Dendrimers with alternating amine and ether generations

Article abstract of DOI:10.1021/jo991042c

Dendrimers having alternating aryl benzyl ether and tertiary amine generations and up to 16 bis-(2-methoxyethyl)amine end groups and four internal tertiary amines were synthesized by sequential etherification, amidation of secondary amines, and LiAlH

Full text of DOI:10.1021/jo991042c

8588
J . Org. Chem. 1999, 64, 8588-8593
Den d r im er s w ith Alter n a tin g Am in e a n d Eth er Gen er a tion s
Yijun Pan and Warren T. Ford*
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078
Received J une 29, 1999
Dendrimers having alternating aryl benzyl ether and tertiary amine generations and up to 16 bis-
(2-methoxyethyl)amine end groups and four internal tertiary amines were synthesized by sequential
etherification, amidation of secondary amines, and LiAlH4 reduction to tertiary amines. The bis-
(2-methoxyethyl)amine dendrimers are soluble in common organic solvents and in aqueous buffer
solutions at pH < 4.7. At 2.8 mM, the dendrimer increases the solubility of pyrene in water 30-
fold, and the solvated pyrene is not aggregated.
Since the pioneering divergent syntheses of Tomalia1
boxylic acids provided confined sites for the polymeriza-
tion of lipophilic monomers in aqueous solution.8 Dendri-
mers with terminal ammonium salts and long all-
hydrocarbon core and branching units trap lipophilic
guest molecules such as diphenylhexatriene, naphtha-
lene, and dyes in aqueous solutions.6d Carboxylic acid
terminated PAMAM dendrimers having a long aliphatic
chain in the core host hydrophobic dyes in aqueous
solution.9 Dendritic unimolecular micelles, unlike dy-
namically aggregated surfactant micelles, retain their
colloid structure no matter how dilute the solution. These
unique properties of dendrimers may enable applications
in medicine10 and catalysis.11
and Newkome2 and the convergent synthesis of Hawker
and Frechet,3 many different types of dendritic macro-
molecules have been synthesized.4 Much emphasis now
is on functional dendrimers.4c,e We have been intrigued
by poly(propylene imine) (PPI) dendrimers that can trap
and release smaller molecules.5 The polar ends of am-
phiphilic dendrimers make them water-soluble, and their
less polar cores and branching units solvate hydrophobic
molecules.2,6 Carboxylic acid terminated dendrimers
serve as micelle substitutes in electrokinetic capillary
chromatography.7 The internal volume of poly(amidoam-
ine) (PAMAM) dendrimers terminated with eight car-
The cores and branch points as well as the end groups
can be reactive functional groups. The commercial PPI
and PAMAM dendrimers have tertiary amines at the
branch points. The PPI and PAMAM dendrimers are
prepared by repetitive conjugate addition of primary
amines to acrylonitrile or methyl acrylate, followed by
conversion to primary amines via hydrogenation of the
resulting nitriles12 or by amidation of the methyl esters
with excess ethylenediamine.1 Amidation also is the key
chain extending step in the synthesis of dendrimers with
three new branches at each branch point.13 The prepara-
tion of wholly polyamine dendrimers by the reduction of
amides is rare,14 although the amide connectivity is
highly useful in dendrimer synthesis because of its
chemical stability1,15 and because many high yield ami-
dation methods are available from synthesis of polya-
mides and polypeptides.
(1) Tomalia, D. A.; Baker, H.; Dewald, J . R.; Hall, M.; Kallos, G.;
Martin, S.; Roeck, J .; Ryder, J .; Smith, P. Polym. J . 1985, 17, 117.
(2) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K. J . Org.
Chem. 1985, 50, 2004-2006.
(3) Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112,
7638.
(4) (a) Tomalia, D. A.; Durst, H. D. Top. Curr. Chem. 1993, 165,
193-313. (b) Dvornic, P. R.; Tomalia, D. A. Curr. Opin. Coll. Interface
Sci. 1996, 1, 221. (c) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F.
Dendritic Molecules; VCH: Weinheim, 1996. (d) Zeng, F.; Zimmerman,
S. C. Chem. Rev. 1997, 97, 1681-1712. (e) Matthews, O A.; Shipway,
A. N.; Stoddart, J . F. Prog. Polym. Sci. 1998, 23, 1-56.
(5) (a) J ansen, J . F. G. A.; de Brabander-van den Berg, E. M. M.;
Meijer, E. W. Science 1994, 266, 1226-1229. (b) J ansen, J . F. G. A.;
J anssen, R. A. J .; de Brabander-van den Berg, E. M. M.; Meijer, E. W.
