rev.,
2010, 39, 1302–1315.
Alternative Solvents for Green Chemistry, RSC Green 20 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
Chemistry Book Series, Royal Society of Chemistry, 2009. Int. Ed., 2001, 40, 2004–2021.
6 (a) M.-C. Scherrmann, S. Norsikian and A. Lubineau, in 21 (a) M. M. McPhee and S. M. Kerwin, Bioorg. Med. Chem.,
Advances in Organic Synthesis. ed. Atta-ur-Rahman and
2001, 9, 2809–2818; (b) T. S. Emrick and K. Breitenkamp,
G. Jenner, Bentham Science Publishers, 2005, vol. 1,
WO 2005/025736 A1, 2005.
pp. 341–401; (b) Organic Reactions in Water: Principles, Strat- 22 (a) L. A. Canalle, S. S. vanBerkel, L. T. de Haan and
egies and Applications, ed. U. M. Lindstrom, Wiley-Black-
well, 2007; (c) Handbook of Green Chemistry–Green Solvents,
Vol. 5: Reactions in water, ed. P. T. Anastas and C.-J. Li,
J. C. M. van Hest, Adv. Funct. Mater., 2009, 19, 3464–3470;
(b) X. Sheng, T. C. Mauldin and M. R. Kessler, J. Polym. Sci.,
Part A: Polym. Chem., 2010, 48, 4093–4102.
Wiley-VCH, 2010; (d) M. O. Simon and C.-J. Li, Chem. Soc. 23 (a) N. Mekni and A. Baklouti, J. Soc. Chim. Tunisie, 2005, 7,
Rev., 2012, 41, 1415–1427.
205–207; (b) S. Mahouche, N. Mekni, L. Abbassi, P. Lang,
C. Perruchot, M. Jouini, F. Mammeri, M. Turmine,
H. B. Romdhane and M. M. Chehimi, Surf. Sci., 2009, 603,
3205–3211.
7 (a) J. Chen, S. K. Spear, J. G. Huddleston and R. D. Rogers,
Green Chem., 2005, 7, 64–82; (b) E. Colacino, J. Martinez,
F. Lamaty, L. S. Patrikeeva, L. L. Khemchyan, V. P. Ananikov
and I. P. Beletskaya, Coord. Chem. Rev., 2012, 256, 24 R. A. Sheldon, Green Chem., 2007, 9, 1273–1283.
2893–2920.
25 C. Jimenez-Gonsalez, C. S. Ponder, Q. B. Broxterman
and J. B. Manley, Org. Process Res. Dev., 2011, 15,
912–917.
26 (a) P. L. Nichols Jr. and E. Yanovsky, J. Am. Chem. Soc.,
1945, 67, 46–49; (b) A. Lubineau, A. Malleron and
C. Le Narvor, Tetrahedron Lett., 2000, 41, 8887–8891.
27 Alternatively, triallyl pentaerythritol can be prepared using
allyl chloride under aqueous conditions. See: C. U. Oertli,
WO 2008/048882 A2, 2008.
8 Handbook of Green Chemistry–Green Solvents, Vol. 6: Ionic
Liquids, ed. P. T. Anastas, P. Wasserscheid and A. Stark,
Wiley-VCH, 2010.
9 Handbook of Green Chemistry–Green Solvents, Vol. 4: Super-
critical Solvents, ed. P. T. Anastas, W. Leitner and
P. G. Jessop, Wiley-VCH, 2010.
10 (a) J. Lu and P. H. Toy, Chem. Rev., 2009, 109, 815–838;
(b) M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003,
103, 3401–3430.
28 Y. Ju, D. Kumar and R. S. Varma, J. Org. Chem., 2006, 71,
6697–6700.
11 (a) R. B. Greenwald, J. Controlled Release, 2001, 74,
159–171; (b) J. Li and W. J. Kao, Biomacromolecules, 2003, 4, 29 The 1,4-disubstitution pattern of the triazole ring in all
1055–1067; (c) S. S. Banerjee, N. Aher, R. Patil and
J. Khandare, J. Drug Deliv, 2012, 2012, 17, DOI: 10.1155/
2012/103973, Article ID 103973.
compounds was supported by the large and positive
Δ(δC4 − δC5) value (17–21 ppm) in their 13C NMR spectra in
agreement
with
previous
observations;
see:
12 F. E. Bailey Jr. and J. V. Koleske, in Poly(ethylene oxide), Aca-
demic Press, New York, 1976.
13 N. Prosa, R. Turgis, R. Piccardi and M.-C. Scherrmann,
Eur. J. Org. Chem., 2012, 2188–2200.
(a) N. A. Rodios, J. Heterocycl. Chem., 1984, 21, 1169–1173;
(b) B. Hoffmann, B. Bernet and A. Vasella, Helv. Chim. Acta,
2002, 85, 265–287; (c) A. Dondoni and A. Marra, J. Org.
Chem., 2006, 71, 7546–7557.
14 (a) M. Benaglia, R. Annunziata, M. Cinquini, F. Cozzi and 30 (a) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtev,
S. Ressel, J. Org. Chem., 1998, 63, 8628–8629;
(b) A. Fishman, M. E. Farrah, J.-H. Zhong,
S. Paramanantham, C. Carrera and E. Lee-Ruff, J. Org.
N. Noodleman, K. B. Sharpless and V. V. Fokin, J. Am.
Chem. Soc., 2005, 127, 210–216; (b) N. Gommermann,
A. Gehrig and P. Knochel, Synlett, 2005, 2796–2798.
Chem., 2003, 68, 9843–9846; (c) M. Ballico, S. Driolli and 31 (a) G. Cravotto, V. V. Fokin, D. Garella, A. Binello, L. Boffa
G. M. Bonora, Eur. J. Org. Chem., 2005, 2064–2073;
and A. Barge, J. Comb. Chem., 2010, 12, 13–15; (b) P. Cintas,
1028 | Green Chem., 2013, 15, 1016–1029
This journal is © The Royal Society of Chemistry 2013

View Article Online
Green Chemistry
Paper
A. Barge, T. Tagliapietra, L. Boffa and G. Cravotto, Nat. 35 F. G. Calvo-Flores, J. Isac-García, F. Hernández-Mateo,
Protoc., 2010, 5, 607–616.
F. Pérez-Balderas, J. A. Calvo-Asín, E. Sanchéz-Vaquero and
32 I. Billault, F. Pessel, A. Petit, R. Turgis and
F. Santoyo-González, Org. Lett., 2000, 2, 2499–2502.
M.-C. Scherrmann, presented at the International Green 36 D. Kumar, G. Patel and V. B. Reddy, Synlett, 2009,
Catalysis Symposium, Rennes, France, 2012, P13. 399–402.
33 (a) C. N. Bowman and C. E. Hoyle, Angew. Chem., Int. Ed., 37 When the reaction was carried out in pure water the con-
2010, 49, 1540–1573; (b) A. Dondoni and A. Marra, Chem.
Soc. Rev., 2012, 41, 573–586.
34 A. Mollard and I. Zharov, Inorg. Chem., 2006, 45,
10172–10179.
version was not total.
38 E. V. Getmanova, A. S. Tereshchenko, G. M. Ignat’eva,
E. A. Tatarinova, V. D. Myakushev and A. M. Muzafarov,
Russ. Chem. Bull., Int. Ed., 2004, 53, 137–143.
This journal is © The Royal Society of Chemistry 2013
Green Chem., 2013, 15, 1016–1029 | 1029