Syntheses of new 1 → (2 + 1) C-branched monomers for the construction of multifunctional dendrimers

Article abstract of DOI:10.1021/ma034319q

For the purpose of providing a route to multifunctionalized dendrimers, new types of 1 → (2 + 1) C-branched monomers, possessing either ester and protected hydroxy groups or mixed esters, were designed and synthesized. Thus, di-tert-butyl 4-(3-[X]oxypropyl)-4-aminoheptanedionate (X = MeCO, 4; X = CH₂CH₂CN, 6; X = CH₂C₆H₅, 7) was prepared in high yields via the protection of the nitro precursor 2(X = H), which was readily accessible from the Michael addition of 4-nitrobutanol with tert-butyl acrylate, followed by catalytic reduction. These monomers were readily attached to an appropriate four-directional core to produce the first-generation dendrimers (e.g., 9-11). The related second-generation dendrimer (15), possessing two different functional groups on both the surface and interior, was convergently synthesized from monomer 3. Alternatively, the mixed ester 17 was prepared starting with benzyl 4-nitrobutanoate (16); selective deprotection offered access to the representative 1 → (2 + 1) C-branched monomer 20, which was converted to dendrimers 29 and 30 with a single novel terminus per dendron. These 1 → (2 + 1) C-branched monomers offer synthetic versatility to place different functionality at different levels within or on the surface of the dendritic construct.

Full text of DOI:10.1021/ma034319q

Macromolecules 2003, 36, 4345-4354
4345
Syntheses of New 1 f (2 + 1) C-Branched Monomers for the
Construction of Multifunctional Dendrimers
Geor ge R. New k om e,*,† Hyu n g J . Kim ,‡ Ch a r les N. Moor efield ,† Him a Ma d d i,† a n d
Kyu n g-Soo Yoo†
Departments of Polymer Science and Chemistry, The University of Akron, Akron, Ohio 44325-4717,
and Department of Applied Chemistry, Chonnam National University, Kwangju 500-757, Korea
Received March 14, 2003
ABSTRACT: For the purpose of providing a route to multifunctionalized dendrimers, new types of 1 f
(2 + 1) C-branched monomers, possessing either ester and protected hydroxy groups or mixed esters,
were designed and synthesized. Thus, di-tert-butyl 4-(3-[X]oxypropyl)-4-aminoheptanedioate (X ) MeCO,
4; X ) CH2CH2CN, 6; X ) CH2C6H5, 7) was prepared in high yields via the protection of the nitro precursor
2 (X ) H), which was readily accessible from the Michael addition of 4-nitrobutanol with tert-butyl acrylate,
followed by catalytic reduction. These monomers were readily attached to an appropriate four-directional
core to produce the first-generation dendrimers (e.g., 9-11). The related second-generation dendrimer
(15), possessing two different functional groups on both the surface and interior, was convergently
synthesized from monomer 3. Alternatively, the mixed ester 17 was prepared starting with benzyl
4-nitrobutanoate (16); selective deprotection offered access to the representative 1 f (2 + 1) C-branched
monomer 20, which was converted to dendrimers 29 and 30 with a single novel terminus per dendron.
These 1 f (2 + 1) C-branched monomers offer synthetic versatility to place different functionality at
different levels within or on the surface of the dendritic construct.
In tr od u ction
Since their inception,1,2 dendrimers as well as their
less-than-perfect, hyperbranched analogues have re-
ceived considerable attention due, in part, to their
unique globular structures, physical properties,3-12 and
catalytic activity.13-16 In general, synthetic methodolo-
gies for dendritic construction are categorized into either
a divergent1,2 or convergent17 mode, which consists of
the stepwise, iterative reaction processes based on
branched18 or traditional commercial linear monomers.
Appropriate selection of monomer, multidirectional core,
and/or mode of assembly thus ultimately defines the
supramacromolecular properties of dendrimers, such as
size, shape, solubility, viscosity, and thermal behaviors,
internal and surface functionality, aptitude for catalysis,
and unimolecular micelle properties.19,20
F igu r e 1. Simple monomer branching patterns with 1 f
(2+1) branched amine and isocyanate examples.
Exp er im en ta l Section
Gen er a l Section . The melting points were determined in
capillary tubes with an Electrothermal 9100 apparatus and
are uncorrected. 1H and 13C NMR spectra were recorded at
300 and 71 MHz, respectively, on a Varian GEMINI 300 MHz
spectrometer and were obtained in CDCl3, unless otherwise
stated. Mass spectral data were obtained on either a Bruker
Esquire electrospray ion trap mass spectrometer (ESI-MS) or
a Bruker Reflex-III MALDI-TOF mass spectrometer. All re-
agents were obtained from Aldrich Chemical Co. and used
without further purification. THF was distilled under nitro-
gen with LiAlH4 as drying agent and triphenylmethane as
indicator.
4-Nitr obu ta n ol (1). To a stirred solution of tert-butyl acry-
late (14 g, 109 mmol) in MeNO2 (300 mL) was added Triton-B
(1 mL, 40 wt % solution in MeOH) at 25 °C, stirred for 12 h,
and then concentrated in vacuo to ca. 50 mL. Et2O (50 mL)
was added, and the mixture was washed with water (50 mL
× 2) and saturated aqueous NaCl solution (50 mL) and then
dried (MgSO4). The mixture was concentrated in vacuo to give
crude tert-butyl 4-nitrobutanoate as a light yellowish liquid
(11.6 g), which was dissolved in formic acid (95%, 40 mL) and
stirred for 4 h at 25 °C. The mixture was concentrated to
dryness in vacuo to afford the crude 4-nitrobutanoic acid.
A solution of this crude acid intermediate (11 g, 82.64 mmol)
in THF (20 mL) was slowly added into a BH3‚THF solution
With respect to dendritic construction, a variety of
branched monomers have been developed over the past
decade. In general, they can be classified as 1 f 2 (A)
and 1 f 3 branching monomers (B, Figure 1), which
generally lead to uniform fractal patterns.3 Although a
combinatorial approach has been presented21-24 to
instill random multifunctionalization, to enhance func-
tional diversity into dendritic materials, we herein
report the simple synthesis of 1 f (2 + 1) C-branching
monomers (C) and demonstrate their utility for the
assembly of new dendritic families possessing tailored
protected moieties for subsequent activation after comple-
tion of the construct. Other monomers specifically
crafted for the purpose of multifunctional group intro-
duction include the P-based building blocks of Majoral
and co-workers25 and others.26-32
† The University of Akron.
‡ Chonnam National University.
* Corresponding author: e-mail newkome@uakron.edu.
10.1021/ma034319q CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/17/2003

4346 Newkome et al.
Macromolecules, Vol. 36, No. 12, 2003
(248 mL, 1 M, 248 mmol) at 0 °C, and then the mixture was
refluxed for 6 h. After cooling to 0 °C, water (20 mL) was added
cautiously to hydrolyze an excess BH3 and alkoxy-boron
complex. After removal of the solvent in vacuo, the residue
was treated with saturated aqueous NaHCO3 (50 mL) and
extracted with Et2O (100 mL × 2). The combined extract was
washed with a saturated aqueous NaCl solution (50 mL), dried
(MgSO4), and concentrated to dryness in vacuo to afford (90%)
(CMe3), 172.9 (CO2-tert-Bu). ESI-MS: found 346.0 (M + H)+
(calcd 346.3).
Di-ter t-bu tyl 4-Am in o-4-[3-(2-cya n oeth oxy)p r op yl]h ep -
ta n ed ioa te (6). To a solution of amine 5 (2.49 mg, 7.21 mmol)
in THF (20 mL) was added powdered KOH (81 mg, 1.44 mmol).
The mixture was stirred 30 min at 25 °C, and then acrylonitrile
(765 mg, 14.42 mmol) was added; the mixture was stirred for
12 h at 25 °C. Et2O (50 mL) was added to the mixture with
rapid stirring, and the resulting yellow solid was filtered, then
the filtrate was washed with water and saturated aqueous
NaCl, and dried (MgSO4). The solvent was removed in vacuo
1
1 as a colorless liquid33 (8.9 g). H NMR: δ 1.47 (m, 2H, CH2-
CH2OH), 1.94 (m, 2H, CH2CH2CH2OH), 3.26 (br s, 1H, OH),
3.49 (t, J ) 6.2 Hz, 2H, CH2OH), 4.31 (t, J ) 7.0 Hz, 2H, O2-
NCH2). 13C NMR: δ 23.6 (CH2CH2CH2OH), 28.6 (CH2CH2OH),
61.0 (CH2OH), 75.2 (O2NC).
1
to give (98%) nitrile 6 as a colorless liquid (2.81 g). H NMR:
δ 1.38 (m, 2H, CH2CH2O), 1.43 [s, 18H, C(CH3)3], 1.58 (m, 2H,
CH2CH2CH2O), 1.64 (t, J ) 8.1 Hz, 4H, CH2CH2CO2), 1.98 (br
s, 2H, NH2), 2.25 (t, J ) 8.1 Hz, 4H, CH2CO2), 2.58 (t, J ) 6.3
Hz, 2H, CH2CN), 3.47 (t, J ) 6.3 Hz, 2H, CH2O), 3.63 (t, J )
6.3 Hz, 2H, OCH2CH2CN). 13C NMR: δ 18.5 (CH2CN), 23.2
(CH2CH2O), 27.7 (CH3), 29.7 (CH2CO2), 34.1 (CH2CH2CO2),
35.5 (CH2CH2CH2O), 52.2 (H2NC), 65.0 (OCH2CH2CN), 71.2
(CH2O), 79.8 (CMe3), 117.6 (CN), 172.8 (CO2-tert-Bu). ESI-
MS: found 398.9 (M + H)+ (calcd 399.3).
