Synthesis of water-soluble, ester-terminated dendrons and dendrimers containing internal PEG linkages

Article abstract of DOI:10.1021/ma049017i

Dendrimers up to three generations, possessing internal PEG units within the branching framework, were synthesized by a convergent approach via the reaction of amine-based dendrons 6, 9, and 11 with 6,6-bis(4-chlorocarbonyl-2- oxabutyl)-4,8-dioxaundecane-1,11-dicarbonyl chloride. These new constructs were fully characterized, shown to exhibit good solubilities in organic as well as aqueous solvents, and demonstrated to solubilize lithium triflate salts in nonaqueous environments, such as chloroform.

Full text of DOI:10.1021/ma049017i

8
262
Macromolecules 2004, 37, 8262-8268
Synthesis of Water-Soluble, Ester-Terminated Dendrons and
Dendrimers Containing Internal PEG Linkages
,
‡
†
§
Geor ge R. New k om e,* Kish or e K. Kotta , Am a r esh Mish r a , a n d
Ch a r les N. Moor efield ‡
Departments of Polymer Science and Chemistry, Department of Chemisry, Maurice Morton Institute of
Polymer Science, The University of Akron, Akron, Ohio 44325-4717, and Department of Chemical
Sciences, Tata Institute of Fundamental Research, Mumbai, 400 005, India
Received May 18, 2004; Revised Manuscript Received August 5, 2004
ABSTRACT: Dendrimers up to three generations, possessing internal PEG units within the branching
framework, were synthesized by a convergent approach via the reaction of amine-based dendrons 6, 9,
and 11 with 6,6-bis(4-chlorocarbonyl-2-oxabutyl)-4,8-dioxaundecane-1,11-dicarbonyl chloride. These new
constructs were fully characterized, shown to exhibit good solubilities in organic as well as aqueous
solvents, and demonstrated to solubilize lithium triflate salts in nonaqueous environments, such as
chloroform.
5
3,60,64
In tr od u ction
Diederich et al. utilized a series of dendroclefts
and heme proteins
5
0,59,61,68,70,91,92
possessing 1 f 3
During this past decade, the syntheses, characteriza-
C-branched monomers capped with small, surface PEGed
subunits and then studied their unique properties such
as their selective recognition of monosaccharides. Ph-
and related benzoporphyrins as well
as metalloclusters have also been made readily water-
soluble by the attachment of small PEG units. Nieren-
garten recently reviewed examples of dendritic encap-
sulation, which is, in part, based on related PEGed
surfaces. The highly stable PEG-functionalized satu-
rated hydrocarbon-type dendrimers act as electrolyte
materials and were shown to improve the efficiency9
of a lithium rocking chair battery. More recently, Itoh
tion, and applications of dendrimers have been intro-
duced into diverse fields of research.1,2 These highly
branched, 3-dimensional, globular macromolecules have
shown promising utility in molecular electronic devices,
such as light-emitting diodes, molecular antennae,
6
5,93
77
thalocyanines
9
4
3
,4
5,6
7
,8
9,10
light-harvesting systems, drug delivery systems,
7
9
1
1
chemical sensors, receptors in molecular recognition
processes,1
2,13
14,15
enhanced binding or sensor effects,
1
6-19
and luminescent materials,
Poly(ethylene glycol)s (PEGs) and their derivatives
are important biocompatible materials that exhibit a
to mention but a few.
5,96
2
0,21
wide range of solubilities
and are generally non-
4
4,97
2
2
9,23,24
et al.
studied the ionic conductivity of hyperbranched
toxic. Hence, their use as drug carriers,
anchors
2
5
PEG derivatives in the presence of lithium metal salts
[LiCF3SO3 and Li(CF3SO2)2N] to determine their ef-
fectiveness as polymer electrolytes. Only three examples
of PEG units being used as noncore, internal linkages
have appeared, to the best of our knowledge: function-
hyperbranched
and in the solid-phase
peptide synthesis of multimeric cyclo-(RGDtE)-pep-
for biological receptors, and metal ion binding for ion
2
6
transport is well documented. In tethered, bilayer
membrane systems, where they are employed as hy-
drophilic linkers, PEG units act as the integral compo-
nent of an ion channel switch biosensor.27 Further,
4
3,46
alization of tetrathiafulvalene (TTF),
Fr e´ chet-type materials,
ether-, ester-, and amine-based linear polymers with
short PEG units in the presence of inorganic salts have
potential applications in high-energy density batteries,
4
7,97,98
4
5
2
8-31
tides.
electrochemical cells, and electrochromic devices.
