Facile synthesis of aliphatic hyperbranched polyesters based on diethyl malonate and their irreversible molecular encapsulation

Article abstract of DOI:10.1039/b404447a

Synthesis of diethyl malonate based wholly aliphatic hyperbranched polyesters having suitable polar matrix for irreversible molecular encapsulation is carried out for the first time.

Full text of DOI:10.1039/b404447a

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Facile synthesis of aliphatic hyperbranched polyesters based on diethyl
malonate and their irreversible molecular encapsulation{
Santimukul Santra and Anil Kumar*
Department of Chemistry, Indian Institute of Technology, Bombay, India. E-mail: anilkumar@iitb.ac.in;
Fax: 91 22 25767152; Tel: 91 22 25767153
Received (in Cambridge, UK) 24th March 2004, Accepted 28th June 2004
First published as an Advance Article on the web 29th July 2004
Synthesis of diethyl malonate based wholly aliphatic
The synthetic strategy for the preparation of AB systems is
3
hyperbranched polyesters having suitable polar matrix for
irreversible molecular encapsulation is carried out for the first
time.
shown in Scheme 1. One of the acidic protons of diethyl malonate
(1) was selectively removed by using Grignard reaction to get
13
triethyl methanetricarboxylate (2). The treatment with sodium
ethoxide on 2 resulted in the sodium salt 3, to which the aliphatic
spacers were incorporated by reacting with 4-bromobutyl acetate
The synthesis, characterization and applications of dendritic
macromolecules are the most widely studied fields of research
due to their unique chemical and physical properties. These are
1
4
(4) or 5-iodopentyl acetate (5) to get colourless liquid monomers
AB3–C4 and AB –C5 respectively. For the synthesis of AB
1
3
2
mainly classified as dendrimers having well-defined structures and
hyperbranched polymers having less controlled branched structure.
2 2
monomers (AB –C4 and AB –C5), the synthetic procedure
15
described by Arumugam et al. was followed, but without using
any catalyst, since the conventional sodium ethoxide method
resulted in mainly dialkylation of diethyl malonate (Scheme 1).
These monomers were then polymerized by the standard melt
polymerization technique using zinc acetate as catalyst to get the
corresponding polymers P(AB –C4), P(AB –C5), P(AB –C4) and
Hyperbranched polymers are synthesized from AB
monomers through a conventional polycondensation route. AB
monomers are the most common but AB , AB and AB
6
x
(x ¢ 2)-type
2
3
4
2
monomers have also been reported. These macromolecules
having highly functionalized globular shape are used in the field
of life sciences such as controlled drug delivery systems (DDS),
3
3
2
P(AB –C5).
2
3
gene therapy, organ transplantation and in other biomimetics. The
wholly aliphatic dendrimer, polyamidoamine (PAMAM) is the
All the polymers were soluble in CHCl , DMF and DMSO
3
when prepared at 190 uC for 8 h. However, when the polymeriza-
tion was carried out further after 8 h under vacuum for 2 h, the
4
most widely used polymer in several bio-applications. There are
only a limited number of aliphatic hyperbranched polymers
reported in the literature such as polyglycerol, polyethers from
3
polymers were found to be insoluble in CHCl but were still soluble
5–7
8
in DMF and DMSO. Yields and weight average molecular weight
(M ) obtained from SEC for the DMF soluble polymers are
summarized in Table 1. The comparison of molecular weights of
9
3
-ethyl-3-(hydroxymethyl) oxetane and polyesters based on 2,2-
w
bis(hydroxymethyl) propionic acid (bis-MPA). The encapsulation
studies with guest molecules have been reported with polyglycerols
and they are known to be biocompatible. Frechet and co-
the AB and AB systems shows that the weight average molecular
3
2
6,7
weights of the former ones were lower than that of the latter. This
could be due to the crowded transition states (TS) in the case of
1
0
workers reported the fully aliphatic hyperbranched polyesters
based on caprolactone derivative which was described to be
biodegradable. Another bio-degradable poly(amino ester) reported
AB
C– group. If one considers the AB
crowded TS is expected since the ester carbonyl is attached to the
C– group. Hence the reaction would be more feasible and high
molecular weight polymer is obtained for the AB systems as
3
systems, where the ester carbonyl carbons were attached to the
9
R
3
2
systems, less sterically
1
1
by Park and co workers showed efficient transfection and
minimum toxicity. Apart from the above mentioned reports on
R
2
5–11
aliphatic systems,
most of the reported hyperbranched polymers
2
12
were mainly aromatic. This is due to the difficulties involved in
design, synthesis and purification of aliphatic monomers with
proper functional connectivity. However, some of the advantages
of the wholly aliphatic hyperbranched polymers are: better
solubility, highly functional surface, globular shape and presence
of polar cavity. Thus, there is a greater need for a facile and efficient
synthesis of wholly aliphatic hyperbranched polyesters. It will be of
great advantage if the synthesis can be achieved in very few efficient
steps and has the potential for easy structural modifications.
In this paper, we report the synthesis and characterization of
expected. In order to study the effect of polymerization time at
2 3
aliphatic hyperbranched polyesters (HBPE) from AB and AB
systems based on diethyl malonate. The salient features of the
present synthetic route are that the monomers can be synthesized
in one step from the commercially available diethyl malonate.
Furthermore, the structural modifications in terms of the length of
the aliphatic spacer (to change the internal cavity size) and the
Scheme 1 Synthesis of aliphatic HBPEs from AB and AB monomers.