Di-ter t-bu tyl 4-Am in o-4-(3-ben zyloxy)pr opylh eptan edio-
a te (7). 1. Ben zyla tion . To a stirred suspension of NaH (60%
in oil; 106 mg, 2.66 mmol) in THF (10 mL) was slowly added
a solution of alcohol 2 (1 g, 2.66 mmol) in THF (5 mL). After
30 min, benzyl bromide (682 mg, 3.99 mmol) and a catalytic
amount of 15-crown-5 were added. The mixture was stirred
at 25 °C for 12 h and then extracted with Et2O (25 mL). The
organic layer was washed with water (5 mL, 2X) and then
saturated NaCl solution (5 mL) and dried (Na2SO4). After
concentration in vacuo, the crude product was column chro-
matographed (SiO2) eluting with a solution of n-hexane/EtOAc
(2:1) to afford (72%) the desired benzyl protected ether as a
colorless oil (891 mg). 1H NMR: δ 1.43 (s, [C(CH3)3], 18 H),
1.56, 1.98, 2.21 (m, 12H), 3.47 (t, CH2OCH2Ph, 2H, J ) 6.1
Hz), 4.49 (s, CH2Ph, 2H), 7.29 (m, ArH, 5H). 13C NMR: δ 23.98
(CH2CH2O), 27.92 (CH3), 29.73 (CH2CO2), 30.39 (CH2CH2CO2),
32.06 (CH2CH2CH2O), 69.25 (CH2O), 72.84 (CH2Ph), 80.88
(CMe3), 92.68 (CNO2), 127.47, 127.53, 128.3, 138.1 (ArC), 171.1
(CO2). ESI-MS: found 488.3 (M + Na)+ (calcd 488.3).
2. Red u ction . To a sonicated solution of NiCl2‚6H2O (357
mg, 1.503 mmol) in MeOH (10 mL) was added NaBH4 (170
mg, 4.509 mmol) in small portions to prevent excess heating.
The in situ generated Ni2B catalyst was sonicated for an
additional 30 min, and then the above benzyl ether (700 mg,
1.505 mmol) in EtOH/toluene (10:1, 11 mL) was added. The
suspension was stirred at 25 °C with the slow addition of
NaBH4 (341 mg, 9.018 mmol) over 2 h. After the final aliquot,
the stirred mixture was maintained for an additional 30 min,
and then the mixture was filtered through a Celite pad; the
pad was washed with MeOH. The combined filtrate was
concentrated in vacuo to generate a pale green solid, which
was dissolved into CH2Cl2 and sequentially washed with
aqueous NH4OH (2%, 2 × 5 mL) and water (2 × 5 mL) and
then dried (MgSO4). The solvent was removed in vacuo to
afford (65%) the desired amine 7 as a colorless oil (425 mg).
1H NMR: δ 1.43 [s, C(CH3)3, 18H], 1.58, 1.84, 2.21, 2.34 (m,
12H), 3.48 (br t, CH2OCH2Ph, 2H), 4.49 (s, CH2Ph), 6.2 (br,
NH2), 7.28 (m, ArH, 5H). 13C NMR: δ 24.9 (CH2CH2O), 27.85
(CH3), 29.82 (CH2CO2), 30.11 (CH2CH2CO2), 34.35 (CH2CH2-
CH2O), 60.9 (CNH2), 69.96 (CH2O), 72.78 (CH2Ph), 80.09
(CMe3), 127.45, 128.21, 138.1 (ArC), 172.4 (CO2). ESI-MS:
found 436.3 (M + H)+ (calcd 436.3).
Di-ter t-bu tyl 4-(3-Hyd r oxyp r op yl)-4-n itr oh ep ta n ed io-
a te (2). To a stirred mixture of 4-nitrobutanol (1; 2.43 g, 20.4
mmol) and tert-butyl acrylate (10.45 g, 81.6 mmol) was added
Triton-B (2 mL, 40 wt % solution in MeOH) at 25 °C; the
mixture was maintained for 36 h at 25 °C. The excess tert-
butyl acrylate was removed in vacuo to give a yellowish
residue, which was dissolved in ether, washed sequentially
with 5% aqueous HCl (25 mL), 10% aqueous NaHCO3 (25 mL),
and saturated aqueous NaCl, and then dried (MgSO4). The
organic mixture was concentrated in vacuo to give a residue,
which was column chromatographed (SiO2) eluting with a 2:1
mixture of n-hexane/EtOAc to afford (75%) ester 2 as a
colorless liquid (5.74 g). 1H NMR: δ 1.42 [s, 18H, C(CH3)3],
1.49 (m, 2H, CH2CH2OH), 1.87 (br s, 1H, OH), 1.99 (m, 2H,
CH2CH2CH2OH), 2.19 (m, 8H, CH2CH2CO2), 3.64 (t, J ) 6.1
Hz, 2H, CH2OH). 13C NMR: δ 26.5 (CH2CH2OH), 27.8 [C(CH3)3],
29.6 (CH2CO2), 30.2 (CH2CH2CO2), 31.6 (CH2CH2CH2OH), 61.4
(CH2OH), 80.8 (CMe3), 92.6 (O2NC), 171.2 (CO2). ESI-MS:
found 397.9 (M + Na)+ (calcd 398.2).
Di-ter t-bu tyl 4-(3-Acetoxyp r op yl)-4-n itr oh ep ta n ed io-
a te (3). To a stirred mixture of 2 (1.85 g, 4.927 mmol) and
pyridine (468 mg, 5.912 mmol) in CHCl3 (20 mL) was added
Ac2O (603 mg, 5.912 mmol) at 0 °C. After stirring for 6 h at 25
°C, the mixture was washed with water (20 mL), dried
(MgSO4), and concentrated in vacuo to dryness. The crude
product was column chromatographed (SiO2) eluting with a
mixture of n-hexane/EtOAc (1:1) to afford (94%) acetate 3 as
a white solid (1.93 g); mp 69.5-70 °C. 1H NMR: δ 1.41 [s, 3H,
C(CH3)3], 1.56 (m, 2H, CH2CH2O), 1.94 (m, 2H, CH2CH2CH2O),
2.04 (s, 3H, CH3), 2.18 (m, 8H, CH2CH2CO2), 4.04 (t, J ) 6.0
Hz, 2H, CH2O). 13C NMR: δ 20.8 (COCH3), 22.9 (CH2CH2O),
27.9 (CH3), 29.7 (CH2CO2), 30.3 (CH2CH2CO2), 31.7 (CH2CH2-
CH2O), 63.4 (CH2O), 81.0 (CMe3), 92.4 (O2NC), 170.8 (CH3CO2),
171.0 (CO2-tert-Bu). ESI-MS: found 439.9 (M + Na)+ (calcd
440.2).
Di-ter t-bu tyl 4-(3-Acetoxyp r op yl)-4-a m in oh ep ta n ed io-
a te (4). To a solution of acetate 3 (1.87 g, 4.479 mmol) in
absolute EtOH (50 mL) was added Raney-Ni34 (5 g); then the
mixture was stirred under 60 psi of H2 for 12 h at 25 °C. The
catalyst was carefully filtered (pyrophoric), and the filtrate was
concentrated in vacuo to afford (87%) amine 4 as a colorless
oil (1.51 g). 1H NMR: δ 1.36 [s, 3H, C(CH3)3], 1.44 (m, 2H,
CH2CH2CH2O), 1.60 (m, 2H, CH2CH2O), 1.72 (t, J ) 7.9 Hz,
4H, CH2CH2CO2), 1.98 (s, 3H, CH3), 2.25 (t, J ) 7.9 Hz, 4H,
CH2CO2), 4.00 (t, J ) 6.1 Hz, 2H, CH2O), 4.30 (br s, 2H, NH2).
13C NMR: δ 21.0 (COCH3), 22.7 (CH2CH2O), 28.1 (CH3), 29.7
(CH2CO2), 33.0 (CH2CH2CO2), 34.3 (CH2CH2CH2O), 55.1
(H2NC), 64.3 (CH2O), 80.7 (CMe3), 171.1 (MeCO2), 172.6 (CO2-
tert-Bu). ESI-MS: found 387.9 (M + H)+ (calcd 388.3).
Di-ter t-bu tyl 4-Am in o-4-(3-h yd r oxyp r op yl)h ep ta n ed io-
a te (5). To a solution of alcohol 2 (3.50 g, 9.32 mmol) in
absolute EtOH (50 mL) was added Raney-Ni (12 g); then the
mixture was stirred under 60 psi of H2 for 12 h at 25 °C. The
catalyst was filtered, and the filtrate was concentrated in vacuo
to afford (81%) amine 5 as a white solid (2.6 g); mp 89-90 °C.