Our interest in the design and application of den-
drimers led us to synthesize a series of useful PEGed
dendrons and dendrimers, which utilize a combination
of (1) amide connectivity affording minimal internal
hydrolytic cleavage in that most PEGed dendrimers
possess the more labile ester connectivity, (2) 1 f 3
C-branching motif, and (3) a noncore, internal PEG
linkage, derived from commercially available triethylene
glycol. Incorporation of PEG functionality within the
dendritic framework is also envisioned to enhance the
dendrimers potential to facilitate the transport of alkali
metal species such as is required of polymer electrolytes
in solid-state batteries.
For dendritic architectures incorporating the PEG
moiety, the most common attachment of PEG moieties
is onto their surface in order to instill aqueous solubility
in general, to water-insoluble species. In that dendrim-
ers have three structural regions in which a PEG unit
3
2-42
can be introduced, namely, the core,
internal con-
nective moieties,4
3-47
and surface groups,
9,36,48-82
the
former and latter attachments predominate due to the
ease of instillation. Also, dendrons have been focally
3
8,83-89
32,36
PEGed.
Gitsov et al.
reported linear-dendritic
block copolymers using large PEG components, as the
internal core as well as surface unit(s), and studied their
properties; a review by Gitsov90 has recently appeared.
Exp er im en ta l Section
†
Department of Chemistry, The University of Akron.
Maurice Morton Institute of Polymer Science, The University
‡
Gen er a l Rem a r k s. Melting point data were obtained in
capillary tubes with an Electrothermal 9100 melting point
apparatus and are uncorrected. All of chemicals were pur-
chased from Aldrich Co. except for the tetradirectional core,
of Akron.
§
Tata Institute of Fundamental Research.
Corresponding author: e-mail newkome@uakron.edu.
*
1
0.1021/ma049017i CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/01/2004

Macromolecules, Vol. 37, No. 22, 2004
Synthesis of Dendrons and Dendrimers 8263
Behera’s amine, and its nitro precursor.99 Tetrahydrofuran
mg, 2 mmol), Behera’s amine100,101 (1 g, 2 mmol) was added;
the mixture was stirred at 25 °C for 15 h. After filtration, the
solvent was evaporated in vacuo to give a viscous oil, which
(THF) was dried by refluxing over benzophenone/Na under N
2
.
Dichloromethane was dried over CaH . All other commercially
2
available solvents were used without further purification.
was column chromatographed (SiO
Cl /EtOAc to give (92%) pure azide 5 as a viscous oil: 1.4 g.
H NMR δ 1.32 (s, 27H, CH ), 1.87 (t, 6H, CH CH CO, J )
8.4 Hz), 2.09 (t, 6H, CH CO, J ) 8.4 Hz), 3.28 (t, 2H, N CH
J ) 4.5 Hz), 3.58-3.59 (m, 10H), 3.78 (s, 2H, OCH CO) 6.40
(s, 1H, NH). 13C NMR δ 28.18 (CH
), 29.69, 29.78 (CH CH
CO), 50.74 (N CH ), 57.28 (NHC), 70.16-71.33, 80.54 (CMe
169.09 (CONH), 172.53 (CO ). IR 2106 (N ), 1726 (CdO), 1677
2 2
) eluting with 95% CH -
Column chromatography was conducted using silica gel (60-
2
1
2
00 mesh) from Fisher Scientific with the stipulated solvent
3
2
2
1
13
mixture. H and C NMR spectra were obtained in CDCl
3
,
2
3
2
,
except where noted, and are recorded at 250 and 52 MHz,
respectively. The NMR spectra of selected samples dissolved
in formic acid were obtained without a lock signal and were
shimmed on the FID. Infrared spectra (IR) were obtained (KBr
pellet, unless otherwise noted) and recorded on an ATI
Mattson Genesis Series FTIR spectrometer. Mass spectral data
were obtained using an Esquire electron ionization mass
spectrometer (ESI) and are reported as (assignment, relative
2
3
2
2
-
3
2
3
),
2
3
-
1
+
(CdO), 1153 cm (C-O). FAB-MS m/z ) 632 (M + H ), calcd
+
m/z ) 631.77 (M + H ).
