A highly selective, one-pot multiple-addition convergent synthesis of polycarbonate dendrimers [3]

Full text of DOI:10.1021/ja002613h

J. Am. Chem. Soc. 2000, 122, 11729-11730
11729
A Highly Selective, One-Pot Multiple-Addition
Convergent Synthesis of Polycarbonate Dendrimers
Scheme 1
,†
‡
Steve P. Rannard* and Nicola J. Davis
Courtaulds Corporate Technology, Coatings and Sealants
P.O. Box 111, Lockhurst Lane, CoVentry, CV6 5RS, UK
ReceiVed July 17, 2000
1
The formation of dendrimers via convergent or divergent
routes2 often uses reiterative growth strategies that require
3
protection/deprotection chemistry or methods that involve gen-
clization with the secondary hydroxyl and elimination of the parent
erating essential reactive functionality. These steps and their
subsequent purification procedures are additional to the actual
molecular architecture construction process.1
alcohol. Another commercially available AB triol is 1-[N,N-bis-
(2-hydroxyethyl)amino]-2-propanol (HEAP) 2. The hydroxyl
groups of HEAP are five atoms apart, and intramolecular cyclic
amino-carbonate formation is unlikely.
2
In our recent reports of the highly selective reactivity of
imidazole carboxylic esters,4 intermediates that were derived
from the reaction of 1,1′-carbonyl diimidazole (CDI) and second-
ary or tertiary alcohols were shown to react selectively with
primary alcohol groups. Carbonate formation occurs in the
presence of unprotected secondary and tertiary hydroxyl func-
tionality. We have no evidence for the formation of dialkyl
carbonates from combinations of secondary or tertiary alcohols
even when they are used as the reaction solvent.
,5
The initial stage of polycarbonate dendrimer synthesis requires
the synthesis of an imidazole carboxylic ester. The synthesis of
the imidazole carboxylic ester of DMH, G0-[DMH]-Im 3a, has
4
been reported and involves the facile reaction of equimolar
amounts of CDI and DMH in anhydrous toluene at 60 °C, in the
presence of a catalytic amount of KOH, Scheme 1. G0-[DMH]-
Im was purified via a conventional aqueous wash, to remove the
imidazole byproduct, and isolated in 97% yield. Confirmation of
the synthesis was obtained using electrospray mass spectrometry
This selectivity seemed ideal for the synthesis of dendrimers
6
+
1
13
using convergent growth. Although Bolton and Wooley have
(MH ) 239.55) and H and C NMR spectroscopy. (G0-[t-
+
described the formation of polycarbonate hyperbranched materials,
we believe that this is the first description of ideal polycarbonate
dendrimer synthesis. The AB branching units required for
2
convergent polycarbonate dendrimer synthesis must contain
mixtures of primary and secondary or tertiary hydroxyls. The
Bu]-Im 3b, MH ) 169.36).
When 2 mol equiv of 3a were reacted with 2, using the same
conditions and purification described above, the first generation
wedge, G1-[DMH-HEAP]-OH 4a, was produced in 93% yield
+
+
(
MH ) 504.68, MNa ) 526.62), Scheme 1. Selectivity of the
carbonate formation was confirmed by the unchanged methyl (δ
1.10; 20.00 ppm) methylene (δ ) inequiv 2.34 and 2.65; 63.30
2
branching unit is actually an AA′ group as the hydroxyl
functionalities differ only in the substituents of the R-carbon atom.
By reacting imidazole carboxylic esters of secondary or tertiary
alcohols with these building blocks, carbonate formation exclu-
sively at the primary hydroxyls can be expected. The unreacted
secondary or tertiary hydroxyl group may then be converted to
the imidazole carboxylic ester via reaction with CDI, without the
risk of symmetric carbonate formation, and reacted with the triol
branching unit to form higher-generation dendrimer wedges.
For the purposes of this study, two surface molecules were
chosen, 2,6-dimethyl-4-heptanol (DMH) 1a and tert-butyl alcohol
)
1
ppm) and methine (δ ) 3.73; 64.00 ppm) resonances in the H
13
+
and C NMR spectra. (G1-[t-Bu-HEAP]-OH 4b, MH ) 364.63,
+
MNa ) 386.58).