1H NMR: δ 1.40 [s, 18H, C(CH3)3], 1.42 (m, 2H, CH2CH2OH),
1.56 (m, 2H, CH2CH2CH2OH), 1.65 (t, J ) 7.8 Hz, 4H, CH2-
CH2CO2), 2.19 (t, J ) 7.8 Hz, 4H, CH2CH2CO2), 2.59 (br s,
3H, NH2 and OH), 3.56 (t, J ) 5.6 Hz, 2H, CH2OH). 13C NMR:
δ 26.8 (CH2CH2O), 27.9 (CH3), 29.9 (CH2CO2), 34.0 (CH2CH2-
CO2), 36.9 (CH2CH2CH2OH), 52.6 (H2NC), 62.8 (CH2OH), 80.4
Den d r im er 9. To a stirred mixture of monomer 4 (997 mg,
2.572 mmol) and diisopropylethylamine (DIEA; 332 mg, 2.572
mmol) in THF (15 mL) was slowly added a solution of the
tetraacyl chloride35 8, prepared from the corresponding acid36
(291 mg, 584 µmol) dissolved in THF (5 mL) at 0 °C; then the
mixture was maintained for 12 h at 25 °C. After filtration,
the filtrate was concentrated in vacuo to give a residue, which
was column chromatographed (SiO2) eluting with a 1:2 mixture
of n-hexane/EtOAc to afford (61%) tetraacetate 9 as a white
solid (680 mg); mp 82-84 °C. 1H NMR: δ 1.43 [s, 72H,
C(CH3)3], 1.59 (m, 8H, CH2CH2O), 1.78 (m, 8H, CH2CH2CH2O),
1.97 (m, 16H, CH2CH2CO2), 2.05 (s, 12H, COCH3), 2.21 (t, J

Macromolecules, Vol. 36, No. 12, 2003
Syntheses of New 1 f (2 + 1) C-Branched Monomers 4347
) 8.4 Hz, 16H, CH2CO2), 2.37 (t, J ) 5.7 Hz, CH2CONH), 3.33
(s, 8H, C4°CH2O), 3.65 (t, J ) 5.7 Hz, 8H, OCH2CH2CONH),
4.03 (t, J ) 6.4 Hz, 8H, CH2OAc), 6.26 (s, 1H, NH). 13C NMR:
δ 20.8 (COCH3), 22.6 (CH2CH2CH2O), 28.0 [C(CH3)3], 29.6
(CH2CO2), 29.7 (CH2CH2CO2), 30.9 (CH2CH2CH2O), 37.3 (CH2-
CONH), 45.3 (C4°), 57.3 (CONHC), 64.4 (CH2OAc), 67.6 (OCH2-
CH2CONH), 68.9 (C4°CH2O), 80.3 (CMe3), 170.6 (CONH), 170.8
(CH3CO2), 172.5 (CO2-tert-Bu). MALDI-TOF MS: found
1924.153 (M + Na)+ (calcd 1924.154).
1.53-2.14 (m, 24H, CH2), 2.06 (s, 9H, COCH3), 2.21 (br t, J )
7.5 Hz, 12H, CH2CO2), 4.04 (m, 6H, CH2COCH3), 6.18 (br s,
2H, NH). 13C NMR: δ 20.6 & 20.7 (COCH3), 22.4 and 22.7
(CH2CH2CH2O), 27.8 (CH3), 29.4 (CH2CO2), 29.6 (CH2CH2CO2),
30.6 (CH2CONH), 30.8 (CH2CH2CH2O), 31.0 (CH2CH2CONH),
31.5 (CH2CH2CH2O), 57.4 (CONHC), 63.4 and 64.1 (CH2O),
80.2 (CMe3), 92.7 (O2NC), 170.2 (CONH), 170.5 and 170.7
(COCH3), 172.4 (CO2-tert-Bu). ESI-MS: found 1066.8 (M +
Na)+ (calcd 1066.6).
Den d r im er 10. To a solution of 9 (400 mg, 210 µmol)
dissolved in MeOH (10 mL) was added powdered K2CO3 (145
mg, 1.05 mmol); the mixture was stirred for 1 h at 25 °C, then
CH2Cl2 (10 mL) was added, and the mixture was filtered. The
filtrate was concentrated in vacuo to dryness and column
chromatographed (SiO2) eluting with EtOAc to afford (82%)
Am in e Den d r on 14. To a solution of 13 (1.03 g, 986 µmol)
in absolute EtOH (30 mL) was added Raney-Ni (2 g), and then
the mixture was stirred under 90 psi of H2 for 12 h at 40 °C.
The catalyst was filtered (pyrophoric), and the filtrate was
concentrated in vacuo to give a crude product, which was
column chromatographed (SiO2) eluting with a mixture of
EtOAc/MeOH (5:1) to afford (75%) amine 14 as a colorless oil
(750 mg). 1H NMR: δ 1.43 [s, 36H, C(CH3)3], 1.55-2.00 (m,
24H, CH2), 2.05 (s, 9H, COCH3), 2.19-2.38 (m, 12H, CH2CO2),
4.04 (m, 6H, CH2COCH3), 6.18 (br s, 2H, NH). 13C NMR: δ
20.99 & 21.04 (COCH3), 22.5 and 22.7 (CH2CH2CH2O), 28.1
[C(CH3)3], 29.8 (CH2CO2), 29.9 (CH2CH2CO2), 30.9 (CH2CH2-
CONH), 31.3 (CH2CONH), 33.7 and 33.8 (CH2CH2CH2O), 57.7
(H2NC), 64.2 & 64.5 (CH2O), 80.7 (CMe3), 171.08 and 171.17
(COCH3), 172.3 (CONH), 173.0 (CO2-tert-Bu). ESI-MS: found
1014.9 (M + H)+ (calcd 1014.7) and 1036.7 (M + Na)+.
1
the tetraol 10 as a colorless liquid (300 mg). H NMR: δ 1.43
[s, 72H, C(CH3)3], 1.52 (m, 8H, CH2CH2OH), 1.72 (m, 8H, CH2-
CH2CH2OH), 1.99 (m, 16H, CH2CH2CO2), 2.21 (t, J ) 7.8 Hz,
16H, CH2CH2CO2), 2.36 (t, J ) 5.7 Hz, CH2CONH), 3.38 (s,
8H, C4°CH2O), 3.40 (br s, 4H, OH), 3.61 (t, J ) 5.9 Hz, 8H,
CH2OH), 3.67 (t, J ) 5.7 Hz, 8H, OCH2CH2CONH), 6.50 (s,
1H, NH). 13C NMR: δ 26.5 (CH2CH2OH), 28.3 [C(CH3)3], 30.1
(CH2CO2), 30.2 (CH2CH2CO2), 31.5 (CH2CH2CH2OH), 37.9
(CH2CONH), 45.6 (C4°), 57.7 (CONHC), 62.4 (CH2OH), 67.9
(OCH2CH2CONH), 69.6 (C4°CH2O), 80.7 (CMe3), 171.3 (CONH),
173.2 (CO2-tert-Bu). MALDI-TOF MS: found 1756.037 (M +
Na)+ (calcd 1756.112).
Secon d -Gen er a tion Den d r im er 15. To a cooled mixture
of amine 14 (730 mg, 720 µmol) and DIEA (93 mg, 720 µmol)
in CH2Cl2 (10 mL) at 0 °C was slowly added a solution of the
tetraacyl chloride 8 (82 mg, 164 µmol) dissolved in CH2Cl2 (5
mL), and then the mixture was stirred for 24 h at 25 °C. After
filtration, the filtrate was concentrated in vacuo to give a crude
product, which was column chromatographed (SiO2) eluting
with a n-hexane/EtOAc mixture (9:1) to afford (35%) 15 as a
Den d r im er 11. To a stirred mixture of monomer 6 (649
mg, 1.628 mmol) and DIEA (210 mg, 1.628 mmol) in THF (15
mL) was slowly added a solution of the tetraacyl chloride35
(230 mg, 1.628 mmol) in THF (5 mL) at 0 °C, and then the
mixture was stirred for 12 h at 25 °C. The mixture was filtered,
and the filtrate was concentrated in vacuo to give a residue,
which was column chromatographed (SiO2) eluting with a
mixture of n-hexane/EtOAc (1:4) to afford (65%) the tetraamide
11 as a clear liquid (515 mg). 1H NMR: δ 1.43 [s, 72H,
C(CH3)3], 1.55 (m, 8H, CH2CH2O), 1.75 (m, 8H, CH2CH2CH2O),
1.95 (m, 16H, CH2CH2CO2), 2.21 (m, 16H, CH2CH2CO2), 2.37
(t, J ) 5.7 Hz, CH2CONH), 2.60 (t, J ) 6.4 Hz, 8H, CH2CN),
3.33 (s, 8H, C4°CH2O), 3.46 (t, J ) 6.2 Hz, 8H, CH2O), 3.63 (t,
J ) 5.7 Hz, 8H, OCH2CH2CONH), 3.65 (t, J ) 6.4 Hz, 8H,
OCH2CH2CN), 6.23 (s, 1H, NH). 13C NMR: δ 18.8 (CH2CN),
23.4 (CH2CH2O), 28.0 [C(CH3)3], 29.8 (CH2CO2), 29.9 (CH2CH2-
CO2), 31.0 (CH2CH2CH2O), 37.4 (CH2CONH), 45.3 (C4°), 57.5
(CONHC), 65.2 (CH2O), 67.6 (OCH2CH2CONH), 68.9 (C4°CH2O),
71.2 (OCH2CH2CN), 80.4 (CMe3), 118.0 (CN), 170.7 (CONH),
172.7 (CO2-tert-Bu). ESI-MS: found 1969.4 (M + Na)+ (calcd
1968.2).