Adv. Mater. 1995, 7, 561-564. (c) J ansen, J . F. G. A.; de Brabander-
van den Berg, E. M. M.; Meijer, E. W. Science 1995, 268, 1592. (d)
J ansen, J . F. G. A.; Meijer, E. W.; de Brabander-van den Berg, E. M.
M. J . Am. Chem. Soc. 1995, 117, 4417.
(6) (a) Newkome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V., K.; Russo,
P. S.; Saunders: M. J . J . Am. Chem. Soc. 1986, 108, 849. (b) Caminati,
G.; Turro, N. J .; Tomalia, D. A. J . Am. Chem Soc. 1990, 112, 8515. (c)
Newkome, G. R.; Moorefield, C. N.; Baker, G. R. J ohnson, A. L.; Behera,
R. K. Angew. Chem., Int. Ed. Engl. 1991, 30, 1176. (d) Newkome, G.
R.; Moorefield, C. N.; Baker, G. R.; Saunders: M. J .; Grossman, S. H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1178. (e) Gopidas, K. R.;
Leheny, A. R.; Caminati, G.; Turro, N. J .; Tomalia, D. A. J . Am. Chem.
Soc. 1991, 113, 7335. (f) Hawker, C. J .; Wooley, K. L.; Fre´chet, J . M.
J . J . Chem. Soc., Perkin Trans. 1 1993, 1292. (g) Ottaviani, M. F.;
Cossu, E.; Turro, N. J .; Tomalia, D. A. J . Am. Chem. Soc. 1995, 117,
4387. (h) Stevelmans, S.; van Hest, J . C. M.; J ansen, J . F. G. A.; van
Boxtel, D. A. F. J .; de Brabander-van den Berg, E. M. M.; Meijer, E.
W. J . Am. Chem. Soc. 1996, 118, 7398. (i) Zhang, H.; Dubin, P. L.;
Kaplan, J .; Moorefield, C. N.; Newkome, G. R. J . Phys. Chem. B 1997,
101, 3494. (j) Ashton, P. R.; Boyd, S. E.; Brown, C. L.; Nepogodiev, S.
A.; Meijer, E. W.; Peerlings, H. W. I.; Stoddart, J . F. Chem. Eur. J .
1997, 3, 974. (k) Pesak, D. J .; Moore, J . S.; Wheat, T. E. Macromolecules
1997, 30, 6467.
(8) Wege, V. U.; Grubbs, R. H. Polym. Prepr. 1995, 36, 239.
(9) Watkins, D. M.; Sayed-Sweet, Y.; Klimash, J . W.; Turro, N. J .;
Tomalia, D. A. Langmuir 1997, 13, 3136.
(10) (a) Reference 4c, pp 245-248. (b) Reference 4e, pp 43-46.
(11) (a) Knapen, J . W. J .; van der Made, A. W.; de Wilde, J . C.; van
Leeuwen, P. W. N. M.; Wijkens, P.; Grove, D. M.; van Koten, G. Nature
1994, 372, 659-663. (b) Miedaner, A.; Curtis, C. J .; Barkley, R. M.;
DuBois, D. L. Inorg. Chem. 1994, 33, 5482-5490. (c) Lee, J .-J .; Ford,
W. T.; Moore, J . A.; Li, Y. Macromolecules 1994, 27, 4632-4634. (d)
Marquardt, T.; Lu¨ning, U. Chem. Commun. 1997, 1681-1682. (e) Mak,
C. C.; Chow, H.-F. Macromolecules 1997, 30, 1228-1230.
(12) de Brabander-van den Berg, E. M. M.; Meijer, E. W. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1308.
(13) Newkome, G. R.; Patri, A. K.; Godinez, L. A. Chem. Eur. J . 1999,
5, 1445 and references therein.
(14) Nagasaki, T.; Kimura, O.; Ukon, M.; Arimori, S.; Hamachi, I.;
Shinkai, S. J . Chem. Soc., Perkin Trans. 1 1994, 75.
(7) (a) Kuzdzal, S. A.; Monnig, C. A.; Newkome, G. R.; Moorefield,
C. N. J . Chem. Soc., Chem. Commun. 1994, 2139. (b) Muijselaar, P.
G. H. M.; Claessens, H. A.; Cramers, C. A.; J ansen, J . F. G. A.; Meijer,
E. W.; de Brabander-van den Berg, E. M. M.; van der Wal, S. J . High
Resol. Chromatogr. 1995, 18, 121. (c) Kuzdzal, S. A.; Monnig, C. A.;
Newkome, G. R.; Moorefield, C. N. J . Am. Chem. Soc. 1997, 119, 2255.
