A cost-effective, column-free route to ethylene glycol oligomers EG 6, EG10, and EG12

Article abstract of DOI:10.1055/s-0031-1289685

Although monodisperse ethylene glycol (EG) oligomers are important in a wide range of applications (ranging from drug therapeutics to materials science and engineering), their cost - especially for longer EG oligomers is often prohibitive. For example, decaethylene, EG₁₀, and dodecaethylene, EG₁₂, glycols cost hundreds of dollars per gram, and are only available from most vendors, including Sigma-Aldrich, in the polydispersed form. This high-cost is, in large part, due to laborious nature of synthesis and, above all, purification steps involved. Therefore, the motivation of our work was to design a cost-effective route to the EG oligomers that would altogether avoid the column-chromatography purification. This was achieved by a simple synthetic strategy, which combines bidirectional growth of the EG chains with the protection scheme using easy-to-remove trityl groups. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289685

PAPER
717
A Cost-Effective, Column-Free Route to Ethylene Glycol Oligomers EG6,
EG10, and EG12
Ethylene
G
lycol h6
O
ligomers
E
r
G
,
E
G
1 i12
,
a
nd E
s
G
M. Gothard, Bartosz A. Grzybowski*
0
Department of Chemistry, Northwestern University, 2145 Sheridan Rd., Evanston, IL 60208, USA
E-mail: grzybor@northwestern.edu
Received 5 October 2011; revised 14 December 2011
son, tetra- and di(ethylene glycol)s can be purchased from
the same company for less than $20/kilogram. Longer EG
oligomers, namely deca- and dodeca(ethylene glycol)s
(EG10 and EG12, respectively), however, are prohibitively
Abstract: Although monodisperse ethylene glycol (EG) oligomers
are important in a wide range of applications (ranging from drug
therapeutics to materials science and engineering), their cost – espe-
cially for longer EG oligomers is often prohibitive. For example,
decaethylene, EG10, and dodecaethylene, EG12, glycols cost hun- more expensive (TCI American: EG10: $360/gram) and
dreds of dollars per gram, and are only available from most vendors,
are only available from most vendors, including Sigma-
including Sigma-Aldrich, in the polydispersed form. This high-cost
Aldrich, in the polydispersed form. Herein, we describe
is, in large part, due to laborious nature of synthesis and, above all,
an efficient, multigram preparation for higher order (EG6,
purification steps involved. Therefore, the motivation of our work
EG10, and EG12) discrete EG oligomers that does not re-
was to design a cost-effective route to the EG oligomers that would
quire traditional column chromatography purification. It
is our hope that this route will allow academic research
groups access to gram quantities of affordable monodis-
persed EG oligomers.
altogether avoid the column-chromatography purification. This was
achieved by a simple synthetic strategy, which combines bidirec-
tional growth of the EG chains with the protection scheme using
easy-to-remove trityl groups.
Key words: ethylene glycol oligomer, monodisperse, column-free,
EG oligomer, PEGs, cost-effective
Due to the high demand of EGs in biological applica-
tions,28 many strategies have been demonstrated for the
preparation of discrete EG oligomers. In previous meth-
ods, benzyl,7,8,14,29 allyl,10,25 and other protection strategies
have been employed to prepare mono-protected EGs. All
these methods come with significant limitations, not only
is the deprotection of these protecting groups tedious and
low yielding, purification steps also remain challenging.
Benzyl protection groups can be difficult to remove by
hydrogenolysis requiring metal-based catalysts and often
require long reaction times, elevated temperatures, and
column chromatography to isolate the product. As an al-
ternative to the benzyl protection strategy, allyl hydroxy
protection has also been used.10 Removal of allyl protec-
tion groups, however, also requires metals like palladium
making traditional column chromatography a necessity.
In contrast, trityl-hydroxy protection recently employed
by Lumpi for the synthesis of monodispersed ethylene
glycol oligomers, allows for easy deprotection under mild
conditions using acetic acid at room temperature or at
slightly elevated temperatures.15 In addition to the easy re-
moval of the trityl groups, the resultant trityl alcohol gen-
erated during deprotection can be easily separated from
the EG product and regenerated to Trt-Cl with SOCl2.