Syn th esis of Den d r on 6. A suspension of azide 5 (3 g, 4.7
mmol) in EtOH (30 mL) with 10% Pd-C under 60 psi of
hydrogen at 20 °C was stirred for 16 h and then carefully
filtered to remove the catalyst (caution: pyrophoric) and
concentrated in vacuo to give a viscous liquid, which was
intensity); ESI samples were typically prepared in MeOH/H
TFA (70:30:01) for positive ion mode or Me CHOH/H O/NH
70:30:1) for negative ion mode and matrix-assisted laser
2
O/
2
2
3
(
desorption ionization time-of-flight (MALDI-TOF) mass spec-
trometer. Differential scanning calorimetry (DSC) data were
obtained using a TA DSC 2910 using scanning rates of 10 °C/
min.
column chromatographed (SiO
MeOH/EtOAc to afford (94%) amine 6: 2.7 g. H NMR δ 1.30
(s, 27H, CH ), 1.84 (t, 6H, CH CH O, J ) 6.6 Hz), 2.07 (t, 6H,
CH O, J ) 6.6 Hz), 3.04 (t, 2H, H NCH , J ) 4.5 Hz), 3.57-
3.79 (m, 10H), 3.84 (s, 2H, CH CO), 5.21 (s, 1H, NH), 6.56 (s,
). C NMR δ 27.94 (CH ), 29.50, 29.56 (CH CH CO),
39.92 (H NCH ), 57.24 (NHC), 67.86-70.57, 80.49 (CMe ),
169.37 (CONH), 172.52 (CO ). IR 3371 (NH ), 1726 (CdO),
2
) eluting with EtOAc f 10%
1
3
2
2
2
2
2
Eth yl [2-[2-(2-Hyd r oxyeth oxy)eth oxy]eth oxy]a ceta te
2
1
3
(
1). To the stirred solution of triethylene glycol (20 g, 133
mmol) and BF ‚THF (2 drops) in CH Cl under N was added
dropwise ethyl diazoacetate (15.4 g, 133 mmol) in CH Cl (50
mL) over 1 h. After stirring at 20 °C for 12 h, the organic phase
was washed with water (50 mL, 2×), dried (MgSO ), filtered,
and evaporated in vacuo to give (70%) 1 as a colorless oil: 21.4
2H, NH
2
3
2
2
3
2
2
2
2
2
3
2
2
2
2
-
1
+
1661 (CdO), 1153 cm (C-O). FAB-MS m/z ) 606 (M + H ),
+
4
calcd m/z ) 605.77 (M + H ).
Syn th esis of Den d r on 7. To the stirred solution of azide
1
g; R
CH
(
7
f
0.41 [SiO
, J ) 7.2 Hz), 3.22 (t, 2H, HOCH
m, 10H), 3.98 (s, 2H, OCH CO), 4.05 (q, 2H, OCH
.2 Hz). C NMR δ 13.91 (CH ), 60.50 (OCH CH
). IR 3500 (OH), 1751 (Cd
2
: EtOAc/hexane (1:1)]. H NMR δ 1.12 (t, 3H,
, J ) 5.4 Hz), 3.43-3.57
CH , J )
), 61.25
2
5 (3 g, 4.7 mmol), HCO H was added and then stirred for 6 h
at 25 °C. The excess reagent was evaporated in vacuo, then
toluene was added, and again evaporated in vacuo to remove
3
2
2
2
3
1
3
3
2
3
the last traces of formic acid to afford (95%) the pure triacid
1
(HOCH
2
), 68.32-72.35, 170.20 (CO
2
7: 2.08 g. H NMR δ 2.03 (t, 6H, CH
2
CH
O, J ) 6.3 Hz), 3.18 (t, 2H, N
3.62-3.66 (m, 10H), 3.87 (s, 2H, CH CO), 6.56 (s, 1H, NH),
9.54 (s, 3H, CO CO), 29.22 (CH
H). 13C NMR δ 28.15 (CH
CH CO), 50.06 (N CH ), 56.60 (NHC), 69.32-70.41, 168.86
(CONH), 174.50 (CO H). IR 3358 (CO H), 2110 (N ), 1716 (Cd
2
O, J ) 6.3 Hz), 2.26
-
1
+
O), 1127 cm (C-O). FAB-MS: m/z ) 258.9 (M + H ); calcd
m/z ) 259.2 (M + H ).
(t, 6H, CH
2
3
CH , J ) 4.5 Hz),
2
+
2
Eth yl [2-[2-(2-Mesyloxyeth oxy)eth oxy]eth oxy]a ceta te
2
2
2
-
(2). To the stirred solution of ester 1 (10 g, 42 mmol), Et
3
N
2
3
2
(4.30 g, 43 mmol), and toluene (50 mL) was added dropwise a
2
2
3
-
1
solution of mesyl chloride (4.85 g, 43 mmol) in toluene (10 mL)
for 30 min at -10 °C. The mixture was stirred for 3 h at 25 °C
then concentrated in vacuo to give a residue, which was column
O), 1668 (CdO), 1104 cm (C-O). FAB-MS m/z ) 463 (M +
+
+
H ), calcd m/z ) 463.45 (M + H ).