(15) (a) Buhleier, E.; Wehner, W.; Vo¨gtle, F. Synthesis 1978, 155.
(b) Uhrich, K. E.; Fre´chet, J . M. J . J . Chem. Soc., Perkin Trans. 1 1992,
1623. (c) Mulders, S. J . E.; Brouwer, A. J .; van der Meer, P. G. J .;
Liskamp, R. M. J . Tetrahedron Lett. 1997, 38, 631. (d) Cardona, C.
M.; Kaifer, A. E. J . Am. Chem. Soc. 1998, 120, 4023.
10.1021/jo991042c CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

Dendrimers with Alternating Amine and Ether Generations
J . Org. Chem., Vol. 64, No. 23, 1999 8589
Sch em e 1
Our aim with amine dendrimers is to evaluate their
potential as catalysts of reactions in aqueous solutions.
Nonpolar organic compounds will partition into the less
polar interiors of the dendrimers. Primary and tertiary
amine end groups and tertiary amine branch points can
serve as ligands for metal ion complexes. Conversion of
the tertiary amines to quaternary ammonium ions gives
compact polyelectrolyte structures that attract counte-
rions as reagents or catalysts. In our first study of
dendrimer catalysis, the activity of a terminal quaternary
ammonium dendrimer with no internal active sites and
little free volume was much less than that of a quater-
nary ammonium ion latex for decarboxylation of 6-ni-
trobenzisoxazole-3-carboxylate and for o-iodosobenzoate-
catalyzed hydrolysis of p-nitrophenyl diphenyl phos-
phate.11c
Sch em e 2
With catalysis as the application goal, we have syn-
thesized dendrimers with both terminal and internal
tertiary amines. An example is dendrimer 1, which has
16 bis(2-methoxyethyl)amine end groups, four internal
tertiary amine groups, a hydrophobic core, and alternat-
ing ether and amine layers. The structures are analogues
of layer block copolymers16 and may solvate large lipo-
philic molecules in the multiple hydrophobic layers. Such
structures cannot be obtained from dynamically ag-
gregated surfactants.
Bis(2-m eth oxyeth yl)a m in e Ter m in a ted Den d r on .
The amide-terminated dendron 4 was synthesized by the
method of Scheme 1. The hydroxyl group of 5-hydroxy-
isophthalic acid was protected using acetyl chloride, and
the two carboxylic acid groups were converted to acid-
chloride using thionyl chloride to give 2. The crude
product 2 was treated with bis(2-methoxyethyl)amine to
form dendron 3, and the protecting group of 3 was
subsequently removed by aqueous methylamine to give
corresponding phenol 4.
Branching monomer 5 was prepared by NBS bromi-
nation of methyl 3,5-dimethylbenzoate in 60% yield.17
The syntheses of the amide terminated amide dendron
7 and the amine terminated amine dendron 8 are shown
in Scheme 2. Ester 6 was synthesized by etherification
of 2 equiv of phenol 4 with 1 equiv of dibromide 5 and
was converted to amide 7 using 40% aqueous MeNH2.
Both the terminal and the focal amide groups of 7 were
converted to amine groups by LiAlH4 in THF to give
amine 8 in 91% yield. The secondary amine formed at
the focal point of 8 becomes the site for subsequent
Resu lts a n d Discu ssion
The strategy for the syntheses of 1 and related amine-
ether dendrimers is to form alternating layers by Will-
iamson ether syntheses and amidations of secondary
amines, and to form tertiary amines by reduction of
amides. Polyamides frequently are insoluble in most
common organic solvents, and so highly solubilizing bis-
(2-methoxyethyl)amine and -amide end groups were used
throughout. The outer layer of end groups and terminal
branches of a dendrimer count for at least half of the
mass and are the interface between dendrimer and
medium that mainly determines its solubility.
(16) (a) Kriz, J .; Masar, B.; Plestil, J .; Tuzar, Z.; Pospisil, H.;
Doskocilova, D. Macromolecules 1998, 31, 41. (b) Hedrick, J . L.;
Trollsas, M.; Hawker, C. J .; Atthoff, B.; Claesson, H.; Heise, A.; Miller,
R. D.; Mecerreyes, D.; J erome, R.; Dubois, Ph. Macromolecules 1998,
31, 8691.
(17) Kurt, K.; Goebel, M. W. Helv. Chim. Acta 1996, 79, 1967.

8590 J . Org. Chem., Vol. 64, No. 23, 1999
Pan and Ford
Sch em e 3
Sch em e 4
coupling reactions. The bis(2-methoxyethyl)amine groups
were stable to the conditions of both amidation and
LiAlH4 reduction, and they may even serve as proton
acceptors in the coupling of polyamine dendrons with the
core units.
