Synthesis of new soluble dendrimers on poly(ethylene glycole) sublayer

Article abstract of DOI:10.1134/S1070428009050248

A rational method of synthesis was developed for new soluble dendrimers on poly(ethylene glycole) sublayer with a high density of functional groups applying 2,4,6-trichloro-1,3,5-triazine as a dendron and piperazine as linker and functional group carrier. The density of functional groups in the synthesized soluble dendrimers calculated from the elemental analysis for chlorine was 2.19 mmol of NH groups per 1 g of polymer. These new water-soluble dendrimers can be used not only as convenient soluble polymer sublayers but also for efficient trapping in purification of reaction products from impurities.

Full text of DOI:10.1134/S1070428009050248

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 5, pp. 788−791. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © C.F. Lu, C. Xie, Z.X. Chen, G.C. Yang, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 5, pp. 800−803.
Synthesis of New Soluble Dendrimers
on Poly(ethylene glycole) Sublayer
C. F. Lu, C. Xie, Z. X. Chen, and G. C. Yang
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules
& School of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China
e-mail: lucf@hubu.edu.cn
Received September 21, 2007
Abstract—A rational method of synthesis was developed for new soluble dendrimers on poly(ethylene glycole)
sublayer with a high density of functional groups applying 2,4,6-trichloro-1,3,5-triazine as a dendron and piperazine
as linker and functional group carrier. The density of functional groups in the synthesized soluble dendrimers
calculated from the elemental analysis for chlorine was 2.19 mmol of NH groups per 1 g of polymer. These new
water-soluble dendrimers can be used not only as convenient soluble polymer sublayers but also for efficient
trapping in purification of reaction products from impurities.
DOI: 10.1134/S1070428009050248
Recently the importance grew of the use of polymer
sublayers, especially in the automated synthesis and
combinatorial chemistry. Soluble polymer sublayers
possess certain advantages over insoluble polymers with
respect to the easy analysis and process monitoring and
especially in establishing homogeneous conditions most
feasible for bimolecular processes [1].
Besides the spherical form of large dendrimers makes
it possible to apply simple purification methods. These
two factors can make dendrimers useful sublayers for
organic synthesis. The additional advantage of soluble
dendrimers is the possibility to investigate the intermediates
on the sublayer by standard analytical methods, like NMR,
IR spectroscopy, and mass spectrometry, due to the highly
ordered and repeating structural element of dendrimers.
We successfully used in our laboratory poly(ethylene
glycol) (PEG) as a polymer sublayer [2–5]. However
due to the fact that each PEG molecule has only two
functional groups for adding reagents, namely, the
terminal hydroxy groups, PEG possesses a low density
of functional groups, and this significant disadvantage
limits its efficient application as a soluble polymer
sublayer.
Here we report on the synthesis of one more soluble
dendrimer on the PEG sublayer as shown on the Scheme.
2,4,6-Trichloro-1,3,5-triazine was selected as dendron
because of its appropriate reactivity and chemoselectivity
of the chlorine atoms in the reactions of compound I at
various temperatures [10]. Therefore it was possible to
reduce the number of cross-links by controlling the
reaction conditions. The piperazine was employed as a
linker and functional groups carrier in dendrimer formation.
Besides the piperazine is a secondary amine therefore
the use of dendrimer with piperazine for linker is potentially
more valuable than a dendrimer with ethylenediamine as
linker at the use of the dendrimer for trapping of protons.
Attempts were made to increase the density of
functional groups on PEG by chemical modification [6,
7]. Our team also carried out a research aiming to
develop two types of soluble polymer sublayers with a
high density of the functional groups, dendrimers on PEG
sublayer [8, 9]. The number of functional groups on the
periphery of a dendrimer increases from generation to
generation resulting in the growth of the number of
functional groups with the growing size of the dendrimer.
The efficient density of functional groups in the
dendrimer was estimated using the elemental analysis for
chlorine. The effective and theoretical density of the
788

SYNTHESIS OF NEW SOLUBLE DENDRIMERS
789
NH
Scheme.
O
N
O
Cl
N
N
N
O
O
Cl
N
N
N
N
N
N
Cl HN
N
Cl
N
N
N
N
N
N
CH3COCl
CH3OH
I
II
OH
O
N
O
O
Cl
O
O
N
NH
G 0.5
G 1.0
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009