Poly(ethylene glycols) (PEGs) are important in a variety
of fields including drug therapeutics,1–5 synthetic chemis-
try,6–16 materials science,17 and engineering.18–20 In phar-
macology, attachment (PEG-ylation) of PEG chains to
therapeutic drugs (small molecules),1,8,21 peptides,21,22 and
proteins22,23 can influence stability, immunogenicity, and
pharmacokinetics.1,21,24 Biologically active molecules that
are conjugated to PEG moieties can have higher water sol-
ubility and improved bioavailability. The fact that PEGs
are nontoxic and biodegradable, and are rapidly excreted
after administration, makes these oligomers one of the
most popular polymeric carriers for drug molecules.
Despite advances in PEG applications, PEG-ylated bio-
pharmaceuticals continue to hold challenges in site-
selectivity25,26 and polydispersity.27 The former issue has
been partly addressed by the incorporation of chemoselec-
tive linkers into protein therapeutics using native chemi-
cal ligation.11,13 The preparation of discrete ethylene
glycol (EG) oligomers, however, remains a synthetic
challenge and is a motivation of the present work.
One of the goals of this work is to provide a general meth-
od for preparing monodispersed EG oligomers that avoids
traditional purification techniques such as column chro-
matography. In our method, we combine the bidirectional
growth method developed by Keegstra26 and the protec-
tion scheme used by Lumpi et al. in which a ditosylated
EG derivative is coupled to two mono-tritylated (Trt) EG
oligomers to produce a single di-Trt protected oligomer.15
We chose bidirectional growth method because longer EG
oligomers can be obtained with fewer coupling steps com-
Although monodispersed di- and tetra(ethylene glycol)s
are both inexpensive, higher order discrete EG oligomers
are often 10–1000-fold more expensive and in some cases
not commercially available in gram quantities. Hexa(eth-
ylene glycol) (EG6), for example, can be purchased from
Sigma-Aldrich for approximately $10/gram. In compari-
SYNTHESIS 2012, 44, 717–722
x
x
.x
x
.2
0
1
1
Advanced online publication: 03.02.2012
DOI: 10.1055/s-0031-1289685; Art ID: M94011SS
© Georg Thieme Verlag Stuttgart · New York

718
C. M. Gothard, B. A. Grzybowski
PAPER
TrtCl
TsCl, KOH
O
Ts
O
Trt
O
H
TsO
3a,b n = 2, 4
HO
4a,b n = 2, 4
HO
2a,b n = 2, 4
n
n
n
THF–H2O
18 h
> 85%
Et3N
CH2Cl2, 18 h
> 80%
Scheme 1 Synthesis of ditosylates 3a,b and mono-tritylated glycols 4a,b
pared to mono-directional growth. Our approach is easy to col) (1c) were prepared in an analogous fashion
carry out and, importantly, eliminates the need for chro- (Scheme 3).
matographic purification steps (which, for EGs, are
known to be painstaking).
The initial building blocks in our scheme, ditosylated The H and 13C NMR spectra of 1a–c all show a similar
EG oligomers 1a–c were characterized by standard ana-
lytical techniques like NMR spectroscopy and ESI-MS.
1
di(ethylene glycol) 3a (Ts-EG2-OTs) and mono-tritylated pattern (Figure 1). The 1H NMR spectra contain two sets
di(ethylene glycol) 4a (Trt-EG2-OH), were chosen for the of triplet resonances; one upfield triplet associated with
simple convenience of being able to crystallize 3a and 4a the four terminal methylene protons and one downfield
and isolate each as pure crystalline solids without requir- triplet associated with the two methylene groups (4 H) ad-
ing column chromatography. Ditosylate 3a was prepared jacent to the terminal methylene. This pattern is mirrored
by reacting di(ethylene glycol) (2a) with excess tosyl in the 13C NMR spectra and for hexa(ethylene glycol)
chloride and potassium hydroxide to provide the product (EG6, 1a) contains one downfield resonance (Figure 1a,
as an oily liquid (Scheme 1). The oil was purified by crys- resonance 1), one upfield resonance (Figure 1a, resonance
tallization from hot methanol to provide Ts-EG2-OTs (3a) 6), and four well-resolved resonances associated with
as a white crystalline solid. Mono-tritylated di(ethylene eight central methylene carbons. The assignments for 13C
glycol) Trt-EG2-OH (4a) was synthesized by reacting tri- resonances 1 and 6 were verified using the assumption
1
tyl chloride with excess di(ethylene glycol) (2a) to give an that H resonances a and b, which have a COSY cross
oily liquid. Crystallization from dichloromethane and peak to each other, are of comparable proximity. The
hexanes provided 4a as a crystalline solid. In both cases, COSY spectrum for dodeca(ethylene glycol) (EG12, 1c) is
3a and 4a, were purified with a single crystallization step shown in Figure 1d.