Tetraacid chloride 13 was synthesized as shown in
Scheme 3. Two equivalents of dimethyl 5-hydroxyisoph-
thalate (9) and 1 equiv of R,R′-dibromo-p-xylene (10) gave
tetraester 11, which was hydrolyzed to tetraacid 12 and
then converted to the acid chloride 13 by reaction with
thionyl chloride in toluene.18
Cou p lin g of th e Den d r on s to th e Cor es. Internal
amide groups in the layer block dendrimers were formed
by amidation of carboxylic acid chloride cores and were
reduced to tertiary amines. The terminal amides were
directly converted to tertiary amines in the dendron prior
to the formation of the dendrimers. Thus, amine 8 reacted
with benzene-1,3,5-tricarbonyl trichloride in DMF to give
dendrimer 14 in 45% isolated yield as shown in Scheme4.
The relatively low yield resulted from the difficulty of
separating 14 from starting material 8. Since the two
compounds tailed badly during chromatography on un-
treated silica gel, dendrimer 14 was purified using
preparative silica gel plates pretreated with trimethyl-
amine. Purity was confirmed by NMR, ESI-MS, TLC and
HPLC analysis. The reduction of 14 by LiAlH4 in THF
gave the polyamine dendrimer 15 in 88% yield (Scheme
4).
The amide-amine dendrimer 16 with 16 terminal
tertiary amine and four internal amide groups was
prepared by the same method as 14 using excess amine
8 with the core unit 13 in DMF and purified using
preparative silica gel plates pretreated with trimethy-
lamine. The interior amide groups of 16 were reduced to
the interior tertiary amine groups by LiAlH4 to afford
the dendrimer 1 (Scheme 5).
Oth er Ap p r oa ch es to Alter n a tin g Am id e-Eth er
Den d r im er s. Some other approaches to terminal amide
functionality gave low yields or separation difficulties.
A dendrimer was synthesized having structure identical
with that of 16 except for methyl carboxylate instead of
bis(2-methoxyethyl)carboxamide end groups. Treatments
of the dendrimer with sixteen methyl esters with me-
thylamine, dimethylamine, and benzylamine gave den-
drimers with sixteen secondary terminal amides in good
yield, but the compounds were soluble only in DMF and
DMSO. Attempts to reduce the polyamides to polyamines
with borane and LiAlH4 were not successful due to their
low solubility in THF and in dioxane and to the formation
of gels. Amidations of terminal esters with secondary
amines suffered from incomplete conversions even at
elevated temperature and with NaCN as a catalyst.
Ch a r a cter iza tion . The polyamine dendron 8 and
1
dendrimers 14-16 and 1 were characterized by IR, H
and 13C NMR, and ESI-MS. LSIMS mass analyses were
used for amide dendrons and monomers. Purities were
analyzed by TLC and HPLC.
FT-IR was very useful for determining the complete-
ness of the amidations from the disappearance of the
carbonyl chloride band of the core units at 1760-1770
cm-1 and for determining the completeness of LiAlH4
reduction from the disappearance of amide band at
1650-1640 cm-1 (Figure 1).
NMR analysis was not very useful for the character-
ization of the aromatic tertiary amide dendrimers be-
cause each amide group exists in two conformations due
(18) Collman, J . P.; Brauman, J . I.; Fitzgerald, J . P.; Hampton, P.
D.; Naruta, Y.; Sparapany, J . W.; Ibers, J . A. J . Am. Chem. Soc. 1988,
110, 3477.

Dendrimers with Alternating Amine and Ether Generations
J . Org. Chem., Vol. 64, No. 23, 1999 8591
Sch em e 5
1
F igu r e 2. 400 MHz H NMR spectra of internal polyamide/
terminal polyamine dendrimer 16 (top) and polyamine den-
drimer 1 (bottom).
(Figure 2). The carbon NMR spectrum of amine den-
drimer 1 was also much better resolved than that of
amide-amine dendrimer 16.
The ESI-MS spectrum of dendron 8 from water/
acetonitrile/acetic acid (50:50:0.5) predominantly con-
tained [M + H]+ and [M + 2H]2+ ions, while the spectra
of dendrimers 14-16 and 1 mainly contained ions with
2+ to 7+ charge in which one charge was due to sodium
or potassium and the rest were due to protons. These
data indicate that the desired dendron and dendrimers
are the predominant species in the samples. The ESI-
MS spectra of dendrimers 14 and 16 showed no peaks
from the starting material 8.