To a solution of 11 dissolved in MeOH was added powdered
K2CO3; the mixture was stirred for 4 h at 25 °C, then CH2Cl2
was added, and the mixture was filtered. The filtrate was
concentrated in vacuo to dryness and column chromatographed
(SiO2) eluting with EtOAc to afford (80+%) the tetraol 10,
identical to that derived from the acetate.
4-(3-Acetoxyp r op yl)-4-n itr oh ep ta n ed ioic Acid (12). The
mixture of ester 3 (1.89 g, 4.526 mmol) dissolved in HCO2H
(20 mL) was stirred for 4 h at 25 °C. The mixture was
concentrated in vacuo to afford (100%) acid 12 as a bright
yellow liquid (1.38 g). 1H NMR: δ 1.58 (m, 2H, CH2CH2CH2O),
1.99 (m, 2H, CH2CH2CH2O), 2.07 (s, 3H, CH3), 2.30 (m, 4H,
CH2CH2CO2), 2.39 (m, 4H, CH2CH2CO2), 4.07 (t, J ) 6.0 Hz,
2H, CH2O), 11.1 (br s, 2H, CO2H). 13C NMR: δ 20.9 (COCH3),
23.0 (CH2CH2CH2O), 28.5 (CH2CO2), 29.9 (CH2CH2CO2), 32.0
(CH2CH2CH2O), 63.8(CH2CH2CH2O), 92.3 (O2NC), 171.9
(CH3CO2), 177.8 (CO2H). ESI-MS: found 305.4 (M + H)+ (calcd
306.1).
1
white powder (250 mg). H NMR: δ 1.30 [s, 144H, C(CH3)3],
1.40-1.82 (m, 48H, CH2CH2CH2O), 1.91 and 1.92 (s, 36H,
COCH3), 2.03-2.06 (m, 96H, CH2CH2CO2), 2.25 (br t, 8H,
OCH2CH2CONH), 3.19 (br s, 8H, C4°CH2O), 3.49 (br t, 8H,
OCH2CH2CONH), 3.90 (m, 24H, CH2COCH3), 6.38 and 6.73
(br s, 12H, NH). 13C NMR: δ 21.1 (COCH3), 22.7 (CH2CH2O),
28.2 [C(CH3)3], 29.9 (CH2CO2), 30.0 (CH2CH2CO2), 31.0 (CH2-
CH2CH2O), 31.7 (CH2CH2CO2), 34.1 (CH2CH2CH2O), 37.6
(CH2CONH), 45.5 (C4°), 57.6 and 58.1 (CONHC), 64.6 and 64.8
(CH2OAc), 67.9 (OCH2CH2CONH), 69.6 (C4°CH2O), 80.6 (CMe3),
171.05 and 171.21 (COCH3), 171.25 and 172.9 (CONH), 172.8
(CO2-tert-Bu). MALDI-TOF MS: found 4430.100 (M + Na)+
(calcd 4429.665).
Ben zyl 4-Nitr obu ta n oa te (16). To a solution of benzyl
acrylate (3 mL, 20 mmol) in MeNO2 (100 mL) was added DIEA
(500 µL), and then the mixture was stirred for 16 h at 25 °C.
The mixture was reduced in vacuo, and the residue was
column chromatographed (SiO2) eluting with 25% EtOAc in
hexane to afford (84%) ester 16 as a clear oil (2.4 g). 1H NMR:
δ 2.34 (quintet, CH2CH2CH2, 2H), 2.54 (t, CH2CO2, 2H, J )
7.5 Hz), 4.48 (t, O2NCH2, 2H, J ) 6.7 Hz), 5.18 (s, CH2Ph,
2H), 7.40 (s, PhH, 5H). 13C NMR: δ 22.4 (CH2CH2CH2), 30.5
(CH2CO2), 66.7 (CH2Ph), 74.3 (O2NCH2), 128.3 (4-ArC), 128.5
(3-ArC), 128.7 (2-ArC), 135.6 (1-ArC), 171.8 (CO2). ESI-MS:
found 224.19 (M + H)+ (calcd 224.24).
Di-ter t-bu tyl 4-(2-ter t-Ben zyloxyca r bon yleth yl)-4-n i-
tr oh ep ta n ed ioa te (17). To a solution of ester 16 (3.26 g, 14.6
mmol) in dried THF (100 mL) was added tert-butyl acrylate
(4.28 mL, 29.2 mmol) and Triton-B (250 µL of a 40% in MeOH),
and then the mixture was stirred for 16 h at 25 °C. The
mixture was concentrated in vacuo to give a residue, which
was column chromatographed (SiO2) eluting with 25% EtOAc
in hexane to give (86%) triester 17 as a white solid (6.01 g).
1H NMR: δ 1.39 [s, C(CH3)3, 18H], 2.16 (s, CH2CH2CO2CH2,
CH2CH2CO2, 8H), 2.30 (dd, CH2CO2, 4H, J ) 10.5 Hz), 5.07
(s, CH2Ph, 2H), 7.31 (s, PhH, 5H). 13C NMR: δ 27.9 [C(CH3)3],
28.5 (CH2CH2CO2CH2), 29.6 (CH2CH2CO2), 30.0 (CH2CO2CH2),
30.2 (CH2CO2), 66.6 (CH2Ph), 81.0 (CMe3), 91.9 (O2NC), 128.2
(4-ArC), 128.3 (3-ArC), 128.5 (2-ArC), 135.3 (1-ArC), 171.5
(CO2), 170.9 (CO2CH2). ESI-MS: found 480.43 (M + H)+ (calcd
480.58).
Den d r on 13. To a solution of 12 (710 mg, 2.325 mmol) in
DMF (10 mL) was added DCC (959 mg, 4.65 mmol) and
1-HOBT (628 mg, 4.65 mmol) at 25 °C. After the mixture was
stirred for 30 min, monomer 4 (1.982 g, 5.115 mmol) was added
and then maintained for 24 h at 25 °C. After filtration, the
filtrate was concentrated in vacuo to give a crude product,
which was column chromatographed (SiO2) eluting with a
mixture of n-hexane/EtOAc (3:2) to afford (76%) dendron 13
as a colorless liquid (1.84 g). 1H NMR: δ1.44 [s, 36H, C(CH3)3],

4348 Newkome et al.
Macromolecules, Vol. 36, No. 12, 2003
4-Nitr o-4-d i(2-ter t-bu toxyca r bon yleth yl)bu ta n oic Acid
(18). A suspension of benzyl ester 16 (2.0 g, 12.1 mmol) and
10% Pd on activated carbon (600 mg) in MeOH (50 mL) was
hydrogenated at 60 psi at 25 °C for 12 h. The solution was
then cautiously filtered through Celite (pyrophoric), and the
solvent was concentrated to afford (94%) acid 18, as a clear
oil (1.7 g). 1H NMR: δ 2.16 (s, CH2CH2CO2, 8H), 2.30 (dd, CH2-
CO2, 4H, J ) 10.5 Hz). 13C NMR: δ 27.9 [C(CH3)3], 28.5, 29.6
(CH2CH2CO2), 30.2 (CH2CO2), 81.0 (CMe3), 91.9 (O2NC), 171.5
(CO2R), 174.0 (CO2H). ESI-MS: found 390.44 (M + H)+ (calcd
390.20).
Di-ter t-b u t yl 4-{2-[5-(4′-Ter p yr id in yloxy)p en t ylca r -
ba m oyl]eth yl}-4-n itr oh ep ta n ed ioa te (19). To a solution of
acid 18 (1.06 g, 2.72 mmol) in dried DMF were added DCC
(1.24 g, 5.97 mmol) and 1-HOBT (920 mg, 5.97 mmol) at 25
°C. The mixture was stirred for 2 h; then 1-amino-(4′-
terpyridinyloxy)pentane37,38 (2.48 g, 5.97 mmol) was added, and
the solution was agitated for 24 h. The white precipitate was
filtered, and the filtrate was concentrated in vacuo to give a
crude oil, which was column chromatographed eluting with
20% EtOAc in hexane to give (93%) amide 19 as a colorless
solid (2.7 g). 1H NMR: δ 1.26 (s, CH3, 18H), 1.39 (m,
NHCH2CH2CH2, 4H), 1.70 (q, CH2CH2O, 2H), 2.05 (m, CH2CH2-
CONH, CH2CH2CO2, 12H), 3.09 (m, NHCH2, 2H), 4.05 (t,
CH2O, 2H), 5.76 (t, CONH, 1H), 7.16 (dd, 5,5′′-tpyH, 2H), 7.67
(dd, 4,4′′-tpyH, 2H), 7.82 (s, 3′,5′-tpyH, 2H), 8.44 (d, 3,3′′-tpyH,
2H), 8.51 (d, 6,6′′-tpyH, 2H). 13C NMR: δ 23.1 (NHCH2-
CH2CH2), 27.7 (CH3), 28.3 (CH2CH2O), 28.9 (NHCH2CH2), 29.5
(CH2CH2CO2), 29.9 (CH2CO2), 30.2 (CH2CH2CONH), 30.9
(CH2CONH), 39.3 (CONHCH2), 67.6 (CH2O), 80.7 (CMe3), 92.3
(O2NC), 107.0 (5,5′′-tpyC), 121.1 (4,4′′-tpyC), 123.6 (3,3′′-tpyC),
136.5 (3′,5′-tpyC), 148.7 (6,6′′-tpyC), 155.7 (2,2′′-tpyC), 156.7
(2′,6′-tpyC), 166.8 (4′-tpyC), 170.6 (CONH), 170.9 (CO2); IR
3312, 1730, 1651 cm-1. ESI-MS: found 706.3 (M + H)+ (calcd
706.4).
amine39 (22; 2.48 g, 5.97 mmol) was added. The mixture was
stirred for 24 h, after which the white precipitate was filtered.