Syn th esis of P r ed en d r on 8. To a stirred solution of 4-(2-
carboxyethyl])-4-nitroheptanedioic acid1
02,103
(530 mg, 1.91
chromatographed eluting with EtOAc/ CH
90%) mesylate 2 as a viscous oil: 12.0 g; R
δ 1.15 (t, 3H, OCH CH , J ) 7.2 Hz), 2.96 (s, 3H, SO
.54-3.59 (m, 10H), 3.64 (t, 2H, MsOCH , J ) 4.5 Hz), 4.00
s, 2H, OCH CO), 4.09 (q, 2H, OCH CH , J ) 7.2 Hz). C NMR
δ 13.94 (OCH CH ), 37.31 (SO CH ), 60.48 (OCH CH ), 68.29-
0.51, 170.10 (CO
2
Cl
) 0.34. H NMR
CH ),
2
(20:80) to give
1
(
f
mmol), HOBT (780 mg, 5.7 mmol), and DCC (1.2 g, 5.7 mmol)
in THF at 25 °C, amine 6 (3.5 g, 5.7 mmol) was added. After
48 h, the mixture was filtered, and then the solvent was
removed in vacuo to give the crude dendron, which was column
2
3
2
3
3
(
2
1
3
2
2
3
2
3
2
3
2
3
chromatographed (SiO
2
) eluting with hexane to remove the
Cl to afford (70%)
the desired predendron 8: 2.7 g. H NMR δ 1.33 (s, 81H, CH ),
1.88 (t, 24H, CH CH CO, J ) 7.2 Hz), 2.10 (t, 24H, CH CO, J
) 7.2 Hz), 3.31 (t, 2H, NHCH , J ) 4.8 Hz), 3.41-3.58 (m,
30H), 3.84 (s, 6H, CH CO), 6.42 (s, 3H, NH), 6.72 (s, 3H,
). C NMR δ 28.04 (CH ), 29.59, 29.70 (CH CH CO),
30.36, 30.78 (CH CH CO), 39.36 (NHCH ), 57.18 (NHC),
69.77-70.81, 80.49 (CMe ), 92.80 (O NC), 169.22 (CONH),
171.04 (CONH), 172.46 (CO ). IR 1726 (CdO), 1670 (CdO),
-
1
7
2
); IR 1750 (CdO), 1174 cm (C-O). FAB-
excess DCC and then 10% MeOH in CH
2
2
+
+
1
MS: m/z ) 336.9 (M + Na ); calcd m/z ) 337.3 (M + Na ).
Eth yl [2-[2-(2-Azid oeth oxy)eth oxy]eth oxy]a ceta te (3).
3
2
2
2
A stirred mixture of 2 (10 g, 32 mmol) and excess NaN
3
(3X)
2
in dry DMF (200 mL) was maintained at 60 °C for 3 h. The
mixture was filtered, concentrated in vacuo, and column
2
1
3
NHCH
2
3
2
2
chromatographed (SiO
2
) eluting with an EtOAc/hexane mix-
2
2
2
ture (1:1) to give (95%) the desired azide 3 as a yellow oil: 7.90
3
2
1
g; R
.06 (t, 2H, N
CH CO), 3.87 (q, 2H, OCH
), 49.66 (N CH ), 59.65 (CH
). IR 2108 (N ), 1751 (CdO), 1125 cm (C-O). ESI-MS
f
) 0.55. H NMR δ 0.95 (t, 3H, OCH
2
CH
3
, J ) 7.2 Hz),
2
-
1
+
3
3
CH , J ) 4.2 Hz), 3.33 (m, 10H), 3.81 (s, 2H,
2
1153 cm (C-O). MALDI-TOF m/z ) 2056.2 (M + Na ); calcd
1
3
+
2
2
CH
3
, J ) 7.2 Hz). C NMR δ 13.19
CH O), 67.51-69.75, 169.47
m/z ) 2059.23 (M + Na )
(CH
CO
3
3
2
3
2
Syn th esis of Den d r on 9. The predendron 8 (1 g, 490 µmol)
was reduced (H , Raney Ni, 60 psi, EtOH, 50 °C), in a
2
-
1
(
2
3
+
+
m/z ) 336.9 (M + Na ), calcd m/z ) 337.3 (M + Na ).