and did not require multiple crystallizations as have been
While hexa(ethylene glycol) EG6 (1a) shows six well-re-
solved resonances corresponding to the six nonequivalent
reported27 previously to obtain pure products.
Ditosylated tetra(ethylene glycol) Ts-EG4-OTs (3b) and carbons and two-fold symmetry, the 13C NMR spectrum
mono-tritylated tetra(ethylene glycol) Trt-EG4-OH (4b)
were prepared under similar conditions used to synthesize
NaH, THF
r.t.
O
Trt
Ts
O
Ts
O
Trt
3a and 4a, with the exception that products 3b and 4b
were isolated as noncrystallizable oils. As an alternative
to crystallization or column chromatography, excess re-
agents such as tosyl chloride or di(ethylene glycol) were
removed by an aqueous extraction during the workup. As
a general strategy, mono-tritylated intermediates 4a,b
were prepared using large excesses of 2a and 2b, respec-
tively, to avoid generating any significant quantities of the
ditritylated by-products. Complete removal of tosyl chlo-
ride (or the hydrolyzed form tosylic acid) from 3b or
di(ethylene glycol) from 4b was confirmed by NMR spec-
troscopy (for these and other spectra, see the Supporting
Information).
+
TrtO
TsO
HO
n
2
n
n
4 d
93%
3a n = 2
4a n = 2
5a n = 6
AcOH–CH2Cl2
TsCl, KOH
O
H
O
HO
TsO
n
n
40 °C, 12 h
76%
THF–H2O
18 h
3c n = 6
1a n = 6
94%
Scheme 2 Synthesis of EG6 (1a) from ditosylate 3a and mono-trity-
lated glycol 4a to provide ditritylated 5a followed by deprotection
with AcOH–CH2Cl2. Tosylation of 1a provides precursor 3c used in
the synthesis of EG10 (1b).
NaH, THF
r.t.
O
Ts
O
Trt
O
Trt
+
Ditritylated oligomers 5a–c and corresponding deprotect-
ed EG oligomers 1a–c were prepared according to pub-
lished procedures.15 Briefly, two equivalents of mono-
tritylated di(ethylene glycol) 4a were treated with three
equivalents of sodium hydride (60% dispersion in mineral
oil) in tetrahydrofuran at room temperature for four hours.
Next, one equivalent of ditosylated di(ethylene glycol) 3a
dissolved in tetrahydrofuran was added to provide ditrity-
lated hexa(ethylene glycol) 5a (Scheme 2). Finally, re-
moval of the trityl protection groups with acetic acid
followed by organic extraction to remove trityl hydroxide
(Trt-OH) provided hexa(ethylene glycol) (1a) as a turbid
oil. Deca(ethylene glycol) (1b) and dodeca(ethylene gly-
TsO
2 HO
4a,b n = 2, 4
TrtO
n
n
n
4 d
70–73%
3c,b n = 6, 4
5b,c n = 10, 12
AcOH–CH2Cl2
TsCl, KOH
O
H
O
Ts
HO
1b,c n = 10, 12
TsO
40 °C, 12 h
73–82%
THF–H2O
2 d
80%
n
n
3d n = 12
Scheme 3 Syntheses of EG10 (1b) and EG12 (1c). EG10 is prepared
by combining Ts-EG6-OTs (3c) and Trt-EG2-OH (4a; 2 equiv) to give
Trt-EG10-OTrt (5b). Deprotection of 5b provides EG10 (1b), which
can be further ditosylated to 3d to form higher order EGs. EG12 is pre-
pared by combining Ts-EG4-OTs (3b) and Trt-EG4-OH (4b; 2 equiv)
to give Trt-EG12-OTrt (5c) followed by deprotection of 5c to provide
EG12 (1c).