The filtrate was concentrated in vacuo to give a crude oil,
which was column chromatographed eluting with 20% EtOAc
1
in hexane to (93%) 23 as a colorless solid (2.7 g). H NMR: δ
1.29 [s, C(CH3)3, 54H], 1.83 (m, CH2CH2CO2, 12H), 2.08 (m,
CH2CO2, CH2CH2CONH, CH2CH2CO2CH2, 20H), 2.26 (m, CH2-
CO2CH2, 2H), 4.98 (s, CH2Ph, 2H), 6.21 (CONH, 2H), 7.21 (s,
Ph, 5H). 13C NMR: δ 27.6 [C(CH3)3], 28.1 (CH2CH2CO2CH2),
29.2 (CH2CH2CONH, CH2CH2CO2), 30.6 (CH2CO2CH2), 30.8
(CH2CONH), 57.1 (CONHC), 66.2 (CH2Ph), 80.0 (CMe3), 92.1
(O2NC), 127.8 (4-PhC), 128.0 (3-PhC), 128.1 (2-PhC), 135.1
(1-PhC), 169.8 (CONH), 171.4 (CO2CH2), 172.2 (CO2). This was
directly debenzylated to the corresponding free acid 24.
Bis(a m id o)a cid 24. An absolute EtOH (100 mL) solution
of heptaester 23 (2.4 g, 2.27 mmol) in the presence of 10% Pd
on activated carbon (400 mg) was hydrogenated at 60 psi at
25 °C for 12 h. The solution was cautiously filtered through
Celite, and the solvent was reduced in vacuo to give (100%)
monoacid 24 as a white solid (2.2 g). 1H NMR: δ 1.36 [s,
C(CH3)3, 54H], 1.89 (m, CH2CH2CO2, 12H), 2.12 (m, CH2CO2,
CH2CH2CONH, CH2CH2CO2CH2, 20H), 2.26 (m, CH2CO2CH2,
2H), 6.34 (CONH, 2H), 9.14 (CO2H). 13C NMR: δ 27.6
[C(CH3)3], 29.4 (CH2CH2CO2H, CH2CH2CONH, CH2CH2CO2),
30.8 (CH2CO2H, CH2CONH), 57.2 (CONHC), 80.3 (CMe3), 92.3
(O2NC), 170.8 (CONH), 172.6 (CO2R), 174.0 (CO2H). ESI-MS:
found 1073.35 (M + H)+ (calcd 1073.33).
Secon d -Gen er a tion Am id e 25. To a stirred solution of
acid 24 (2.8 mg, 2.8 mmol) in dry DMF were added DCC (598
mg, 2.8 mmol) and 1-HOBT (391 mg, 2.8 mmol) at 25 °C; after
2 h, amine 20 (1.9 g, 2.8 mmol) was added. The mixture was
stirred for 24 h, after which the white precipitate was fil-
tered. The filtrate was concentrated in vacuo to give a crude
oil, which was column chromatographed eluting with 20%
1
EtOAc in hexane to give (80%) 25 as a white solid (3.6 g). H
Di-ter t-b u t yl 4-{2-[5-(4′-Ter p yr id in yloxy)p en t ylca r -
ba m oyl]eth yl}-4-a m in oh ep ta n ed ioa te (20). An absolute
EtOH (100 mL) suspension of 19 (1 g, 1.59 mmol) and T-1
Raney-Ni (7 g) was hydrogenated at 120 psi at 40 °C for 20 h.
The solution was cautiously filtered (pyrophoric) through
Celite, after which the solvent was concentrated in vacuo. The
residue was dissolved in EtOAc and then sequentially washed
with dilute aqueous NaOH, water, and brine. The solution was
dried (Na2SO4), filtered, and concentrated in vacuo to give
NMR: δ 1.21 [s, C(CH3)3, 72H], 1.37 (m, NHCH2CH2CH2, 4H),
1.76 (m, CH2CH2O, CH2CH2CO2, CH2CH2CONH, 20H), 2.01
(CH2CH2CONH, CH2CO2, CH2CONH, 30H), 3.04 (m, NHCH2,
2H), 4.01 (t, CH2O, 2H, J ) 5.8 Hz), 6.28 (CONH, 3H), 6.64
(CONH, 1H), 7.11 (dd, 5,5′′-tpyH, 2H), 7.62 (dd, 4,4′′-tpyH, 2H),
7.78 (s, 3′,5′-tpyH, 2H), 8.39 (d, 3,3′′-tpyH, 2H), 8.45 (d, 6,6′′-
tpyH, 2H). 13C NMR: δ 23.0 (NHCH2CH2CH2), 27.6 (CH3),
28.2 (CH2CH2O), 28.8 (NHCH2CH2), 29.3 (1st-CH2CH2CONH,
2nd-CH2CH2CO2), 30.1 (2nd-CH2CH2CONH), 30.8 (2nd-CH2CH2-
CO2), 33.4 (2nd-CH2CONH), 39.1 (NHCH2), 57.0 (2nd-CN-
HCO), 57.1 (2nd-CNHCO), 67.5 (CH2O), 79.9 (CMe3), 80.0
(CMe3), 92.5 (O2NC), 106.9 (5,5′′-tpyC), 120.0 (4,4′′-tpyC),
123.4 (3,3′′-tpyC), 136.3 (3′,5′-tpyC), 148.5 (6,6′′-tpyC),
155.6 (2,2′′-tpyC), 156.5 (2′,6′-tpyC), 166.7 (4′-tpyC), 170.3
(CONH), 170.7 (CONH), 172.3 (CO2). IR: 3332, 2978, 2934,
1730, 1679, 1653, 1154 cm-1; this tert-butyl ester was directly
transformed to the corresponding methyl ester for mass
spectral analysis.
Meth yl Ester 26. A stirred solution of ester 25 (3 g, 1.84
mmol) in MeOH (100 ML) and a trace of concentrated H2SO4
(200 µL) was refluxed for 24 h, after which the mixture was
reduced in volume in vacuo to give residue, which was
dissolved in CH2Cl2 and then sequentially washed with dilute
aqueous NaOH, water, and brine. The solution was dried
(Na2SO4), filtered, and reduced in vacuo to give an oil, which
was column chromatographed (Al2O3) eluting with 5% MeOH
in EtOAc to afforded (66%) methyl ester 26 as white solid
(1.6 g). 13C NMR: δ 23.2 (NHCH2CH2CH2), 27.9 (CH2CH2-
CONH, CH2CH2CO2), 28.3 (CH2CH2O), 28.9 (NHCH2CH2), 29.1
(CH2CO2), 30.6 (CH2CONH), 39.3 (CONHCH2), 51.5 (CO2CH3),
57.0 (2nd-CCONH), 57.2 (2nd-CCONH), 67.7 (CH2O), 92.9
(O2NC), 107.0 (5,5′′-tpyC), 121.0 (4,4′′-tpyC), 123.6 (3,3′′-tpyC),
136.5 (3′,5′-tpyC), 148.7 (6,6′′-tpyC), 155.7 (2,2′′-tpyC), 156.7
(2′,6′-tpyC), 166.9 (4′-tpyC), 170.7 (CONH), 173.4 (CO2).
MALDI-TOF MS: found 1394.19 (M + H)+ (calcd 1394.53).