2-[2-(2-Azid oeth oxy)eth oxy]eth oxy]a cetic Acid (4). Es-
ter 3 (5 g, 19.1 mmol) was hydrolyzed in aqueous KOH at 20
C for 6 h. The resultant solution was neutralized with 10%
procedure similar to that of 6, to give (80%) the corresponding
1
[
amine 9 as a pale yellow liquid: 780 mg. H NMR δ 1.24 (t,
24H, CH
CH CO, J ) 7.5 Hz), 2.20 (t, 6H, CH
6H, NHCH , J ) 4.8 Hz), 3.53-3.69 (m, 30H), 3.97 (s, 6H, CH
CO), 6.51 (s, 8H, NH, NH
29.54 (CH CH CO), 30.52, 34.72 (CH
57.02 (NHC), 57.96 (H NC), 69.71-70.77, 80.33 (CMe
(CONH), 172.27 (CONH), 173.25 (CO ). IR 3333 (NH
2
CH
2
CO, J ) 6.9 Hz), 1.43 (s, 81H, CH
3
), 1.97 (t, 18H,
°
2
2
CO, J ) 7.5 Hz), 3.41 (t,
aqueous HCl and then concentrated in vacuo to give an oil,
which was extracted with THF, filtered, and evaporated in
2
2
-
1
3
2
). C NMR δ 27.90 (CH
CH CO), 39.10 (NHCH
), 169.02
), 1728
3
), 29.43,
1
vacuo to give (96%) the pure acid 4 as a colorless oil: 4.3 g. H
2
2
2
2
2
),
NMR δ 3.26 (t, 2H, N
3
CH
CO), 10.66 (s, 1H, CO
8.02-70.71, 173.54 (CO ). IR 3450 (CO
2
, J ) 4.5 Hz), 3.57 (m, 10H), 4.01 (s,
2
3
1
3
2
6
H, OCH
2
2
H). C NMR δ 50.31 (N
3
CH
2
),
2
2
-
1
2
2
H), 2108 (N ), 1743
3
+
(CdO), 1672 (CdO), 1153 cm (C-O). MALDI-TOF m/z )
-
1
+
+
(CdO), 1123 cm (C-O). ESI-MS m/z ) 234 (M + H ), calcd
2030.34 (M + Na ), calcd m/z ) 2030.55 (M + Na ).
+
m/z ) 234.22 (M + H ).
Syn th esis of Azid e 10. To the stirred solution of 7 (1 g,
2.16 mmol), EDC (1.24 g, 6.4 mmol), and HOBT (880 mg, 6.4
mmol), amine 6 (3.9 g, 6.4 mmol) was added in DMF at 25 °C.
Syn th esis of Den d r on 5. To the stirred solution of acid 4
(560 mg, 2 mmol), DCC (496 mg, 2 mmol), and HOBT (325

8
264 Newkome et al.
Macromolecules, Vol. 37, No. 22, 2004
Sch em e 1. Syn th esis of Key Exten d er s 3 a n d 4a
a
(
a) N
2
CHCO
O, THF, 20 °C, 6 h.
2
CH
2
CH
3
, BF
3
3 2 3 3
‚THF, 20 °C, 12 h; (b) CH SO Cl, toluene, Et N, 6 h; (c) excess NaN , dry DMF, 60 °C, 3 h; (d)
KOH, H
2
After 15 h, the residue was filtered and the solution evaporated
in vacuo to afford the crude product, which was column
Sch em e 2. Con str u ction of Exten d ed Den d r on s
6 a n d 7a
chromatographed eluting with 10% MeOH in CHCl
(
3
to give
65%) pure azide 10: 3.12 g. H NMR δ 1.31 (s, 81H, CH ),
CO), 3.27 (t,
, J ) 4.5 Hz),
CO), 6.41 (s, 3H, NH),
1
3
1
6
3
6
.88 (br m, 24H, CH
H, H NCH , J ) 4.5 Hz), 3.41 (t, 2H, N
52-3.57 (m, 40H), 3.80 (s, 8H, OCH
.43 (t, 3H, NHCH , J ) 6 Hz), 6.45 (s, 1H, NHC). C NMR
), 28.05, 29.39 (CH CH CO), 30.31, 30.68 (CH CH
CO), 39.09 (NHCH ), 50.42 (N CH ), 56.98 (NHC), 57.68
NHC), 69.64-70.80, 80.26 (CMe ), 168.92 (CONH), 169.06
CONH), 172 0.23 (CONH), 172.51 (CO ). IR 3335 (NH), 2106
2
CH
2
CO), 2.08 (br, 24H, CH
2
2
2
3
CH
2
2
1
3
2
δ 27.82 (CH
3
2
2
2
2
-
2
3
2
(
(
(
3
2
a
-
1
(a) DCC, 1-HOBT, THF, 25 °C, 15 h; (b) EtOH, 10% Pd/C,
N ), 1726 (CdO), 1673 (CdO), 1152 cm (C-O). MALDI-
3
+
+
2 2
H (60 psi), 20 °C, 16 h; (c) HCO H, 25 °C, 6 h.
