Macromol. Syrnp.
102, 9-17 (1996) 9
Polypropylenimine dendrimers:
improved synthesis and characterization
E.M.M. de Brabander*, J. Brackman, M. Mure-Mak,
H. de Man, M. Hogeweg, J. Keulen, R. Scherrenberg,
B. Coussens, Y. Mengerink and Sj. van der Wal
DSM Research, P.O. Box 18, 6160 MD Geleen,
The Netherlands
Abstract: Both the Michael addition and the
hydrogenation steps in the large scale synthesis of
polypropylenimine dendrimers have been improved: by
adding ammonia during the hydrogenations the
substrate concentrations can be increased 8 times,
the catalyst concentration can be lowered 10 times
and the average selectivity remains > 99.5% per
conversion. The dimensions of the dendrimers have
been studied with SANS and with molecular
calculations.
INTRODUCTION
Dendritic macromolecules are hyperbranched macromolecules
that are synthesized in a stepwise way via a repetitive
reaction sequence (Ref. 1). On the one hand this allows for
control over parameters like size, shape and reactivity, but
on the other hand the multi step synthesis really hampers
the production of large quantities. Two years ago we
published a method which for the first time allowed for
large scale synthesis of dendrimers (Ref. 2 ) . The reaction
sequence (Scheme l), was based on the first approaches to
0 1996 Huthig & Wepf Verlag, Zug CCC 1022-1360/95/$04.00
10
highly branched structures by Vogtle et al. in 1978 (Ref.
3 ) , and is a repetition of a double Michael addition of
acrylonitrile to primary amines, followed by the
heterogeneously catalyzed hydrogenation of the nitrile
groups. This resuls in a doubling of the number of primary
amine groups. 1,4-Diaminobutane (DAB) has been used as a
core-molecule, but a variety of molecules with primary or
secondary amine groups can be used as core as well.
Here we will discuss a greatly improved process for the
synthesis of these structures. Furthermore the analysis and
characterization of the resulting dendrimers is discussed.
11
Scheme 1: Synthetic scheme for polypropylenimine
dendrimers using diaminobutane as core.
12
SYNTHESIS OF POLYPROPYLENIMINE DENDRIMERS
All Michael reactions are performed in a similar way: 2.2
equivalents of acrylonitrile per primary amine are used at a
concentration of up to 50 weight % in water. After the reac-
tion the excess acrylonitrile is distilled off as a water
azeotrope leaving a clear two-phase system. Pouring off the
water layer yields the nitrile-terminated dendrimers. If
necessary the residue of nitrile-terminated den- drimers is
washed with water. Via this washing procedure water-soluble
side products e.g. HOCH,CH,CN (the Michael addition adduct of
H20 to acrylonitile) or incompletely cyanoethylated products
are separated efficiently from the pure dendrimers. Analysis
of the products showed that an additional side product was
present in some cases: the diadduct of acrylonitrile and
water, NCCH,CH,OCH,CH,CN. Further studies clearly showed that
the formation of this undesired product strongly depends on
the pH at the beginning of the reaction. Slight
neutralization with e.g. acetic acid slows down its rate of
formation in such a way that the extraction procedures are
no longer necessary (values of below 0.1 weight percent are
present in the dendrimers as concluded from HPLC analysis).
The hydrogenations of the cyanoethylated structures with H,
and Raney Co as catalyst at pressures higher than 30 bar
used to be performed in water as well. The large amounts of
catalyst and the long reaction times especial- ly for the
higher generations were from an economical point of view the
main drawbacks of this procedure. Furthermore, the catalyst
had to be activated with hydroxide which induced additional
side product formation during the subsequent Michael
additions. Further studies revealed that the rate of
reaction, the selectivity, the productivity and the yields
all are enhanced dramatically by adding ammonia to the
reaction mixture and changing the solvent to methanol. The
use of ammonia during hydrogenations of nitriles to primary
amines has been known in the literature for a long time
(Ref. 4). Generally, its main function is to prevent secon-
dary amine formation. In our process, products from such
13
side reactions can not be detected (Ref. 5). Nevertheless
the use of ammonia increases the selectivity. By increasing
the rate of reaction the period that both nitrile groups and
primary amino groups are present is shortened which results
in a decrease of retro Michael addition and thus in an
increased selectivity. With this new procedure 10 times less
catalyst is required and the dendrimer concentration can be
increased about 8 times thus making this process even more
suitable for large scale synthesis of dendri-mers. Via this
improved procedure even the hydrogenation of DAB-dendr-CN,,
is complete within a couple of hours.
