Polynitrile- and Polyamine-Functional

Poly(trimethy1ene imine) Dendrimers""

X
By Christof Wiirner and Rolf Miilhaupt *
Dedicated to Professor K. Takernoto -X
x\, f
Symmetrical cascade polymers, often referred to as den-
drimers o r starburst polymers, can be prepared by divergent
or convergent synthetic methods.['I In the divergent synthe-
Y
X

G1X
sis the generation are prepared by sequential construction of
X I
stepwise branched polymers starting from a polyfunctional X
G2X
core and multiplying the functionalities in each branching
The ideal starburst-type growth is restricted to a X
certain limiting generation,'". ' ' I and when the density of G3X
the functional groups reaches a limit, steric hindrance ac-
counts for incomplete branching reaction and consequently
increased content of structural defects. Furthermore, for the
divergent syntheses large excesses of the reagents must be
used. In contrast, in the convergent synthetic strategy large
dendritic precursors are prepared which are subsequently
coupled.['', 1 3 1 Our research is aimed at the development of
high yield divergent syntheses which d o not require large
excess of reagents and purification.
Vogtle et a1.'21 had first proposed a conceptual approach
involving a branching reaction sequence through cyano-
ethylation of amines with acrylonitrile followed by chemical
reduction to double the amine end group functionality and
stepwise branching the dendritic polyamines, thus forming G4X
poly(trimethy1ene imines). As a consequence of rather low G5X

RNH, - RN:
CH2CH2CN

CH2CH2CN
- RN,
, C H Z C H ~ C H ~H2
N

c n 2 c i i 2 c H 2 NH,
(a)
Scheme 1. Starburst poly(trimethy1eneimine) generations GnX (n = 1-5) with
X = N for nitrile (CN) and X = A for amino (CH,NH,) end groups.

molecules by repeating the cyanoethylation/catalytic hydro-

yields obtained in the reduction step, this reaction sequence genation reaction sequence (Table 1). Although according to
was restricted to low molecular weight polyamine-functional growth statistics, the fifth generation is not considered to be
oligo(trimethy1ene imines). The nitriles are quantitatively the theoretical limitation for ideal growth, GSN could not be
hydrogenated in the presence of Raney-nickel at room tem- completely hydrogenated. Most likely, the steric hindrance
perature and 8 bar hydrogen pressure, when small amounts of 48 nitrile groups located at the surface is sufficient to
of sodium hydroxide is added to the ethanol solvent.['41 Un- reduce the catalytic activity of the Raney-nickel. In fact, the
der such reaction conditions, the only partially ethanol-solu- reaction time required for quantitative hydrogenation in-
ble polynitrile-functional poly(trimethy1ene imine) is sus- creases substantially with increasing number of generations:
pended and hydrogenated to form ethanol-soluble poly- G I N is hydrogenated in seven hours, G 4 N in four days.
amine-functional poly(trimethy1ene imines). This hydro-
genation slurry process eliminates side reactions between
amines and nitriles. Also it was found that in the presence of Table 1. Polynitrile- and polyamine-functional poly(trimethy1ene imines).
methanol the cyanoethylation occurs without formation of GnX represents the generations from n =1-5 with X = N for nitrile- and
X = A for amine end groups.
monosubstituted side products. In acetic acid['] colored re-
action products are formed that contain small quantities of GnX End Yield M, Mn[a1 M , [bl RIM,
monocyanoethylated amines, which lead to the structural groups theor. [bl
defects in the dendrimers. [molmol-'1 [%I [gmol-'I [gmol-'1 [gmol-'1
~ ~~ ~~

Since acrylonitrile, methanol, and cyanoethylated methanol GIN 3 11 116 - 180 1.02
are readily removed under vacuum, this synthetic route does GlA 3 61 188 - 185 1.05
not require special purification processes. G2N 6 96 506 494 480 1.02
Starting from ammonia as initiator core, it was possible to G2A 6 86 530 - 530 1.07
G3N 12 94 1161 1060 1200 1.02
build five generations of polynitrile- (X = CN) and G3A 12 79 1216 - 1250 1.08
polyamine-functional (X = CH,NH,, Scheme 1) cascade G4N 24 96 2489 2470 2570 1.04
G4A 24 69 2586 - 2480 1.08
[*I
Prof. Dr. R. Mulhdupt, C. Worner G5N 48 93 5133 4880 4810 1.07
Institut fur Makromolekuldre Chemie
Hermann-Staudinger-Haus [a] Determined by vapor pressure osmometry (VPO). [b] Determined by gel
Stefan-Meier-Strasse 31, D-79104 Freiburg (FRG) permeation chromatography (GPC).
Telefax: Jnt. code +(761)276-453
I**]
This work was supported by the Deutsche Forschungsgemeinschaft. Dur-
ing preparation of this manuscript the authors became aware of similar
results from E. M. M. de Brabander-van den Berg. E. W. Meijer, Angew.
For applications of such poly(trimethy1ene imines) cas-
Chnn. 1993.105. 1310-1372; Angew. Chrm. Int. Ed. Engl. 1993.32, 1308- cade molecules it is important to identify structural defects
1311 which may account for changes in the supramolecular archi-