TOF m/z ) 2245.76 (M + Na ), calcd m/z ) 2245.76 (M + Na ).
Syn th esis of th e Secon d -Gen er a tion Den d r on 11. Azide
1
1
0 (2 g, 890 µmol) was converted to its corresponding amine
1 by reduction with 10% Pd/C at 60 psi at 25 °C, as noted
3.28 (s, 8H, CH
CO, J ) 3.9 Hz), 3.54 (t, 24H, NHCH
120H), 3.82 (s, 24H, OCH CO), 6.38 (s, 12H, NH), 6.81 (s, 4H,
NHCH ), 29.60, 29.77
), 6.92 (s, 4H, NH). 13C NMR δ 28.05 (CH
(CH CH CO), 30.5, 30.72 (CH CH CO), 37.47 (CH CO), 39.29
(NHCH ), 45.33 ( °C), 57.17 (NHC), 57.71 (NHC), 66.19 (CH
OCH ), 67.80 (CH OCH ), 69.75-70.97, 80.48 (CMe ), 169.00
(CONH), 172.41 (CONH), 173.29 (CONH), 173.36 (CO ); IR
(C-O).
2
O), 3.33 (s, 8H, OCH
2
), 3.42 (t, 8H, OCH
2 2
CH -
2
, J ) 6.0 Hz), 3.59 (m,
above. After 24 h, the mixture was filtered through the Celite
to remove the catalyst (caution: pyrophoric), and then the sol-
vent was removed in vacuo to give (94%) the pure amine 11:
1
CO), 2.20 (br m, 24H, CH
CH
2
2
3
2
2
2
2
2
1
4
.85 g. H NMR δ 1.36 (s, 81H, CH
3
), 1.99 (br m, 24H, CH
CO), 3.41 (br m, 8H, NHCH
), 3.49-3.69 (m, 40H), 3.94 (s, 8H, OCH
H, NH), 7.31 (s, 5H, NHCH2, NCH ), 7.44 (s, 1H, NHC).
), 29.53, 29.67 (CH CH CO), 30.55, 31.23
CO), 39.22 (NHCH ), 39.63 (NH CH ), 57.15 (NHC),
8.19 (NHC), 69.53-70.92, 80.46 (CMe ), 169.15 (CONH),
70.08 (CONH), 172 0.39 (CONH), 173.60 (CO ). IR 3334
), 1724 (CdO), 1670 (CdO), 1153 cm (C-O). MALDI-
2
CH
2
-
2
2
-
2
2
,
2
2
2
3
2
N
3
2
CO), 6.52 (s,
2
-
1
3
H
2
2
3331 (NH), 1726 (CdO), 1669 (CdO), 1153 cm
MALDI-TOF m/z ) 8406.10 (M + Na ), calcd m/z ) 8405.59
1
3
+
C NMR δ 28.01 (CH
3
2
2
+
(CH CH
2
2
2
2
2
(M + Na ).
5
1
3
Syn th esis of Secon d -Gen er a tion Bis-P EG Exten d ed
Den d r im er 14. The second-generation dendrimer can be
prepared via amine 11 (1.75 g, 790 µmol) and tetraacyl chloride
(100 mg, 200 µmol) using the general procedure. The residual
2
-
1
(NH
2
+
+
TOF m/z ) 2218.40 (M + Na ), calcd m/z ) 2218.34 (M + Na ).