Synthesis 2012, 44, 717–722
© Thieme Stuttgart · New York

PAPER
Ethylene Glycol Oligomers EG6, EG10, and EG12
719
Figure 1 13C NMR spectra of (a) hexa(ethylene glycol) (1a), (b) deca(ethylene glycol) (1b), and (c) dodeca(ethylene glycol) (1c). COSY (top)
and 1H NMR (bottom) spectra of (d) dodeca(ethylene glycol) (1c).
for deca(ethylene glycol) EG10 (1b) is more complicated. longer EG oligomers (e.g., starting from ditosylated pre-
For 1b, the 13C spectra shows five resonances associated cursor 3d in Scheme 3). Making these oligomers purer
with five nonequivalent carbons and one larger resonance with discrete lengths means their faster accessibility for
associated with the remaining five nonequivalent carbons. pharmaceutical and chemical applications.
In a similar fashion, the 13C spectrum for dodeca(ethylene
glycol) EG12 (1c) contains five nonequivalent resonances
Commercial solvents and reagents were used without further purifi-
that each integrate to approximately two carbons and one
larger resonance associated with the 14 remaining car-
bons.
cation, unless otherwise stated. Reactions were carried out under an
atmosphere of N2 and were monitored by TLC using 250 mm fluo-
rescent silica gel glass plates with UV visualization. Solvents were
removed by rotary evaporation. Precipitated and recrystallized
products were dried under vacuum or by air suction through a filter
funnel. NMR spectra were recorded on Bruker Avance III 500 or
600 MHz spectrometer at 298 K, with working frequencies of
Analysis of EG oligomers 1a–c by ESI-MS provides an
effective method for both product identification as well as
for detecting shorter oligomer precursors that remain from
previous steps. The ESI-MS spectrum for hexa(ethylene 499.373 and 600.168 MHz for 1H, and 125.579 and 150.928 MHz
for 13C nuclei, respectively. Chemical shifts are reported in ppm and
referenced to the residual nondeuterated solvent frequencies (7.26
ppm for CHCl3). High-resolution mass spectra were recorded on an
Agilent 6210 LC-TOF electrospray ionization (ESI) mass spec-
trometer. All other mass spectra were recorded on a Thermo Finni-
gan LCQ Advantage ESI mass spectrometer.
glycol) 1a, for example, shows ion peaks [M + H]+, [M +
Na]+, and [M + NH4]+, but is devoid of precursors diethyl-
ene glycol (2a) and tetra(ethylene glycol) (2b). Similarly,
the mass spectrum for deca(ethylene glycol) (1b) does not
indicate masses associated with precursors hexa(ethylene
glycol) (1a) or di(ethylene glycol) (2a). Finally, the spec-
trum of dodeca(ethylene glycol) (1c), which was prepared
from ditosylated tetra(ethylene glycol) 3b and mono-trity-
lated tetra(ethylene glycol) 4b, does not show any remain-
ing tetra(ethylene glycol) (for all 1H, 13C NMR, and ESI-
MS spectra, please see SI).
Ts-EG2-OTs (3a)
A solution of di(ethylene glycol) (2a; 2.00 g, 18.9 mmol), TsCl
(10.8 g, 56.5 mmol), and THF (30 mL) was cooled to 0 °C in an ice
bath. A solution of KOH (7.0 g, 124.7 mmol) in H2O (15 mL) was
added dropwise over a period of 30 min. The resultant solution was
allowed to warm to r.t. and was stirred under an atmosphere of N2
for 24 h. The reaction mixture was then poured into ice water (ca.
75 mL) and the aqueous layers were extracted with CH2Cl2 (2 × 50
mL). The combined organic layers were washed with H2O (3 × 100
mL), brine (150 mL), dried (MgSO4, 18 h), filtered, and concentrat-
ed to provide a yellow oil. The oil was crystallized from methanol
to give 3a (6.9 g, 89%) as a white crystalline solid; mp 81–83 °C.