1306 CJ VCH Verlugs~esellschaf~

mbH, D-69451 Wernheim, 1993 0570-0833193j0909-1306 $ 10.00+ .25/0 Angeu,. Chem. hi.Ed. Engl. 1993, 32, No. 9
tecture. The structures proposed for the individual genera-
tions in Scheme l have been confirmed with elemental anal-
ysis, end group titration, ' H N M R , I3C NMR, and IR spec-
troscopy, mass spectrometry, vapor pressure osmometry
(VPO) and gel permeation chromatography (GPC). In addi-
tion to the molecular weights, the content of primary NH,
end groups, and secondary NRH structural defects were de-
termined. By potentiometric end group titration, it was pos-
sible to distinguish between primary and tertiary amine con-
tent only in the first generation GlA."'] The ' H N M R
spectra of polynitrile-functional G4N (Fig. 1 ) and in
polyamine-functional G4A (Fig. 2) show no secondary
NHR structural defects, since the signals of the methylene
group adjacent to the secondary amino group at 6 = 2,7
(between a and c in Fig. 1) and 6 = 2,s (between b and d in
Fig. 2) are observed in the expected region. According to the
I , I I I I
7 6 5 4 3 2 1 0
-6
Fig. 1. ' H NMR spectrum (400 MHz, CD,CI,) of G4N
-NCHZCH,CH2N(CH,CH2CH2NH,),
g f e d c b a (
-1 1- I I
i
I
7 6 5 4 3 2
-8
Fig. 2. 'H N M R spectrum (250 MHz, CDCI,) of G4A
signal intensity ratio, highly symmetrical cascade polymers
are formed. Also the signals of the CH, groups bound to the
end groups have been assigned (triplet a in Fig. 1 at 6 = 2,83
triplet b in Fig. 2 a t 2.67). The I3CNMR spectra of the
generations 1-4 confirm the high purities of the dendrimers.
In the cyanoethylation of G4N small quantities of mono-
cyanoethylated secondary NHR end groups are observed
since steric hindrance increases drastically in the fifth reac-
tion sequence. The I3C NMR spectrum of the generation
G5N (Fig. 3) reveals the signals of the methylene groups
adjacent to the secondary amine (signals n and 1 a t 6 = 47.9
and 45.5 respectively) and to the tertiary amine (signals d
and c at 6 = 51.6 and 49.8 respectively). In a rough estimate
based upon the signal intensities, the proportion of den-
drimers with structural defects is less than 2 mol%. This
Angew Chem. Int. Ed. Engl. 1993, 32, No. 9 0 VCH
means that on the surface of G5N, on average only 47 of the
48 possible nitrile groups per mol of dendrimer is achieved.
This NMR study confirms that the cyanoethylation/hydro-
genation reaction sequence provides excellent control of the
molecular structure of these highly symmetrical cascade mol-
ecules.
C b
-NCH,CH&HzN(CH&HzCH,N(CH,CH&N),),
i h g f e d c b a
I k a I
I_
I I I I I I I I I I
200 180 160 140 120 100 80 60 40 20 0
-6
Fig. 3. I 3 C N M R spectrum (100 MHz, CD,CI,) of G5N. Spectrum confirms
structural defects in the Cascade molecule through monosubstitution (sec-
ondary amino end groups).
For the determination of the molecular weights, end group
titration confirms the expected values for G I A and mass
spectrometry for the generations GI(N, A) and G2(N, A).
As apparent from Table 1, vapor pressure osmometry gives
good agreement with the theoretical molecular weights over
the entire range. Since in each generation size and hydrody-
namic volume of the cascade molecules change substantially,
gel permeation chromatography (GPC) has proven to be the
best method for the characterization of the polyamine- and
polynitrile-functional poly(trimethy1ene imines). In order to
overcome adsorption problems of the highly surface-func-
tional cascade molecules, which cause a broadening of the
GPC chromatographs, electrolytes must be added to the elu-
ent used in GPC chromatography. The characterization of