Secon d -Gen er a tion Den d r on 27. A suspension of methyl
ester 26 (1.2 g, 930 µmol), T-1 Raney-Ni (10 g), and absolute
EtOH (100 mL) was hydrogenated at 120 psi at 40 °C for 48
h. The solution was cautiously filtered (pyrophoric) through
Celite, after which the solvent was removed in vacuo to give a
1
(91%) amine 20 as a yellow oil (860 mg). H NMR: δ 1.33 (s,
CH3, 18H), 1.48 (m, NHCH2CH2CH2, 4H), 1.76 (q, CH2CH2O,
2H, J ) 6.1 Hz), 2.15 (m, CH2CH2CONH, CH2CH2CO2, 12H),
3.15 (m, NHCH2, 2H), 4.10 (t, CH2O, 2H, J ) 6.1 Hz), 6.13 (s,
CONH, 1H), 7.23 (dd, 5,5′′-tpyH, 2H), 7.75 (dd, 4,4′′-tpyH, 2H),
7.89 (s, 3′,5′-tpyH, 2H), 8.53 (d, 3,3′′-tpyH, 2H), 8.51 (d, 6,6′′-
tpyH, 2H). 13C NMR: δ 23.3 (NHCH2CH2CH2), 27.7 (CH3), 28.4
(CH2CH2O), 29.1 (NHCH2CH2), 29.7 (CH2CH2CO2), 30.7 (CH2-
CH2CONH), 34.1 (CH2CO2), 34.9 (CH2CONH), 39.2 (CON-
HCH2), 52.3 (H2NC), 67.7 (CH2O), 80.1 (CMe3), 107.1 (5,5′′-
tpyC), 121.1 (4,4′′-tpyC), 123.6 (3,3′′-tpyC), 136.6 (3′,5′-tpyC),
148.8 (6,6′′-tpyC), 155.8 (2,2′′-tpyC), 156.8 (2′,6′-tpyC), 166.9
(4′-tpyC), 172.8 (CONH), 172.9 (CO2). IR: 3299, 1727, 1648
cm-1. ESI-MS: found 677.8 (M + H)+ (calcd 677.8).
4-(2-Ben zyloxycar bon yleth yl)-4-n itr oh eptan edioic Acid
(21). A solution of triester 17 (4.57 g, 9.53 mmol) in HCO2H
(100 mL, 95%) was stirred at 25 °C for 16 h. After concentra-
tion in vacuo, toluene (50 mL) was added, and the solution
was again evaporated in vacuo to azeotropically remove
residual formic acid. The resultant solid was recrystallized
from water to give (96%) monoester 21 as a white solid (3.6
g). 1H NMR: δ 2.13 (s, CH2CH2CO2, CH2CH2CO2H, 10H), 2.34
(d, CH2CH2CO2, 4H, J ) 7.8 Hz), 5.04 (s, CH2Ph, 2H), 7.32 (s,
Ph, 5H). 13C NMR: δ 28.2 (CH2CH2CO2), 29.5 (CH2CH2CO2H),
29.8 (CH2CO2), 30.7 (CH2CO2H), 65.9 (CH2Ph), 92.8 (O2NC),
128.1 (4-PhC), 128.2 (3-PhC), 128.5 (2-PhC), 136.1 (1-PhC),
171.7 (CO2CH2), 173.3 (CO2H). ESI-MS: found 389.97 (M +
H)+ (calcd 390.34).
Hep ta ester 23. To a stirred solution of acid 21 (1.06 g, 2.72
mmol) in dry DMF were added DCC (1.24 g, 5.97 mmol) and
1-HOBT (920 mg, 5.97 mmol) at 25 °C; after 2 h, Behera’s

Macromolecules, Vol. 36, No. 12, 2003
Syntheses of New 1 f (2 + 1) C-Branched Monomers 4349
Sch em e 1. Syn th esis of th e In itia l Mon om er sa
crude solid, which was column chromatographed (Al2O3)
eluting with 66% MeOH in EtOAc to give (76%) amine 27 as
1
a clear solid (900 mg). H NMR: δ 1.37 (m, NHCH2CH2CH2,
4H), 1.76 (m, CH2CH2O, CH2CH2CO2, CH2CH2CONH, 20H),
2.01 (CH2CH2CONH, CH2CO2, CH2CONH, 30H), 3.04 (m,
NHCH2, 2H), 3.50 (s, CH3, 24H), 4.01 (t, CH2O, 2H, J ) 5.8
Hz), 6.28 (CONH, 3H), 6.64 (CONH, 1H), 7.11 (dd, 5,5′′-tpyH,
2H), 7.62 (dd, 4,4′′-tpyH, 2H,), 7.78 (s, 3′,5′-tpyH, 2H), 8.39
(d, 3,3′′-tpyH, 2H), 8.45 (d, 6,6′′-tpyH, 2H). 13C NMR: δ 23.2
(NHCH2CH2CH2), 28.1 (CH2CH2CONH, CH2CH2CO2), 28.4
(CH2CH2O), 29.2 (CH2CO2), 29.6 (NHCH2CH2), 31.1 (CH2-
CONH), 34.6 (CH2CONH), 39.3 (CONHCH2), 51.6 (CO2CH3),
53.6 (H2NC), 56.7 (2nd-CNHCO), 57.1 (2nd-CNHCO), 67.8
(CH2O), 107.1 (5,5′′-tpyC), 121.1 (4,4′′-tpyC), 123.7 (3,3′′-tpyC),
136.6 (3′,5′-tpyC), 148.8 (6,6′′-tpyC), 155.8 (2,2′′-tpyC), 156.8
(2′,6′-tpyC), 166.9 (4′-tpyC), 172.8 (CONH), 173.5 (CO2).
MALDI-TOF MS: found 1386.27 (M + Na)+ (calcd 1386.54).
F ir st-Gen er a tion Den d r im er 29. A mixture of tetraacid
2836 (97 mg, 230 µmol), 1-HOBT (136 mg, 1.01 mmol), and DCC
(208 mg, 1.01 mmol) in DMF (20 mL) was stirred at 25 °C for
2 h, and then amine 20 (683 mg, 1.01 mmol) in DMF (10 mL)
was added, followed by stirring for 3 days. After filtration, the
solvent was removed in vacuo to give a residue, which was
dissolved in EtOAc (500 mL) and washed with water (3×) and
then saturated brine. The organic phase was dried (Na2SO4),
concentrated in vacuo, and chromatographed (Al2O3) eluting
with EtOAc to give (67%) 29 as a spongy white solid (469 mg).
1H NMR: δ 1.33 (s, CH3, 18H), 1.48 (m, NHCH2CH2CH2, 4H),
1.76 (q, CH2CH2O, 2H, J ) 6.2 Hz), 2.15 (m, CH2CH2CONH,
CH2CH2CO2, 12H), 3.15 (m, NHCH2, 2H), 4.10 (t, CH2O, 2H,
J ) 6.1 Hz), 6.13 (s, CONH, 1H), 7.23 (dd, 5,5′′-tpyH, 2H),
7.75 (dd, 4,4′′-tpyH, 2H), 7.89 (s, 3′,5′-tpyH, 2H), 8.53 (d, 3,3′′-
tpyH, 2H, J ) 7.9 Hz), 8.51 (d, 6,6′′-tpyH, 2H, J ) 4.2 Hz).
13C NMR: δ 23.0 (NHCH2CH2CH2), 27.6 (CH3), 28.3 (CH2-
CH2O), 28.8 (NHCH2CH2), 29.3 (CH2CH2CO2), 29.8 (CH2CO2),
30.1 (CH2CH2CONH), 30.4 (CH2CONH), 36.9 (OCHCH2), (39.1
a
(i) CH2dCHCO2-t-Bu (xs), Triton-B, 25 °C; (ii) Ac2O, pyr,
CHCl3, 0 °C, then 25 °C, 6 h; (iii) Raney-Ni, EtOH, 60 psi of
H2, 25 °C, 12 h; (iv) CH2dCHCN, KOH, p-dioxane, 25 °C, 12
h; (v) C6H5CH2Br, NaH, 15-crown-5, THF 25 °C, 12 h; Ni2B,
NaBH4, EtOH, 25 °C, 2 h.
residue that was dissolved in EtOAc and sequentially washed
with dilute aqueous NaOH, water, and brine. The solution was
dried (Na2SO4), filtered, and concentrated in vacuo to give a
Sch em e 2. Syn th esis of F ir st-Tier Den d r im er sa
a
(i) 4 (4 equiv), DIEA, THF, 0 °C, then 25 °C, 12 h; (ii) K2CO3, MeOH, 1 h, 25 °C; (iii) 6 (4 equiv), DIEA, THF, 0 °C, then
25 °C.

4350 Newkome et al.
Macromolecules, Vol. 36, No. 12, 2003
(CONHCH2), 44.9 (CCH2O), 57.0 (CNHCO), 67.2 (CCH2O),
67.4 (CH2Otpy), 68.6 (OCH2CH2CONH), 106.8 (5,5′′-tpyC),
120.8 (4,4′′-tpyC), 123.4 (3,3′′-tpyC), 136.3 (3′,5′-tpyC), 148.5
(6,6′′-tpyC), 155.5 (2,2′′-tpyC), 156.5 (2′,6′-tpyC), 166.6 (4′-
tpyC), 170.6 (CONH), 172.3 (CO2). MALDI-TOF MS: found
3077.14 (M + Na)+ (calcd 3077.72).