In summary, we have developed a simple and efficient
route to discrete EG oligomers EG6 (1a), EG10 (1b), EG12
(1c). Utilization of the trityl (Trt) protection strategy pro-
vides a more efficient alternative protection scheme com-
pared to previously used benzyl and allyl schemes. Our
method is unique because the products and all intermedi-
ates are isolated without column chromatography. We be-
lieve that this method can be extended to prepare even
1H NMR (500 MHz, CDCl3): d = 7.78 (d, J = 7.0 Hz, 4 H), 7.35 (d,
J = 6.5 Hz, 4 H), 4.09 (app t, J = 4.0 Hz, 4 H), 3.61 (app t, J = 4.0
Hz, 4 H), 2.45 (s, 6 H).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 717–722

720
C. M. Gothard, B. A. Grzybowski
PAPER
13C NMR (125 MHz, CDCl3): d = 145.0, 132.9, 129.9, 128.0, 69.0,
68.8, 21.7.
HRMS (ESI): m/z calcd for C38H66NO17S2 [M + NH4]+: 872.3767;
found: 872.3766.
HRMS (ESI): m/z calcd for C18H23O7S2 [M + H]+: 415.0880; found:
415.0882; m/z calcd for C18H26NO7S2 [M + NH4]+: 432.1145;
found: 432.1150; m/z calcd for C18H22NaO7S2 [M + Na]+: 437.0699;
found: 437.0702.
Trt-EG2-OH (4a)
A solution of di(ethylene glycol) (2a; 168.0 g, 1583 mmol), Et3N
(27.8 mL, 200 mmol), and CH2Cl2 (200 mL) was cooled to 0 °C un-
der an atmosphere of N2 in an ice bath. Trityl chloride (22.0 g, 79.0
mmol) dissolved in CH2Cl2 (30 mL) was added dropwise over 20
min. The solution was then allowed to warm to r.t. and stirred under
an atmosphere of N2 for 24 h. The reaction mixture was concentrat-
ed by rotary evaporation and the resultant slurry was partitioned be-
tween CH2Cl2 (200 mL) and sat. aq NaHCO3 (200 mL). The organic
layer was washed with H2O (3 × 150 mL), brine (150 mL), dried
(Na2SO4, 18 h), filtered, and concentrated to provide a white solid.
The crude white solid was crystallized from 150 mL of CH2Cl2–
hexanes (9:1) to provide 4a as a crystalline solid (27.5 g, 85%); mp
107–109 °C.
1H NMR (500 MHz, CDCl3): d = 7.47 (d, J = 6.5 Hz, 6 H), 7.31 (t,
J = 6.5 Hz, 6 H), 7.24 (t, J = 6.0 Hz, 3 H), 3.76–3.74 (m, 2 H), 3.69
(t, J = 4.0 Hz, 2 H), 3.63 (t, J = 3.5 Hz, 2 H), 3.28 (t, J = 4.0 Hz, 2
H), 2.17–2.11 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 144.0, 128.7, 127.8, 127.0, 86.7,
72.3, 70.6, 63.4, 61.9.
Ts-EG4-OTs (3b)
A solution of tetra(ethylene glycol) (2b; 5.0 g, 25.7 mmol), TsCl
(14.7 g, 77.2 mmol), and THF (50 mL) was stirred under an atmo-
sphere of N2 and cooled to 0 °C in an ice bath. A solution of KOH
(9.5 g, 169.6 mmol) in H2O (10 mL) was added dropwise over a pe-
riod of 30 min. The solution was then allowed to warm to r.t. and
stirred under an atmosphere of N2 for 2 d. At the conclusion of the
reaction, the reaction mixture was concentrated under reduced pres-
sure and the resultant white solid was partitioned between H2O (150
mL) and CH2Cl2 (150 mL). The organic layer was washed with H2O
(100 mL), brine (100 mL), dried (MgSO4), and concentrated to give
3b (12.9 g, 92%) as a yellow oil, which was used in subsequent
steps without further purification.