the dendrimers was achieved by using an aqueous 0.05 M
K,HPO, buffer solution and a methanol/water (70: 30) sol-
vent mixture a t pH = 11 and 60 "C. In Figure 4 the GPC
chromatographs of the polyamine- and polynitrile-function-
a1 generations are shown.
0
- M [gmol-'1 c _ M [gmol-'1
Fig. 4. Molecular weight distributions of the polyamine- and polynitrile-func-
tional dendrimers (determined with GPC).
Using the values from vapor pressure osmometry for cali-
bration, the polydispersities and number as well as weight
average molecular weights have been determined. All gener-
ations exhibit monodisperse molecular weight distributions
with polydispersities MJM,increasing with increasing num-
ber of the generation from 1.02 to 1.08. On the basis of the
Verlagsgesellschafr mbH, 0.69451 Weinheim, 1993 0570-0833/93/0909-I307 S l0.00+.25/0 1307
GPC analyses, coupling reactions can be excluded. Interest-
ingly, the solution behavior of poly(ethy1ene oxide), a typical
random-coil polymer, is quite different from that of the two
types of highly functional poly(trirnethy1ene imine) cascade
molecules prepared by us. As apparent from Figure 5, the
polyamine-functional cascade molecules require higher elu-
tion volumes, which increase with increasing number of gen-
erations. In agreement with earlier observations,". 'I it ap-
M
I a Perkin-Elmer Molecular Weight Apparatus Type 115 at 30 C with CHCI, as
[g mol-
12 14 16 18 20 22 24 26
v, [mLI -
Fig. 5. Correlation of molecular weight M and elution volume V, in G P C
analyses of poly(ethy1ene oxide) (o),polynitrile- (A) and polyamine-functional
poly(trimethylene imines) (*).
pears likely that cascade molecules when compared with
conventional random-coil polymers exhibit higher densities,
which increase with increasing molecular weight. The very
high elution volumes found for the polynitrile-functional
cascade molecules may result from adsorption phenomena,
which d o not interfer with the GPC analysis of the molecular
weight distributions. In all three polymers there exists a lin-
ear correlation between molecular weight, determined by
vapor pressure osrnometry, and elution volume.
In conclusion, the divergent synthesis involving cyano-
ethylation and catalytic hydrogenation efficiently doubles
the amino groups. With this reaction sequence poly(tri-
methylene imine) cascade molecules can be prepared in high
yields and purity without requiring extensive purifications
and excess reagent.
Experimental Procedure
Typical syntheses for the higher generations G4N. G4A, and GSN; the yields
are summarized in Table I .
G4N: To a cold solution of G3A (2.56 g, 2.10 mmol) in methanol (20 mL) were
added acrylonitrile (20.0 mL. 305 mmol) (distilled over CaH, and stabilized
with 0.05 wt% hydroquinonemonomethyl ether) within 90 minutesat 5 - 10 C.
After stirring 1 h at 10 C and 4 days at 60 'C. the quantitative bis(cyanoethyla-
tion) was obtained. For separation of the stabihzer. the reaction mixture was
passed through a neutral AI,O, column and eluted with methanol/ethyl acetate
(7:3). and the methanol content was increascd slowly to 100%. The solvent was
evaporated in vacuo to obtain 5.02 g (96%) of the highly viscous G4N. Correct
elemental analysis for C135HLZ2N+h (2489.55 gmol-I); ' H N M R (400 MHz,
CD,CI,): /i = 1.62 (q, J = 7 Hz. 4 2 H ; CH,CH,CH,). 2.56 (ni. 132H; CH,N),
2.83 (t. J = 7 Hz, 4 8 H ; CH,CN), " C N M R (100 MHz, CD,CI,): 6 =17.3
(CH,CN), 23.9, 25.1 (CH,CH,CH,), 49.9 (CH,CH,CN), 51.7, 51.9, 52.2, 52.4
(CH,N), 119.5 (CN); IR (neat). i,[cm-'] = 2920,2800,2220, 1450,1410.1350,
1250, 1160, 1120, 1050.