LU et al.
790
Functional groups density of dendrimers on PEG sublayer,
mmol per 1 g of polymer
procedures. Poly(ethylene glycol) and compounds on
PEG sublayer were heated in a vacuum at 80°C before
use to remove the moisture traces. IR spectra were
recorded on a spectrophotometer IR-Spectrum one (PE),
1H NMR spectra were registered on a spectrometer
VarianAS 300 from solutions in CDCl3, internal reference
TMS. Thermogravimetric analyses were performed on
a Perkin-Elmer analyzer. The qualitative analysis for
chlorine was carried out as described in [11].
tert-Butyl piperazine-1-carboxylate (I). A solution
of 32.73 g (0.15 mol) of di-tert-butyl dicarbonate in 50 ml
of anhydrous CH2Cl2 was added dropwise within 20 min
to a stirred solution of 25.0 g (0.3 mol) of anhydrous
piperazine in 300 ml of anhydrous CH2Cl2. The separated
precipitate was filtered off and washed with
dichloromethane (3 × 100 ml). The solvent was removed
in a vacuum, the colorless oily residue was dissolved in
300 ml of water and filtered to remove the insoluble
bis(tert-butoxycarbonyl) derivative. The water filtrate was
saturated with K2CO3 and extracted with ethyl ether
(3×100 ml). The solvent was removed in a vacuum. Yield
21.3 g (64%), viscous oily substance of sufficient purity.
functional groups are presented in the table. It is seen
that the effective density is less than theoretical. The
functional groups density decreases with the growing size
of the substrate molecule. This phenomenon may be
ascribed to the combination of steric strain due to the
short distance between the polar functional groups and
intramolecular hydrogen bonds with the growing number
of generations. Still the functional groups density of
dendrimer G 3.0 on PEG sublayer (2.19 mmol NH per 1 g
of polymer) is considerably higher than that of com-
mercial PEG 3400 (0.59 mmol NH per 1 g of polymer).
1
IR spectrum, ν, cm–1: 3321, 1710. H NMR spectrum,
One of important factors in the liquid-phase organic
synthesis is the attaining the compromise between the
functional groups density of the sublayer and the general
solubility of the system. Therefore we investigated also
the solubility of dendrimers on PEG sublayer and found
that they were soluble in many solvents, like DMF, H2O,
etc. We also studied the thermal stability of dendrimers
by thermogravimetric analysis and revealed that these
dendrimers were stable at heating up to ~450°C. The
good thermal stability of these dendrimers shows that
they are usable in many organic syntheses both at room
temperature and at heating.
δ, ppm: 1.47 s [9H, C(CH3)3], 2.80–2.90 m (2H, HNCH2),
3.08–3.17 m (2H, CH2NBoc).
The removal of protective Boc-group. General
procedure. In 30 ml of ethyl acetate was dissolved 35.5
ml (0.05 mol) of acetyl chloride, and the solution was
added dropwise to a solution of 8.3 mmol of polymer
protected with N-Boc-group in 56 ml of methanol; thus
formed a solution of 5 mol l−1 of HCl in methanol. The
mixture was stirred at room temperature for 40 min. On
completion of the reaction to the solution was added
triethylamine to pH 7. The solution was concentrated in
a vacuum, and the residue was recrystallized from cold
ethyl ether (100 ml Et2O per 1 g of polymer), washed
with cold ethyl ether (3 × 100 ml) to give the product
with removed protective Boc-group.
Note in conclusion that we developed new soluble
dendrimers on PEG sublayer with a high functional groups
density. These dendrimers are suitable for application in
liquid-phase organic synthesis and in the combinatorial
chemistry as good substrates on soluble polymer sub-
layers. Moreover, they can be used for efficient trapping
for purification of reaction products due to the enhanced
number of the active functional NH groups. Therefore
the synthesis of these dendrimers is promising, and their
applications will be described in further publications.
Dichlorotriazine on PEG sublayer (G 0.5). To
40 ml of benzene containing 1 mg of 1,10-phenanthroline
as indicator was added under nitrogen atmosphere 2 ml
of 5 M butyllithium solution in hexane. The bright-orange
solution obtained was titrated with a solution of 10.0 g of
PEG 3400 in 100 ml of benzene till yellow color in the
final point indicating a slight excess of PEG. This solution
was added dropwise to a solution of 5.42 g (29 mmol) of
trichlorotriazine in 150 ml of benzene, and the reaction
mixture was stirred at room temperature for 1 h. On
EXPERIMENTAL
All organic solvents were dried by standard
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009