Activation of 4a with CDI was an identical reaction to the
formation of 3a. Isolation of the imidazole carboxylic ester 5 via
an aqueous wash gave the activated wedge G1-[DMH]-Im 5 in
+
+
9
2% yield (MH ) 598.69, MNa ) 620.51). Subsequent
reaction of 2 mol equiv of 5 with 2 yields the second-generation
wedge G2-[DMH-HEAP
222.23, MNa ) 1245.27), Scheme 2. (G2-[t-Bu-HEAP ]-OH,
+
2
]-OH 6 in 99.6% yield (MH
)
(t-Bu) 1b although any secondary or tertiary alcohol may be used.
+
1
2
Synthetic details throughout this report will describe dendrimers
with a DMH surface, but the reactions are identical when using
+
MH ) 942.84).
There are many advantages of using CDI in the synthesis of
dendrimers. First, the carbonate formation is completely selective,
and no impurities from reaction at the secondary hydroxyl of 2
have been detected. Second, the imidazole carboxylic ester
functionality is much more stable to hydrolysis than a chloro-
formate, which allows the simple purification through an aqueous
wash. Third, both CDI and the imidazole byproduct are soluble
in warm toluene but insoluble when cold. This allows much of
the purification of the products to be conducted through a filtration
of imidazole after cooling, prior to removal of toluene in vaccuo.
Finally, residual imidazole is not detrimental to further generation
growth, and therefore we have not needed to purify the materials
using column chromatography at any stage.
1
b and analytical details showing results when using 1b are also
given.
To accomplish a convergent polycarbonate dendrimer synthesis,
the AB branching group should contain two primary hydroxyls
2
and one secondary or tertiary group. Initially, glycerol was
considered as a candidate building block but, as we have recently
4
reported, the use of 1,2-diols results in cyclic carbonate formation
through initial selective reaction of the imidazole carboxylic ester
with the primary hydroxyl and subsequent intramolecular cy-
†
Current address: Unilever Research Port Sunlight, Quarry Road East,
Bebington, Wirral, CH63 3JW, UK. E-mail: steven.rannard@unilever.com.
‡
Current address: Dextra Laboratories Ltd, Reading University, Earley
Gate, Whiteknights Road, Reading RG6 6BZ, UK.
(
It is the final advantage that led us to attempt a one-pot
multiple-addition synthesis of polycarbonate dendrimers. In
principle, there is no need to isolate and purify the imidazole
carboxylic esters as selective asymmetric carbonate formation can
1) For recent reviews see: (a) Archut, A.; Vogtle, F. Handb. Nanostruct.
Mater. Nanotechnol. 2000, 5, 333. (b) Voit, B. J. Polym. Sci., Part A: Polym.
Chem. 2000, 38, 2505.
(
2) (a) Hawker, C. J.; Fr e´ chet, J. M. J. J. Chem. Soc., Chem. Commun.
1
990, 1010, (b) Tomalia, D. A.; Baker H.; Dewald, M.; Kallos. G.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117.
be achieved in a single pot reaction by sequential addition of
(3) Butz, T.; Murer, P.; Seebach, D. PMSE. 1997, 77, 132.
(4) Rannard, S.; Davis, N. Org. Lett. 1999, 1(6), 933.
(5) Rannard, S.; Davis, N. Org. Lett. 2000, 2(14), 2117.
(6) Bolton, D. H.; Wooley, K. L. Macromolecules 1997, 30, 1890.
secondary alcohol, CDI and primary alcohol.4 The one-pot
multiple-addition synthesis of 6 was conducted on a 100 g scale
in a 1 L flask starting from 1a followed by two CDI/2 sequential
1
0.1021/ja002613h CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/10/2000

11730 J. Am. Chem. Soc., Vol. 122, No. 47, 2000
Communications to the Editor
Scheme 2
7
additions, Scheme 2. Each stage of the reaction was monitored
by TLC to ensure full conversion of alcohol to imidazole
carboxylic ester and full reaction of the imidazole carboxylic ester
to carbonate. The reaction was stopped at this stage as the solution
had become quite viscous due to the concentration of imidazole
byproduct and the dendron 6. The facile purification of the product
via a series of aqueous washes yielded 6 in 89% yield. The
atmospheric pressure ionization mass spectrum of 6 produced
from the one-pot reaction is shown in Figure 1.