G4A: The hydrogenation was carried out in a 2 L stainless steel autoclave
(Biichi AG, UsteriSwitzerland). To 100 m L of a 1.4 M solution of NaOH iu
EtOHjH,O (95:s). G4N (4.20g. 1.69mmol) was added. Under nitrogen the
mixture was treated with Raney-nickel(2.5 g) (slurry in water. Aldrich). and the
mixture was hydrogenated at 1000 rpm a t 8 bar H, pressure for 4 days at 25 C.
The catalyst was filtered and washed with EtOHjH,O (95j5). After diluting the
filtrate with H,O (100 mL). EtOH was evaporated and the residue extracted
several times with CH,CI,. Thereby. the NaOH concentration in the aqueous
phase was increased in every extraction step. The organic layers were dried with
Na,SO, and the solvent evaporated in vacuo to give 3.01 g (69%) G4A. Correct
elemental analysis for C,,,H,,,N,, (2586.31 gmol-I); ' H NMR (250 MHz,
CDCI,): /i =1.54(m. 138H,CH,CH,CH,, NH,), 2.36(m. 8 4 H ; CH,N), 2.42
(t. J=7Hz.48H;CHzCH,CH,NH,). 2.67(t, J = 7 H z , 4 8 H ; C H 2 N H , ) ; " C
NMR (100 MHz, CDCI,): ii = 24.6 (NCH,CH,CH,N), 30.9 (CH,CH,NH,).
1308 TI VCH Verlug.~gesell.schufimhH, 0-69451 Weinherm, IYY3 0570-oX33193jo9o9-130n d 10.00+ 2SiO
40.7 (CH,NH,). 51.9. 52.3, 52.4, 52.6 (CH,N); IR (neat): i.[cm-'] = 3300,
3260,2910. 2780, 1570. 1450, 1360. 1170. 1070.960-770.
G5N: The procedure was equivalent to that reported for the synthesis of G4N.
From G4A (600 mg. 0.232 mmol) was obtained 1.1 1 g (93%) of the highly
viscous substance G5N Correct elemental analysis for C,,,H,,,N,,
(5133.35 gmol-'): ' H N M R (400MHz. CD,CI,): 6 =1.62 (m. 9 0 H ;
CH,CH,CH,), 2.52 (m. 276H; CH,N), 2.82 (t. J = 7 Hz, 96H; CH,CN); I3C
NMR (100 MHz, CD,CI,): 6 = 17.2 (CH,CN), 23.8.25.1 (CH,CH,CH,), 49.8
(C'H,CH,CN), 51.6, 51.8, 52.1. 52.3 (CH,N). 119.5 (CN); IR (neat):
i'[cm-'] = 2920.2790, 2220. 1450, 1410. 1350, 1230, 1160, 1120, 1060.
The ' H NMR and "C N M R spectra were measured with a Bruker AC 400
spectrometer with tetramethylsilane as internal standard; CD,CI, was used for
the nitrile-functional and CDCI, for the amine-functional generations. End
group titration was performed in a solution of H,O/Et,O (1 : 1) with 0.1 N HCI
with a Mettler DC 25 titrator. Vapor pressure osmometry wiis carried out with
solvent. The GPC analysis was performed on a Shimadzu LC-4A at 60JC with
a 0.05 M K,HPO, buffer MeOH/H,O (70: 30) at pH = 11 (HEMA 40 and HE-
MA 100 column (MZ Analysentechnik), flow rate 0.5 m L m i n - ' , UV detector
228 nm, R1 detector. calibrated with the values obtained from vapour pressure
osmometry).
Received: April 1, 1993 [Z 5968 IE]
German version: Angew. Chem. 1993. 105. 1367
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Poly(propy1ene imine) Dendrimers: Large-Scale
Synthesis by Hetereogeneously Catalyzed
Hydrogenations**
By Ellen M . M . de Brabander-van den Berg*
and E. W Meijer
Dendritic macromolecules are hyperbranched polymers
that emanate from a central core, have a defined number of
generations and functional end groups, and are synthesized
in a stepwise way by a repetitive reaction sequence."] The
syntheses described so far are either convergent, this is discrete
[*] Dr. E. M. M. de Brabander-van den Berg, Prof. Dr. E. W Meijer 1''
DSM Research
P.O. Box 18, NL-6160 M D Geleen (The Netherlands)
['I Present address:
Laboratory of Organic Chemistry, Eindhoven University of Technology
P.O. Box 513, NL-5600 M B Eiiidhoven (The Netherlands)
Telefax: Int. code + (31)40-451036
[**I We thank many colleagues at DSM Research, especially A. Nijenhuis, J.
Keulen, M. Mure, B. Bosman, F. Vanderbooren, R. Reintjens. and S. van
der Wal for their vahxable input.
Angeic.. Chem. In!. Ed. Engl. 1993, 32. No. 9