Sch em e 3. Con ver gen t Syn th esis of Secon d -Tier
Den d r im er a
Secon d -Gen er a tion Den d r im er 30 was prepared in an
identical manner to that of 27 from the tetraacid 28 (230 µmol),
except using amine 27 (1.01 mmol) to give (67%) 30 as a spongy
white solid (469 mg). 1H NMR: δ 1.37 (m, NHCH2CH2CH2,
4H), 1.76 (m, CH2CH2O, CH2CH2CO2, CH2CH2CONH, 20H),
2.01 (CH2CH2CONH, CH2CO2, CH2CONH, 30H), 3.04 (m,
NHCH2, 2H), 3.50 (s, CH3, 24H), 4.01 (t, CH2O, 2H, J ) 5.8
Hz), 6.28 (CONH, 3H), 6.64 (CONH, 1H), 7.11 (dd, 5,5′′-tpyH,
2H), 7.62 (dd, 4,4′′-tpyH, 2H), 7.78 (s, 3′,5′-tpyH, 2H), 8.39 (d,
3,3′′-tpyH, 2H, J ) 7.9 Hz), 8.45 (d, 6,6′′-tpyH, 2H, J ) 4.4
Hz). 13C NMR: δ 23.3 (NHCH2CH2CH2), 28.2 (CH2CH2-
CONH, CH2CH2CO2), 28.4(CH2CH2O), 29.2 (CH2CO2), 29.6
(NHCH2CH2), 31.1 (CH2CONH), 34.8 (CH2CONH-tpy), 37.4
(OCHCH2CONH), 39.4 (CONHCH2), 45.3 (CCH2O), 51.6
(CO2CH3), 56.9 (2nd-CCONH), 57.1 (2nd-CCONH), 66.7
(CCH2O), 67.9 (CH2Otpy), 69.2 (OCH2CH2CONH), 107.2 (5,5′′-
tpyC), 121.1 (4,4′′-tpyC), 123.7 (3,3′′-tpyC), 136.7 (3′,5′-tpyC),
148.9 (6,6′′-tpyC), 155.9 (2,2′′-tpyC), 156.9 (2′,6′-tpyC), 167.1
(4′-tpyC), 171.0, 173.6 (CONH, CO2). MALDI-TOF: found
5829.27 (M + Na)+ (calcd 5829.21).
Resu lts a n d Discu ssion
Syn th eses of Ester a n d Alcoh ol Bu ild in g Block s.
Considering complementary selective protection or depro-
tection for monomeric functional groups, amine D or its
related isocyanate E, both possessing ester and a
protected hydroxyl groups, was initially chosen as a key
target, although numerous alternative modifications can
be envisioned. Hence, to obtain the desired monomers,
nitrobutanol 1 was initially prepared by the modified
procedure of Wehrli33 by reacting an excess of tert-butyl
acrylate with MeNO2 in the presence of a catalytic
amount of Triton-B to afford the tert-butyl 4-nitrobu-
tanoate that was subsequently treated with formic acid
and then reduced with BH3‚THF to afford (90% overall
yield) the desired 4-nitrobutanol (1).
Diester 2 was then prepared by treatment of butanol
1 with excess tert-butyl acrylate and added Triton-B,
as catalyst (Scheme 1). Michael addition proceeded
smoothly at 25 °C and afforded (75%), after column
chromatography, the diadduct 2; its formation was
supported by a chemical shift (13C NMR) from 75.2 to
92.6 ppm, assigned to the CNO2 moiety, along with the
molecular ion peak (ESI-MS) at m/z 397.9 [M + Na]+.
Notably, there were isolatable yields of the monoadduct,
tert-butyl 4-nitro-7-hydroxyheptanoate, which offers
entrance to a 1 f (1 + 1 + 1) C-branched monomer
series.
To introduce a selective, removable protecting group
for the hydroxyl moiety, alcohol 2 was treated with Ac2O
in pyridine to give (94%) the corresponding acetate 3;
the acetate moiety is well-known to be stable under both
mildly acidic conditions (HCO2H) used for hydrolysis of
the tert-butyl ester groups and Raney-Ni-catalyzed
reduction of the focal nitro group.40 Therefore, as
expected, acetate 3 was successfully reduced (87%) to
amine 4 by means of Raney-Ni catalyst under 60 psi of
hydrogen in EtOH at 25 °C. Structural confirmation of
amine 4 included (13C NMR) the appropriate shift for
the C4° center from 92.4 (O2NC) to 55.1 ppm (H2NC) as
well as the peak for the molecular ion (ESI-MS) at m/z
439.9 [M + Na]+. Alternatively, alcohol 2 was directly
subjected to a catalytic hydrogenation (Raney-Ni) at 25
°C affording (81%) amine 5, showing an identical shift
a
(i) HCO2H, 4 h, 25 °C; (ii) 4 (2 equiv), 1-HOBT, DCC, DMF,
24 h, 25 °C; (iii) Raney-Ni, EtOH, 90 psi of H2, 12 h, 40 °C;
(iv) C(CH2OCH2CH2COCl)4 (8), DIEA, CH2Cl2, 24 h, 25 °C.
(13C NMR) for the C4° center and the expected peak
(ESI-MS) at m/z 346.0 [M + H]+. During these reduc-
tions, lactonization products were not detected; however,
it is crucial to maintain strict adherence to a 25 °C
temperature limit; increased temperatures can result
in intramolecular cyclization.36 Employing Bruson’s
method,35,41 reaction of amino alcohol 5 with acryloni-
trile in the presence of powdered KOH in p-dioxane
furnished (98%) nitrile 6, which was characterized (13C
NMR) by the signals at 65.0 and 71.2 ppm indicative of
ethereal bond (C-O-C) formation and a signal at 117.6
ppm corresponding to the newly attached cyano moiety.
A molecular ion peak (ESI-MS) for 6 was detected at
398.9 [M + H]+. Acrylonitrile is herein used as a
protecting group42-45 that either can be subsequently
removed under basic conditions or can be reduced to the
terminal amine.46 The O-benzylated counterpart to 6
was readily prepared in two steps from alcohol 2 by
initial O-protection (72%) via treatment with benzyl
bromide and then selective reduction of the nitro group
with NaBH4 in the presence of the in situ generated
Ni2B to give (65%) ether 7.
Syn th esis of Den d r im er s Utilizin g th e Ester a n d
P r otected Alcoh ol Mon om er s. Initially, the first-
generation dendrimer 9 was synthesized (61%) by
amidation with tetraacid chloride35 8 with 4 equiv of
monomer 4 (Scheme 2). 13C NMR spectra of tetraacetate
9 revealed the expected downfield shift of the C4° signal
from 55.1 (H2NC) to 57.3 ppm (CONHC) as well as a

Macromolecules, Vol. 36, No. 12, 2003
Syntheses of New 1 f (2 + 1) C-Branched Monomers 4351
Sch em e 4. Syn th esis of Mon ofu n ction a lized Den d r on 20a
a
(i) CH2dCHCO2-t-Bu (xs), Triton-B, 16 h, 25 °C; (ii) Pd-C, MeOH, 60 psi of H2, 12 h, 25 °C; (iii) H2N(CH2)5O-4′-tpy, DCC,
1-HOBT, DMF, 25 °C, 24 h; (iv) Raney-Ni, EtOH, 120 psi H2, 20 h, 40 °C.
Sch em e 5. Syn th esis of Tier F u n ction a lized Den d r on sa
a
(i) HCO2H, 16 h, 25 °C; (ii) H2NC(CH2CH2CO2-t-Bu)3, DCC, 1-HOBT, DMF, 24 h, 25 °C; (iii) Pd-C, EtOH, 60 psi of H2, 12 h,
25 °C; (iv) amine 20, DCC, 1-HOBT, DMF, 25 °C, 24 h; (v) MeOH, H2SO4 (traces), 24 h; (vi) Raney-Ni, EtOH, 120 psi of H2, 48
h, 40 °C.
peak at 170.6 ppm (CONHC), confirming the conversion;
an indicative molecular ion peak (MALDI-TOF MS) at
m/z 1924.153 [M + Na]+ was also observed. Deacetyla-
tion of dendrimer 9 via transesterification (K2CO3,
MeOH) generated the corresponding tetraol 10, as
confirmed (13C NMR) by the absence of the acetyl group
resonances (170.8 and 20.8 ppm), the presence of tert-
butyl group signals [80.3 and 28.3 ppm corresponding
to the CMe3 and CH3 groups, respectively], and the
appearance of a new resonance at 62.4 ppm assigned
to the CH2OH termini. Dendrimer 11, possessing cyano
terminal moieties, was analogously synthesized (65%)
employing amine monomer 6. Identical shifts (13C NMR)
associated with the C4° and amide carbonyl moieties
(57.5 and 170.7 ppm, respectively) as well as the ESI-
MS molecular ion peak (m/z 1969.4 [M + Na]+) validated
its structure. Treatment 11 with base in methanol
generated the free tetraol, as formed by deprotection of
the above acetate.