Syn th esis of F ir st-Gen er a tion Den d r im er 12. Gen er a l
P r oced u r e. To a stirred solution of amine 6 (2.5 g, 4.13 mmol)
solid was column chromatographed (SiO
MeOH in CH Cl to give (63%) the pure dendrimer 14 as a
waxy solid: 1.1 g. H NMR δ 1.29 (s, 324H, CH
CH CH CO, J ) 8.4 Hz), 2.06 (t, 96H, CH CO, J ) 8.4 Hz),
2.29 (t, 8H, OCH CH , J ) 4.8 Hz), 3.26 (t, 8H, OCH , J ) 4.8
Hz), 3.39 (t, 32H, NHCH , NHCH J ) 5.1 Hz), 3.50-3.55 (br
m, 160H), 3.78 (s, 32H, OCH CO), 6.37 (s, 16H, NH, NH), 6.69
). C NMR δ 27.90 (CH ), 29.44, 29.58
CO), 30.40, 30.85 (CH CH CO), 36.46 (CH CO), 39.13
), 45.38 (C), 57.04, 57.76 (2 NHC), 67.26, 68.97 (2
OCH ), 69.61-70.78, 80.32 (CMe ), 168.95, 169.35, 171.25,
172.28 (4 CONH), 172.95 (CO ); IR 3334 (NH), 1724 (CdO),
2
) eluting with 5%
2
2
1
and NEt
3
(2 g, 19.6 mmol) in dry CH
2
Cl
2
was added tetraacid
3
), 1.84 (t, 96H,
1
04
chloride (500 mg, 1.0 mmol), prepared from the correspond-
ing tetraacid
stirred for 30 min at 0 °C and then for 6 h at 25 °C. The
mixture was washed sequentially with 10% cold HCl, water,
2
2
2
1
05
in CH
2
Cl
2
added dropwise. The mixture was
2
2
2
2
2
2
1
3
and saturated brine solution, then dried (MgSO
rated in vacuo to give the crude product, which was column
chromatographed (SiO ) eluting with 7% MeOH in CH Cl to
afford (83%) the pure dendrimer 12 as a viscous oil: 2.2 g. H
), 1.98 (t, 24H, CH CH
CO, J ) 8.7 Hz), 2.44 (t, 8H, OCH
CO, J ) 6.0 Hz), 3.31 (s, 8H, OCH ), 3.45 (t, 8H, OCH
4
), and evapo-
(br m, 16H, NHCH
(CH CH
(NHCH
CH
2
3
2
2
2
2
2
2
2
2
2
1
2
2
3
NMR δ 1.44 (s, 108 H, CH
Hz), 2.21 (t, 24H, CH
3
2
2
CO, J ) 8.7
2
-
1
2
2
CH
2
-
-
1670 (CdO), 1153 cm (C-O). MALDI-TOF m/z ) 9115.98
(M + Na ), calcd m/z ) 9120.36 (M + Na ).
+
+
2
2
CH
2
CO, J ) 4.8 Hz), 3.56 (t, 8H, NHCH
2
, J ) 4.8 Hz), 3.66-3.68
CO), 6.47 (s, 4H, NH), 6.83 (t, 4H,
, J ) 2.0 Hz). C NMR δ 27.71 (CH ), 29.26, 29.40
CO), 36.34 (CH CO), 38.92 (NHCH
6.85 (NHC), 67.04 (OCH CH ), 68.80 (CH OCH
0.67, 80.04 (CMe ), 168.80 (CONH), 171.07 (CONH), 172.03
). IR 3342 (NH), 1724 (CdO), 1672 (CdO), 1153 cm (C-
(m, 40H), 3.93 (s, 8H, OCH
2
Resu lts a n d Discu ssion
1
3
NHCH
2
3
4
The treatment (Scheme 1) of triethylene glycol with
ethyl diazoacetate in the presence of BF3‚Et2O gave the
monoester 1, which with mesyl chloride in the presence
of Et3N, followed by NaN3 in DMF at 60 °C gave (95%)
(CH
2
CH
2
2
2
), 45.12 ( °C),
), 69.57-
5
7
2
2
2
2
3
-1
(CO
2
+
1
O). MALDI-TOF m/z ) 2792.35 (M + Na ), calcd m/z )
2
the desired azidoester 3, which was supported ( H NMR)
+
794.50 (M + Na ).
by the upfield shift (3.64-3.06 ppm) for the ω-CH2
triplet upon substitution. Ester 3 was then saponified
to give (96%) the azidoacid 4, which was identical to a
sample generated in four steps from chlorotriethylene
Syn th esis of Secon d -Gen er a tion Mon o-P EG Exten d ed
Den d r im er 13. The second-generation dendrimer was pre-
pared using the amine 9 (8.1 g, 4.03 mmol) and tetraacyl
chloride (500 mg, 1.0 mmol), following the above general
procedure. Purification was accomplished by chromatography
eluting with 5% MeOH in CH
dendrimer 13 as a waxy semisolid: 5.8 g. H NMR δ 1.33 (s,
1
06
glycol.
Both ester 3 and acid 4 were used as the
simple PEG connectors between branching points within
a dendrimer framework. Treatment (Scheme 2) of the
2 2
Cl to afford (70%) the pure
1
1
00,101
3
9
24 H, CH
3
), 1.88 (t, 96H, CH
2
CH
2
CO, J ) 7.5 Hz), 2.16 (t,
CH2, J ) 3.9 Hz),
azidoacid 4 with Behera’s amine
coupling conditions
under peptide
1
07,108
6H, CH CO, J ) 7.5 Hz), 2.78 (t, 8H, OCH
2
2
afforded (92%) the PEG-

Macromolecules, Vol. 37, No. 22, 2004
Synthesis of Dendrons and Dendrimers 8265
Sch em e 3. Syn th esis of Den d r on s 9 a n d 11a
a
(a) DCC, 1-HOBT, dry THF, 25 °C, 24 h; (b) H
2
(60 psi), Raney Ni, EtOH, 50 °C, 12 h; (c) EDC, 1-HOBT, anhydrous DMF,
amine 6, 25 °C, 24 h; (d) EtOH, 10% Pd/C, H
2
(60 psi), 25 °C, 24 h.