1H NMR (500 MHz, CDCl3): d = 7.78 (d, J = 7.0 Hz, 4 H), 7.35 (d,
J = 6.5 Hz, 4 H), 4.14 (app t, J = 4.8 Hz, 4 H), 3.68 (app t, J = 4.8
Hz, 4 H), 3.58–3.56 (m, 8 H), 2.45 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 144.9, 133.0, 129.9, 128.0, 70.8,
HRMS (ESI): m/z calcd for C27H36NO5 [M + NH4]+: 366.2064;
found: 366.2062; m/z calcd for C27H32NaO5 [M + Na]+: 371.1618;
found: 371.1617.
70.6, 69.3, 68.7, 21.7.
HRMS (ESI): m/z calcd for C22H31O9S2 [M + H]+: 503.1404; found:
503.1408; m/z calcd for C22H34NO9S2 [M + NH4]+: 520.1669;
found: 520.1694; m/z calcd for C22H30NaO9S2 [M + Na]+: 525.1223;
found: 525.1234.
Trt-EG4-OH (4b)
A solution of tetra(ethylene glycol) (2b; 172 g, 897 mmol), Et3N
(18.0 g, 179 mmol), and CH2Cl2 (200 mL) was stirred under an at-
mosphere of N2 at 0 °C in an ice bath. Trityl chloride (25.0 g, 89.7
mmol) dissolved in CH2Cl2 (25 mL) was added dropwise over 20
min. The solution was then allowed to warm to r.t. and was stirred
under an atmosphere of N2 for 24 h. The reaction mixture was con-
centrated by rotary evaporation and the resultant slurry was parti-
tioned between CH2Cl2 (200 mL) and sat. aq NaHCO3 (200 mL).
The organic layer was washed with H2O (3 × 150 mL), brine (150
mL), dried (Na2SO4, 18 h), filtered, and concentrated to provide 4b
as a yellow oil (35.5 g, 85%), which was used in subsequent steps
without further purification.
Ts-EG6-OTs (3c)
A solution of hexa(ethylene glycol) (1a; 0.70 g, 2.50 mmol), TsCl
(1.42 g, 7.50 mmol), and THF (20 mL) was stirred under an atmo-
sphere of N2 and cooled to 0 °C in an ice bath. A solution of KOH
(0.93 g, 16.5 mmol) in H2O (5 mL) was added dropwise over a pe-
riod of 10 min. The solution was then allowed to warm to r.t. and
stirred under an atmosphere of N2 for 24 h. At the conclusion of the
reaction, the reaction mixture was concentrated under reduced pres-
sure to remove most of the THF. The resultant slurry was parti-
tioned between H2O (40 mL) and CH2Cl2 (40 mL). The organic
layer was washed with H2O (40 mL), brine (40 mL), dried (MgSO4),
and concentrated to provide 3c (1.39 g, 94%) as a yellow oil; which
was used in subsequent steps without further purification.
1H NMR (500 MHz, CDCl3): d = 7.46 (d, J = 7.5 Hz, 6 H), 7.29 (t,
J = 7.5 Hz, 6 H), 7.23 (t, J = 7.0 Hz, 3 H), 3.71–3.67 (m, 12 H), 3.60
(t, J = 4.5 Hz, 2 H), 3.24 (t, J = 5.0 Hz, 2 H), 2.46 (t, J = 6 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 7.80 (d, J = 8.5 Hz, 4 H), 7.34 (d,
J = 8.0 Hz, 4 H), 4.16 (app t, J = 5.0 Hz, 4 H), 3.68 (app t, J = 5.0
Hz, 4 H), 3.62–3.58 (m, 16 H), 2.45 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 144.1, 128.7, 127.8, 126.9, 72.5,
70.8, 70.7 (2), 70.4, 63.3, 61.8, 53.4.
HRMS (ESI): m/z calcd for C27H36NO5 [M + NH4]+: 454.2588;
found: 454.2589; m/z calcd for C27H32NaO5 [M + Na]+: 459.2142;
found: 459.2145.