Preparation of a second-generation dendrimer 15 was
achieved convergently (Scheme 3). Diester 3 was con-
verted (100%) with formic acid to the corresponding
diacid 12, as confirmed by the absence of the relevant
13C NMR absorptions. Using standard amidation condi-
tions47 to couple diacid 12 to amine 4 afforded (76%)
the nitrodiamide 13 as shown by the appearance (13C
NMR) of four different carbonyl peaks corresponding to
the two different acetate moieties (171.08 and 171.17
ppm), the amide carbonyls (172.3 ppm), and the ter-
minal esters (173.0 ppm). The ESI-MS spectrum of
trisacetate 13 revealed the expected molecular ion at
1066.8 amu [M + Na]+. Catalytic reduction of the nitro
moiety of dendron 13 with Raney-Ni yielded (75%) the
second-generation aminotriacetate dendron 14 as con-
firmed by the appearance (13C NMR) of a new peak at
56.0 ppm for the CNH2 group. Subsequently, the second-
generation dendrimer 15 was accessed (35%) by ami-
dation of the known tetraacid chloride35 8 using diiso-

4352 Newkome et al.
Macromolecules, Vol. 36, No. 12, 2003
Sch em e 6. Syn th esis of F u n ction a lized Den d r im er sa
a
(i) Dendron 20 (4 equiv), DCC, 1-HOBT, DMF, 25 °C, 3 days; (ii) dendron 27 (4 equiv), DCC, 1-HOBT, DMF, 25 °C, 3 days.
propylethylamine (DIEA) with dendron 14 and confirmed
(13C NMR) by the observation of the shift of the dendron
focal quaternary carbon absorption to the corresponding
C4°NHCO group position in the dendrimer (56.0-58.1
ppm), the appearance of two different amide carbonyl
signals (171.25 and 172.9 ppm), and the molecular ion
peak (MALDI-TOF MS) at m/z 4430.10 [M + Na]+.
Syn th esis of Den d r im er s Utilizin g Br a n ch ed
P olyester Mon om er s. As an alternative approach, 1
f (2 + 1) branched monomers possessing different ester
groups were prepared in which a controlled or selective
hydrolysis will free either one or two ester moieties. The
approach (Scheme 4) utilizes the Michael addition of
MeNO2 to commercially available benzyl acrylate in the
presence of diisopropylethylamine to afford (84%) benzyl
4-nitrobutyrate (16), which was characterized (13C
NMR) by the appearance of a new resonance at 74.3
ppm (CNO2) and the disappearance of the acrylate
double-bond absorptions. Triester 17, possessing a single
benzyl ester, was then synthesized (86%) by treatment
of nitroester 16 with tert-butyl acrylate (Triton B, THF)
under typical Michael reaction conditions and shown to

Macromolecules, Vol. 36, No. 12, 2003
Syntheses of New 1 f (2 + 1) C-Branched Monomers 4353
exhibit (13C NMR) the expected chemical shift for the
C4°NO2 moiety at 91.9 ppm and the molecular ion signal
(ESI-MS) at m/z 480.43 [M + H]+.
[M + H]+. Nitro group reduction of methyl ester 26 with
Raney-Ni afforded the desired amine 27, which was
analogously identified (13C NMR) by the chemical shift
change for C4° moiety from 92.9 to 53.6 ppm, confirming
the desired C4°NO2 to C4°NH2 transformation and the
peak (MALDI-TOF MS) at m/z 1386.27 [M + Na]+.
The versatility of the modular protocol is represented
by attachment of these dendrons to generate the first-
generation dendrimer 29 possessing four terpyridine
functional groups (one in each quadrant) via peptide
coupling of known tetraacid core36 28 with 4 equiv of
building block 20 (Scheme 6). The conversion was
demonstrated (13C NMR) by the disappearance of the
signal at 52.3 ppm C4°NH2 moiety of the dendron and
the appearance of a peak at 57.0 ppm corresponding to
the new C4°NHCO group as well as the correct molec-
ular ion peak at m/z 3077.14 [M + Na]+. Analogously,
a second-generation dendrimer 30 was prepared by DCC
amidation of 1 equiv of tetraacid 28 and 4 equiv of the
larger, terpyridinyl-modified dendron 27. Nearly identi-
cal 13C NMR absorptions were observed for the second-
generation construct, when compared to its smaller
counterpart; the correct molecular ion peak (MALDI-
TOF MS) at m/z 5829.27 [M + Na]+ affirmed the
assembly. These dendrimers possessing one unique
functional group per dendron have been shown48 to form
(ca. 90%) of spirometallodendrimers by treatment with
FeCl2, supporting the facile intramolecular interactions
in these hyperbranched constructs.
Deprotection with catalytic hydrogenation of the
benzyl ester group gave (94%) the corresponding mono-
acid diester 18 whose structure was supported by the
disappearance (13C NMR) of absorptions due to the
benzyl group, a new peak at 174.0 ppm (CO2H), and a
molecular ion peak (ESI-MS) at m/z 390.44 [M + H]+.
Monoacid 18 was subsequently coupled with 1-amino-
5-[4′-(terpyridinyloxy)]pentane37,38 using traditional pep-
tide coupling conditions47 to afford (93%) nitroamide 19
which was characterized (13C NMR) by the observation
a new peak at 170.6 ppm (CONH) and the disappear-
ance of the acid carbonyl peak (174.0 ppm) as well as a
molecular ion peak (ESI-MS) at m/z 706.3 [M + H]+.
Reduction of the nitro moiety with Raney-Ni catalyst
in absolute EtOH at 40 °C afforded (87%) the corre-
sponding amine 20, whose structure was identified (13C
NMR) by the anticipated upfield chemical shift of the
resonance assigned to the C4° from 92.3 to 52.3 ppm. A
molecular ion peak (ESI-MS) at m/z 677.8 [M + H]+
further confirmed the desired NO2 to NH2 transforma-
tion. Amine 20 can also be prepared in three steps by
amidation of 4-nitrobutanoic acid with 1-amino-5-[4′-
(terpyridinyloxy)]pentane, subsequent treatment with
a slight excess of tert-butyl acrylate, and reduction
catalyzed with Raney-nickel.
Focusing on the tert-butyl ester groups of monomer
17, treatment with formic acid at 25 °C for 24 h afforded
(ca. 100%) the corresponding diacid 21 (Scheme 5).
Characterization (13C NMR) included the disappearance
of the peaks attributed to the tert-butyl ester groups and
appearance of the acid carbonyl peak at 173.3 ppm.
Treatment of diacid 21 with an aminotriester building
block 2239 under DCC amidation conditions gave the bis-
(amide) 23 as indicated by the expected downfield shift
(13C NMR) of the C4°NH signal at 52.9 (for 22) to 57.1
ppm (C4°NHCO) and by the disappearance of the acid
carbonyl resonance. Catalytic deprotection with Pd/C of
the benzyl-modified acid moiety of monomer 23 afforded
the monoacid 24, as shown by the disappearance (13C
NMR) of benzyl group absorptions, the observation of a
new peak at 174.0 ppm (CO2H), and the molecular ion
peak (ESI-MS) at m/z 1073.35 [M + H+].
The second-generation, terpyridinyl-modified mono-
mer 25 was then prepared by treatment of monoacid
24 with amine 20 using DCC with 1-HOBT in DMF.
Key assignments (13C NMR) characterizing the trans-
formation included the disappearance of the acid car-
bonyl resonance, the observation of a signal at 170.3
ppm assigned to the newly formed amide carbonyl
moiety, and a downfield shift (∆ 5 ppm) of the C4° signal
analogous to that observed in monomer 23. Reduction
of the nitro moiety 25 with Raney-Ni in absolute EtOH
at various temperatures, hydrogen pressures, and reac-
tion times failed to afford the desired focal amine; thus
to circumvent this problem, the tert-butyl ester groups
were transesterified, thereby reducing the inherent
steric hindrance.
Con clu sion
New 1 f (2 + 1) C-branching building blocks were
synthesized from the key intermediate 2, which was
readily prepared from Michael addition reaction of
4-nitrobutanol (1) and tert-butyl acrylate in the presence
of Triton-B, as a catalyst. A series of simple monomers
building blocks 4, 6, and 7 can be readily used to prepare
the first-generation dendrimers (9-11) based on the
tetraacid chloride as a core. The second-generation
dendrimer 15 was synthesized by means of a convergent
method in which each tier possesses the common 1 f
(2 + 1) functional groups. Deprotection of 15 with formic
acid can then generate the free octaacid, which has been
demonstrated on a related dendrimer series49,50 to afford
the higher level tiers with (1 f 3) Behera’s amine39 or
deprotection with base will free the acetate moieties
leaving the tert-butyl ester intact. Using the same
thought process with minor modification, the 1 f (2 +
1) tris(ester) 17 was synthesized and then debenzylated,
amidated, and catalytically reduced to give 20, which
with formic acid to remove the ester groups gave the
diacid that can be divergently treated with Behera’s
amine and reduced to give dendron 27. Combination of
these 1 f (2 + 1) monomers permits the selective
placement of a single unique moiety either at an
internal level or on the surface per dendron depending
of the order of construction. Therefore, controlled modi-
fications of appropriately placed functional groups can
lead to new types of dendrimers with specifically located
utilitarian moieties.
Ack n ow led gm en t. We gratefully thank the Na-
tional Science Foundation (DMR 99-01393) and the
Office of Naval Research (N00014-99-1-0082) and the
Ohio Board of Regents.
Transesterification of dendron 25 with MeOH and a
trace of H2SO4 afforded the corresponding octa(methyl
ester) dendron 26, which was confirmed (13C NMR) by
the presence of a new methyl ester absorption (51.5
ppm) coupled with the complete absence of resonances
typically associated with tert-butyl groups as well as the
MALDI-TOF MS data with the peak at m/z 1394.19
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