1
3
extended branched amide 5, which was supported by
the 3:1 integration ( H NMR) of the triplet (1.87 ppm)
for the R-CH2CO2R to the singlet for the R-OCH2CON
as well as the MS peak at m/z 632 for the desired parent
ion.
9, which was supported by the shift ( C NMR) for the
O2NC to H2NC conversion (92.8-57.9 ppm) and the MS
1
+
peak at 2030.34 (M + Na) .
The double PEG-extended 11 was obtained in two
steps from azide 7 with amine 6 using the same
amidation procedure, except using EDC, to give (65%)
the heptaamide intermediate 10; catalytic reduction
using Pd/C at 60 psi hydrogen then transformed (94%)
the azide moiety to the corresponding amine 11. The
Deprotection of 5 with formic acid at 25 °C quanti-
tatively generated the corresponding triacid 7, evi-
denced by the absence of the tert-butyl resonances and
appearance of a peak at 9.54 ppm for the carboxylic acid,
whereas subjecting 5 to reductive conditions using Pd
on carbon gave (94%) the desired amine 6, which was
1
3
C NMR data confirm this structure: 169.15, 170.08,
and 172.39 ppm for the three different amide carbons
and the expected shift for the N3CH2 to H2NCH2 (50.4-
39.6 ppm) conversion as well as the observed mass peak
for the parent ion 2218.34 (M + Na ).
Treatment of 4.4 equiv of amine 6 and tetraacyl
1
13
spectrally ( H and C NMR) similar to the azide except
for the shift noted for the N3CH2- to H2NCH2- conver-
sion; the mass spectral data showed a peak at m/z 606
+
+
for the M + H , further supporting the assignment.
1
09
The PEG-extended dendron 9 was constructed (Scheme
chloride
15 in the presence of Et3N afforded the
1
3
3
) by initially treating 4-(2-carboxyethyl)-4-nitrohep-
desired polyester 12 (Scheme 4). The C NMR spectrum
of dodecaester 12 showed peaks at 45.12 ppm for the
core quaternary carbon and peaks at 168.80, 171.07, and
172.03 ppm for the three distinct carbonyl groups as
well as the MALDI-TOF MS showed a peak at 2792.35
1
01-103
tanedioic acid
with amine 6 under typical ami-
dation conditions to give (70%) the second-generation
predendron 8, which was chromatographed to remove
the excess DCC and urea byproducts. The 1 C NMR
spectral data revealed peaks at 57.31, 57.96, and 80.67
ppm for the three different quaternary centers repre-
senting the two branching carbons and intact termini;
the three carbonyl groups (169.33, 172.54, and 172.58
ppm) as well as MALDI-TOF MS peak at 2056.2 (M +
3
+
(M + Na ), supporting dendrimer formation.
When amine 9 was subjected to the same procedure,
pure dendrimer 13 was isolated (70%) and characterized
( C NMR) by the peaks (45.33, 57.17, and 57.71 ppm)
for the three different quaternary centers representing
one central and two branching carbons as well as the
presence of four different carbonyl groups (169.00,
172.41, 173.29, and 173.36 ppm); the peak (MALDI-
1
3
+
Na) support the successful amidation. Reduction of the
focal nitro substituent was accomplished using T1
Raney nickel to afford (80%) the corresponding amine

8
266 Newkome et al.
Macromolecules, Vol. 37, No. 22, 2004
Sch em e 4. Syn th esis of Den d r im er s 12-14a
Con clu sion
Monomer 4 was prepared in four steps from trieth-
ylene glycol. The first-generation dendron was prepared
by the coupling reaction of the acid 4 and Behera’s
amine to produce 5, which was reduced to give amino
building block 6. The second (9) and third (10) genera-
tion dendrons were prepared using similar coupling
conditions. The first-third generation dendrimers were
synthesized from monomers 6, 9, and 11, respectively,
using a tetraacyl chloride, as the core, via a convergent
approach. These materials are soluble in organic sol-
vents as well as in aqueous solvents. Dissolution of
lithium triflate in CHCl3 was shown with added den-
drimer.
Ack n ow led gm en t. We gratefully thank the Na-
tional Science Foundation (DMR 0401780), the Korea
Research Foundation (KRF 2003-042-C00069), Office of
Naval Research (N00014-01-1-0856), Air Force Office of
Scientific Research (F349620-02-1-0428), and the Ohio
Board or Regents.
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