Ts-EG12-OTs (3d)
A solution of dodeca(ethylene glycol) (1c; 0.25 g, 0.46 mmol), TsCl
(0.262 g, 1.37 mmol), and THF (10 mL) was cooled to 0 °C in an
ice bath. A solution of KOH (0.170 g, 3.04 mmol) in H2O (3 mL)
was added dropwise over a period of 10 min. The solution was then
allowed to warm to r.t. and was stirred under an atmosphere of N2
for 2 d. At the end of the reaction, the reaction mixture was concen-
trated under reduced pressure to remove most of the THF. The re-
sultant slurry was partitioned between H2O (40 mL) and CH2Cl2 (40
mL). The organic layer was washed with H2O (40 mL), brine (40
mL), dried (MgSO4), and concentrated to provide 3d (0.315 g, 80%)
as a yellow oil.
1H NMR (500 MHz, CDCl3): d = 7.80 (d, J = 8.0 Hz, 4 H), 7.34 (d,
J = 6.5 Hz, 4 H), 4.16 (d, J = 4.0 Hz, 4 H), 3.69 (d, J = 4.0 Hz, 4 H),
3.66–3.62 (m, 32 H), 3.58 (app s, 8 H), 2.45 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 144.8, 133.0, 129.9, 128.0, 70.8,
70.6 (2), 70.5, 69.3, 68.7, 61.8, 30.3, 21.7.
Trt-EG6-OTrt (5a)
A flame-dried 3-necked 250 mL round-bottomed flask equipped
with a N2 inlet adapter was charged with NaH (60% dispersion in
mineral oil, 0.58 g, 14.49 mmol). Hexane was added by syringe to
the NaH and oil mixture and the resultant hexane solution was re-
moved by syringe (3 × 50 mL) and then quenched by expelling the
solution into i-PrOH (The hexane solution contained mineral oil
from the hydride mixture and a small amount of NaH). A solution
of mono-tritylated di(ethylene glycol) 4a (2.52 g, 9.65 mmol) and
anhyd THF (ca. 100 mL) was added by syringe in one portion and
the reaction mixture was stirred for 4 h at r.t. under an atmosphere
of N2. Next, the solution was cooled to 0 °C in an ice-water bath be-
fore a solution of ditosylated di(ethylene glycol) 3a (1.50 g, 4.83
mmol) in THF (50 mL) was added dropwise over a period of 10
min. The reaction mixture was then warmed to 40 °C in an oil bath
and the turbid solution was vigorously stirred for an additional 80 h.
Synthesis 2012, 44, 717–722
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PAPER
Ethylene Glycol Oligomers EG6, EG10, and EG12
721
At the conclusion of the reaction, the reaction mixture was poured
into ice water (ca. 75 mL) and extracted with CH2Cl2 (2 × 100 mL).
The combined organic layers were washed with brine (100 mL),
dried (MgSO4), filtered, and concentrated by rotoevaporation to
yield 5a (3.70 g, 93%) as a turbid orange oil.
1H NMR (500 MHz, CDCl3): d = 7.46 (d, J = 6.0 Hz, 12 H), 7.29 (t,
J = 6.5 Hz, 12 H), 7.22 (t, J = 6.0 Hz, 6 H), 3.67–3.63 (m, 20 H),
3.23 (t, J = 4.5 Hz, 4 H).
1H NMR (500 MHz, CDCl3): d = 3.72 (t, J = 5.0 Hz, 4 H), 3.68–3.64
(m, 32 H), 3.61 (t, J = 4.5 Hz, 4 H), 3.31–1.85 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 72.6, 70.6, 70.6 (2), 70.5, 70.3,
61.7.
HRMS (ESI): m/z calcd for C20H43O11 [M + H]+: 458.2800; found:
459.2816; m/z calcd for C20H46NO11 [M + NH4]+: 476.3065; found:
476.3076; m/z calcd for C20H42NaO11 [M + Na]+: 481.2619; found:
481.2645.
Trt-EG10-OTrt (5b)
EG12 (1c)
Compound 5b was prepared from 4b (1.62 g, 4.64 mmol), follow-
ing the same procedure as for 5a and isolated as a turbid orange oil
(1.52 g, 70%).
1H NMR (500 MHz, CDCl3): d = 7.46 (d, J = 7.0 Hz, 12 H), 7.29 (t,
J = 7.5 Hz, 12 H), 7.22 (t, J = 7.0 Hz, 6 H), 3.68–3.61 (m, 36 H),
3.23 (t, J = 5.0 Hz, 4 H).