wedges was first introduced by Hawker and Fr e´ chet. During this
example, the G2 wedge 6 was activated with CDI to form the
imidazole carboxylic ester G2-[DMH-HEAP
2
]-Im and reacted
in situ with a 10-fold excess of 1,5-pentanediol (PND) to form
+
G2-[DMH-HEAP -PND]-OH in 87% yield (MH ) 1352.83,
2
MNa+ ) 1374.85). Coupling with G2-[t-Bu-HEAP
2
]-Im pro-
+
duced 7 in 85% yield (MH ) 2319.56) (Figure 2).
Figure 2. Asymmetric polycarbonate dendrimer
In summary, we have demonstrated the use of a new selective
carbonate synthesis in the formation of the first ideal polycar-
bonate dendrimers. The synthesis proceeds very well and has
allowed two generations of convergent growth to be achieved on
a 100 g scale in a single reaction vessel without purification
between synthetic steps. The synthesis of higher generations will
be the focus of further work.
Figure 1. API-MS spectrum of 6 from a one-pot synthesis.
8
+
The API-MS spectrum of the one-pot reaction shows the MH
1222.23 and MNa ) 1245.27 signals for the controlled
+
)
formation of 6. This confirms that we have successfully achieved
four sequential selective reactions in a single reaction vessel
including the two selective imidazole carboxylic ester syntheses.
The spectrum also shows a significant signal corresponding to a
species with a mass of 674.5 daltons. Assuming this is a
protonated molecular ion, it may correspond to carbonate forma-
tion by the reaction of 3a with the secondary hydroxyl group of
JA002613H
(7) Hawker, C. J.; Fr e´ chet, J. M. J. J. Am. Chem. Soc. 1993, 115, 4375.
(8) General procedure for the formation of polycarboante dendrimers is
exemplified by the one-pot synthesis of 4a. Dry toluene (100 mL) was added
to a 250 mL round-bottom flask fitted with a dry N inlet and magnetic stirrer.
4a (MW ) 673.98). This contradicts the small-molecule model
2
reactions that we have reported as we have not observed carbonate
formation between two secondary alcohols. An alternative
explanation is an impurity in our sample of 2. This impurity could
possibly be [N,N-bis(2-hydroxyethyl)]-2-aminopropan-1-ol which
would contain three primary hydroxyl groups and may be formed
during the ring opening of propylene oxide by diethanolamine,
the probable synthetic route to 2. No species of mass greater than
that of 6 were detected.
1,1′-carbonyl diimidazole, CDI, (0.16 mol), 1a (0.14 mol) and KOH (12 mmol)
were added to the flask. The mixture was heated at 60 °C with stirring until
the complete formation of 3a was determined by TLC. 2 (70 mmol) was added
dropwise to the solution and left to stir until complete carbonate formation
was determined by TLC. The mixture was left to cool to rt, filtered and
concentrated in vacuo. The residue was dissolved in CH
water (3 × 50 mL), dried with anhydrous Na SO , and concentrated in vacuo
to give 4a as a clear liquid (93%). Selected analytical data for 4a, H NMR
(CDCl ), 3.73
2 2
Cl , washed with
2
4
1
3
, 300 MHz) δ ) 0.92 ppm (m, CH
m, HOCH-CH ) 4.20 (t, O(CdO)OCH ), 4.88 (m, O(CdO)OCH), C NMR
CDCl , 75 MHz) δ ) 64.00 (HOCH-CH ), 67.95 (O(CdO)OCH ), 75.97
O(CdO)OCHR ), 155.55 (CdO). m/z (Es ) 504.68 (MH , 100%). For higher
3
), 1.10 ppm (d, CH-CH
3
13
(
(
(
3
2
3
3
2
Finally, we have investigated the asymmetric coupling of
different polycarbonate wedges. Asymmetric coupling of dendritic
+
+
2
generations, CDI and 2 are added alternately and monitored by TLC.