SYNTHESIS OF NEW SOLUBLE DENDRIMERS
791
was dried with anhydrous MgSO4, filtered, and
concentrated in a vacuum; the residue was recrystallized
from cold Et2O and washed with cold Et2O (3 × 100 ml).
Yield 7.66 g (83%) of G 1.5 that was subjected to TLC
(eluent EtOAc–petroleum ether, 1 : 4) to prove that it
contained no low-molecular reagents. IR spectrum, ν,
cm–1: 2884, 1530, 1111, 1071. 1H NMR spectrum, δ,
ppm: 3.2–3.3 m (1H, CH2), 3.4–3.6 m (1H, PEG), 3.8–
4.0 m (1H, PEG–OCH2CH2OC3N3). Cl 6.0%.
evaporating the solvent the residue was dissolved in 200
ml of CH2Cl2 and washed with water (3×25 ml). The
organic layer was dried with anhydrous MgSO4, filtered,
and concentrated in a vacuum; the residue was
recrystallized from 500 ml of cold Et2O and washed with
cold Et2O (3 × 100 ml). We obtained 10.10 g (94%) of G
0.5 that was subjected to TLC (eluent EtOAc–petroleum
ether, 1 : 4) to prove that it contained no low-molecular
reagents. IR spectrum, ν, cm–1: 2884, 1530, 1111. 1H NMR
spectrum, δ, ppm: 3.4–3.6 m (1H, PEG), 3.8–4.0 m
(PEG–OCH2CH2OC3N3Cl2). Cl 3.7%.
Dendrimers G 2.0 and G 3.0 on PEG sublayer were
synthesized analogously to dendrimer G 1.0 on PEG
sublayer, and dendrimer G 2.5 on PEG sublayer, similarly
to dendrimer G 1.5 on PEG sublayer.
Dendrimer on PEG sublayer (G 1.0). In 200 ml of
acetonitrile was dissolved 10.0 g of dendrimer G 0.5 and
6.04 g (32.4 mmol) of substituted piperazine II, to the
mixture was added 3.43 g (32.4 mmol) of Na2CO3, and
the reaction mixture was boiled at stirring for 12 h. On
evaporation of the solvent the residue was dissolved in
200 ml of CH2Cl2 and washed with water (3×50 ml).
The organic layer was dried with anhydrous MgSO4,
filtered, and concentrated in a vacuum; the residue was
recrystallized from 500 ml of cold Et2O and washed with
cold Et2O (3 × 100 ml). We obtained N-Boc-protected
polymer. IR spectrum, ν, cm–1: 1710, 1530. 1H NMR
spectrum, δ, ppm: 1.47 s [9H, C(CH3)3], 2.8–2.9 m (2H,
NHCH2), 3.02–3.15 m (2H, CH2NBoc), 3.4–3.7 s (1H,
PEG).
The study was carried out under a financial support
of National Foundation for Natural Sciences of China (¹
20772026).
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Then the protective Boc-group was removed. We
obtained 8.53 g (81%) of G 1.0 that was subjected to
TLC (eluent EtOAc–petroleum ether, 1:4) to prove that
it contained no low-molecular reagents. IR spectrum, ν,
1
cm–1: 3321, 2884, 1530, 1140, 1111. H NMR spectrum,
δ, ppm: 1.9–2.1 m (NH), 2.7–2.8 m (1H, CH2), 3.1–3.2
m (1H, CH2), 3.4–3.6 s (1H, PEG), 3.8–4.0 m (1H, PEG–
OCH2CH2OC3N3). Cl 0.2%.
Dendrimer on PEG sublayer (G 1.5). A mixture of
4.67 γ (25.3 mmol) of compound I and 6.0 ml (25.3 mmol)
of diisopropylethylamine was added to 100 ml of CHCl3
and it was stirred at 0°C. 8.0 g of dendrimer G 1.0 was
dissolved in 50 ml of CHCl3, and this solution was added
dropwise to the above mixture maintaining the
temperature below 5°C for 1 h, then the reaction mixture
was stirred for 4 h at room temperature and afterwards
it was washed with water (3 × 50 ml). The organic layer
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009