Following the typical procedure for 1a, 5c (1.70 g, 1.65 mmol) gave
1c (0.79 g, 73%) as a clear yellow oil.
1H NMR (500 MHz, CDCl3): d = 3.73 (t, J = 5.0 Hz, 4 H), 3.67–3.65
(m, 40 H), 3.60 (t, J = 4.5 Hz, 4 H), 2.70–1.41 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 73.2, 70.9, 70.8 (2), 70.4, 61.9.
MS (ESI): m/z calcd for C24H54NO13 [M + NH4]+: 564.36; found:
Trt-EG12-OTrt (5c)
564.91.
A flame-dried 3-necked 250 mL round-bottomed flask equipped
with a N2 inlet adapter and rubber septum was charged with NaH
(60% dispersion in mineral oil, 0.32 g, 7.96 mmol). Hexane was
added by syringe to the NaH and oil mixture and the resultant hex-
ane solution was removed by syringe (2 × 50 mL) and then
quenched by expelling the solution into i-PrOH (The hexane solu-
tion contained mineral oil from the hydride mixture and a small
amount of NaH). A solution of Trt-EG4-OH (4b; 1.74 g, 3.98 mmol)
and anhyd THF (75 mL) was added by syringe in one portion and
the reaction mixture was stirred for 4 h at r.t. Then, the solution was
cooled to 0 °C in an ice-water bath before a solution of Ts-EG4-OTs
(3b; 1.00 g, 1.99 mmol) in THF (30 mL) was added in dropwise
over a period of 10 min. The reaction mixture was warmed to 40 °C
in an oil bath and the turbid solution was vigorously stirred for 3 d
under an atmosphere of N2. At the conclusion of the reaction, the re-
action mixture was poured into ice water (ca. 75 mL) and then ex-
tracted with CH2Cl2 (2 × 100 mL). The combined organic layers
were washed with brine (100 mL), dried (MgSO4), filtered, and con-
centrated by rotoevaporation to yield 5c (1.7 g, 81%) as a turbid or-
ange oil.
1H NMR (500 MHz, CDCl3): d = 7.46 (d, J = 6.5 Hz, 12 H), 7.29 (t,
J = 6.5 Hz, 12 H), 7.22 (t, J = 6.0 Hz, 6 H), 3.69–3.61 (m, 44 H),
3.24 (t, J = 4.5 Hz, 4 H).
13C NMR (125 MHz, CDCl3): d = 144.2, 128.7, 127.8, 126.9, 88.6,
70.8, 70.7 (2), 70.6 (2), 68.0, 63.4, 25.6.
HRMS (ESI): m/z calcd for C62H82NO13 [M + NH4]+: 1048.5781;
found: 1048.5819.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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EG6 (1a); Typical Procedure
A solution of Trt-EG6-OTrt (5a; 3.45 g, 4.49 mmol), AcOH (80
mL), and CH2Cl2 (20 mL) was stirred under an atmosphere of N2 at
40 °C for 4 h. The reaction mixture was allowed to cool to r.t. and
then poured into ice water (ca. 75 mL). The precipitate was filtered
off and the filtrate was concentrated by rotoevaporation to provide
1a (0.97 g, 76%) as a turbid oil.
1H NMR (500 MHz, CDCl3): d = 3.73 (t, J = 4.5 Hz, 4 H), 3.68–3.66
(m, 16 H), 3.61 (t, J = 4.5 Hz, 4 H), 3.28 (br s, 2 H).
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HRMS (ESI): m/z calcd for C12H27O7 [M + H]+: 283.1751; found:
283.1760; m/z calcd for C12H30NO7 [M + NH4]+: 300.2023; found:
300.2017; m/z calcd for C12H26NaO7 [M + Na]+: 305.1571; found:
305.1577.
EG10 (1b)
Following the typical procedure for 1a, 5b (1.50 g, 1.59 mmol) gave
1b (0.60 g, 82%) as a clear yellow oil.
© Thieme Stuttgart · New York
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© Thieme Stuttgart · New York