CHARACTERIZATION OF THE DENDRIMERS
In order to be able to optimize the process and adjust the
reaction conditions, accurate analysis of the products and
quantitative identification of side products is a prere-
quisite. To achieve this the products have been analyzed
with NMR, IR, HPLC and GPC. All I3C and 'H NMR spectra have
been assigned unambiguously and are in full agreement with
the proposed dendrimer structures. NMR spectroscopy ap-
pears to be a very suitable technique to detect and assign
failures in the outermost layer of the dendrimer structure
at each generation (Ref. 2 ) . Reversed phase HPLC allowed us
to separate the various nitrile-ended dendrimers and detect
the presence of dendrimer defects. The nitrile terminated
dendrimers can be analyzed on polystyrene-divinylbenzene
based column packings using THF as the mobile phase. More
detailed analysis of nitrile terminated POPAM dendrimers is
possible by reversed phase adsorption chromatography using
silica and polystyrene-divinylbenzene based packings. In
combination with mass spectrometry and the use of model
compounds defect structures have been detected and assigned.
For the amine terminated POPAM dendrimers several basic and
acidic aqueous phase exclusion chromatography systems were
compared. The optimum system consists of a desacti- vated
reversed-phase silica stationary phase and a mobile phase of
dilute aqueous formic acid at 60°C (Ref. 6). In figure 1 a
14
.GPC plot of the first five amino terminated dendrimers is
shown.
11
76.00 18.00 20.00 22.W 24.00 26.00 28.00
Actenrim rhe k mhrtes
Figure 1. Typical GPC-trace of first five generations of
amine terminated dendrimers.
PROPERTIES OF POLY(PROPYLENEIM1NE) DENDRIMERS
Previously, we reported about the thermal stability, the
viscosity behaviour, the solubility and the glass transition
temperatures of the first five dendrimer generations. It was
shown that apart from the intrinsic viscosity these
parameters mainly depend on the nature of the end group. For
the intrinsic viscosity the for dendrimers characteristic
maximum as a function of the molecular weight was observed
at generations 4-5 of the nitrile terminated dendrimers
(Ref. 2 ) . Here the main focus will be on the dimensions of
15
the dendrimers which have been studied both experimentally
with S A X S and SANS and via molecular modelling. A detailed
insight into the three-dimensional structure of dendrimer
molecules can be obtained by using atomistic modelling
techniques. Atomic-level force field methods have been
applied to calculate the sizes of the dendrimers as a
function of the genera- tion number, to calculate radial
density profiles and to make a prediction about the
starburst-dense packed genera- tion. The sizes of the
dendrimers were determined by cal- culating the radii of
gyration for several configurations of the dendrimers as
obtained from a molecular dynamics simulation at room
temperature. The solvent influence on the calculated radii
was estimated by scaling the non-bonded interactions between
the atoms. Average radii for ensembles of 500 configurations
of the DAB(PA), dendrimers have been collected in the
following table (Ref. 7). Also given are the radii of
gyration as obtained by means of SANS measurements.
"All interactions (Coulombic and VDW) taken into account.
bOnly repulsive VDW interactions taken into account.
'Neutron data, 1 % solutions in D,O.
dOnly 189 configurations.
The calculated radii with all interactions included (second
column) are somewhat smaller than the SANS radii, whereas
the radii obtained with only the VDW repulsions taken into
account are somewhat larger. From the calculated volumes of
the dendrimers, it has been predicted that the starburst
16
dense-packed generation will occur around generation 7. Some
typical radial distribution curves for the DAB(PA),
dendrimers are shown in figure 2 . F o r the higher
generations, the curves clearly show minima and maxima. This
might be attributed to the existence of holes in the
dendrimers. A more quantitative analysis of these holes is
currently being performed.
Figure 2. Radial density distributions of amine terminated
dendrimers, calculated (with SEGDENMDX) from the centre of
the core.
CONCLUSIONS
Polypropylenimine dendrimers have been synthesized via a
strongly improved procedure for both the Michael addition
and the hydrogenation steps. The dimensions of the
dendrimers have been determined experimentally and via
calculation and the results of both approaches are in good
agreement. The dendrimers are being used for a multitude of
applications some of which have been published recently
(Ref. 8).
17
REFERENCES
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Ed. Engl. 1993, 32, 1308-1311.
(3) E. Buhleier, W. Wehner, F. Vogtle, Synthesis 1978, 1 5 5 -
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(4) E.J. Schwoegler and H. Adkins, J. Am. Chem. SOC., 61
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(5) Intramolecular addition of a primary amine to an
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unfavorable eight-membered ring, whereas intermolecular
addition is unlikely because of the low concentrations
used.
(6) Y. Mengerink, M. Mure, E.M.M. de Brabander and Sj. van
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