3
2
Table 1 Properties of the polymers
2 3
nature of the monomer, i.e., AB or AB (to change the surface
a
b
functionality) can be easily achieved. Therefore, the present design
has the potential for the design and synthesis of a whole range of
new aliphatic hyperbranched polyesters. Encapsulation studies
were also carried out by using methyl orange as a guest molecule
and the results are discussed.
Polymer
Yield (%)
Tdec (uC)
Mw (PD)
P(AB
P(AB
P(AB
P(AB
a
3
3
2
2
–C4)
–C5)
–C4)
–C5)
45
48
52
54
245
260
250
276
32900 (1.1)
36700 (1.6)
74800 (1.7)
122500 (2.1)
Decomposition temperature at 10% weight loss in TGA studies;
Weight average molecular weight obtained from SEC analysis in
DMF solvent; the polydispersity (PD) values are given in parenthesis.
{
Electronic supplementary information (ESI) available: Experimental
b
details along with the spectral data and UV/Vis spectra for encapsulation
studies. See http://www.rsc.org/suppdata/cc/b4/b404447a/
2
1 2 6
C h e m . C o m m u n . , 2 0 0 4 , 2 1 2 6 – 2 1 2 7
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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w
190 uC on the weight average molecular weight (M ), the samples
were taken from the reaction mixture during the polymerization
and were analyzed by SEC. It was observed that with increase in
time, there was a gradual increase in molecular weight for the first
8
h when the polymerization was done at atmospheric pressure.
However, a sharp increase in molecular weight was observed after
h when the polymerization was carried out under low pressure.
8
When this low pressure polymerization was continued beyond 2 h,
it resulted in the formation of insoluble materials. This insolubility
could be because of the very high molecular weight polymer
formation. Thermogravimetric analysis (TGA) indicated moderate
thermal stability for these polymers. The decomposition tempera-
tures at which 10% weight loss occurred were ranging from 245 uC
to 276 uC.
Fig. 1 Absorbance of dye molecules into the polymer matrix as a function
of different dye concentrations.
For highly branched polyesters, calculation of the degree of
branching is an important parameter. However, in the present case,
these calculations were not possible because the NMR (both H
1
1
3
and C) signals of the internal methylene units were not sensitive if
these belong to the dendritic, terminal or linear units. However, in
the case of hyperbranched polymers, the number of internal units
approaches the number of terminal units at higher degree of
could be a promising factor in the field of drug delivery. Non-
toxicity and biodegradation studies of the polymers using microbes
collected from soil are currently in progress.
We would like to thank the MHRD and DST India for financial
help and the RSIC, Bombay for instrumental facilities. S.S. thanks
the CSIR, India for a Senior Research Fellowship.
1
6
polymerization. In the present hyperbranched polyesters, one
can calculate the number of terminal units from the methyl protons
(-COOCH
methylene protons (–CH COOCH CH –) in H NMR spectro-
scopy. The number of terminal units was found to be comparable
to that of internal units indicating highly branched structures for
the polymers synthesized.
Encapsulation studies using methyl orange dye were carried out
to explore the efficiency of the polar binding sites in the polymer
matrix, which would be used for drug encapsulation. For these
2 3
CH ) and the number of internal units from the
1
2
2
2
Notes and references
1
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2
studies, the chloroform soluble hyperbranched polyester, P(AB –
C4), (Mw ~ 49 000, PD ~ 3.4) was synthesized by carrying out
the polymerization at 190 uC for 8 h under atmospheric pressure.
The chloroform solution of polyester was agitated briefly with
different concentrations of dye dissolved in the aqueous phase. The
observation of an absorbance maximum at 400 nm in the UV/Vis
spectrum confirmed the presence of dye in the organic layer. In all
cases a linear change in the color intensity of both the layers was
observed below the saturation point. After the saturation point,
there was no change in absorption with further increase of the dye
concentration (Fig. 1). Methyl orange (dye) was quantitatively
extracted into the organic layer and it was calculated that an
average load of 0.61 molecules of the dye were encapsulated per
polymer molecule. These calculations have been done quantita-
tively from UV/Vis experiments by assuming the same absorption
3
4
5
7
8
A. Sunder, R. Mulhaupt and H. Frey, Macromolecules, 2000, 33, 309.
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0 M. Liu, N. Vladimirov and J. M. J. Frechet, Macromolecules, 1999, 32,
9
1
1
5
coefficient for the dye in both the layers. Irreversible encapsulation
of the dye molecules was confirmed by recording UV/Vis spectra
after sonication.
6881.
11 Y. Lim, S. Kim, Y. Lee, W. Lee, T. Yang, M. Lee, H. Suh and J. Park,
J. Am. Chem. Soc., 2001, 123, 2460.
1
2 (a) A. Kumar and E. W. Meijer, Chem. Commun., 1998, 1629;
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In summary, a series of diethyl malonate based aliphatic hyper-
branched polyesters containing flexible aliphatic spacers were
synthesized for the first time. High molecular weight polymers were
(
1
obtained from AB
2
3
systems compared to the AB systems due to
3
the less crowded structures of the AB
2
monomers. The polymers
1
1
showed moderate thermal stability in TGA studies. The presence of
the binding sites in the polymer matrix was confirmed by the
observation of the irreversible molecular encapsulation, which
3677.
16 D. Holter, A. Burgath and H. Frey, Acta Polymer, 1997, 48, 30.
C h e m . C o m m u n . , 2 0 0 4 , 2 1 2 6 – 2 1 2 7
2 1 2 7