Solu bility a n d Molecu la r In clu sion . The bis(2-
methoxyethyl)amine terminated polyamide and polyamine
dendrimers are readily soluble in toluene, ether, THF,
chloroform, acetone, methanol, and DMF. Solubility in
organic solvents is essential for synthesis and purifica-
tion. Polyamine dendrimers 1 and 15 are also soluble in
aqueous acetic acid/sodium acetate buffer solutions at pH
4.74, but the solubility decreases dramtically above pH
4.74. The lipophilic compatability and the solubility in
aqueous solution are desired properties for the catalytic
application of the polyamine dendrimers as unimolecular
micelles.
The microenvironment of the hydrophobic interior of
the bis(2-methoxyethyl)amine terminated dendrimers
was probed by solubilizing pyrene in aqueous solution
at pH 3.0. The limiting solubility of pyrene in a 2.8 ×
10-3 M solution of dendrimer 1 measured by UV-vis
absorption spectrophotometry is ∼2.5 × 10-5 M, more
than 30 times higher than in pure water (8 × 10-7 M).
Pyrene has been dissolved into poly(propylene imine)
dendrimer solutions at similar concentrations.19 Pyrene
aggregates in water as shown by concentration-depend-
ent λmax. The UV-vis spectra of pyrene in dendrimer 1
obey Beer’s law up to 2.31 × 10-5 M, and λmax does not
change with concentration as shown in Figure 3. This
proves that the pyrene dissolves into the dendrimer
unimolecularly.
F igu r e 1. FTIR spectra of polyamine dendron 8 (top), internal
polyamide/terminal polyamine dendrimer 16 (middle), and
polyamine dendrimer 1 (bottom).
to slow rotation about the carbonyl C-N bond and each
conformation gives its own spectrum. However, the NMR
spectra of the polyamine dendrimers were much sharper.
1
The H NMR spectra of the interior amide dendrimer 16
and the wholly polyamine dendrimer 1 are compared in
Figure 2. The proton NMR spectrum of dendrimer 16
containing interior amides shows the NCH3 signal spread
over 2.7-3.2 ppm and the broad NCH2 signal spread over
4.4-4.9 ppm. The signals in the aromatic region are also
complicated. The proton NMR spectrum of the corre-
sponding polyamine dendrimer 1, on the other hand, has
an extremely clean NMR spectrum, and the coupling
between the terminal ethylene groups could be identified
(19) Pistolis, G.; Malliaris, A.; Tsiourvas, D.; Paleos, C. M. Chem.
Eur. J . 1999, 5, 1440.

8592 J . Org. Chem., Vol. 64, No. 23, 1999
Pan and Ford
washed with water, dried over Na2SO4, and evaporated to give
9.70 g (97%) of 4 as a light yellow thick oil: IR (film on NaCl)
νmax 3195, 1638, 1595 cm-1; 1H NMR (CDCl3, δ) 3.3-3.4 (2 br
s, 6H each), 3.4-3.8 (4 br s, 4H each), 6.82 (s, 2 H), 6.85 (s,
1H), 8.58 (br, 1H); 13C NMR (CDCl3, δ) 44.63, 49.40, 58.00,
69.73, 70.33, 120.80, 122.25, 137.80, 149.75, 168.01; LSIMS
(m/z) calcd for C20H32N2O7 412.2, found 413 [M + H]+.
Meth yl 3,5-Bis(br om om eth yl)ben zoa te (5).17 A mixture
of 1.97 g (12.0 mmol) of 4, 4.38 g (24.6 mmol) of NBS, 34 mg
of dibenzoyl peroxide, and 36 mL of carbon tetrachloride in a
50 mL round-bottom flask fitted with a condenser was stirred,
heated to reflux with an IR lamp, and irradiated with a
medium-pressure 450 W Hg lamp for 60 min. After cooling,
the mixture was filtered, and the solid was washed with
dichloromethane. The combined organic solution was washed
with 1% aqueous sodium carbonate and with water, dried, and
evaporated to a gummy residue that was crystallized from
hexane at -20 °C and recrystallized from hexane at room
temperature to give 58% of white solid 5: mp 91-93 °C (lit.17
mp 92-93 °C); IR (film on NaCl) νmax 1730, 1438, 1317, 1231,
1
776, 705, 698 cm-1; H NMR (CDCl3, δ) 3.92 (s, 3H), 4.50 (s,
4H), 7.59 (s, 1H), 7.93 (t, 2H); 13C NMR (CDCl3, δ) 52.10, 81.74,
129.82, 133.27, 133.40, 138.70, 164.50; LSIMS (m/z) calcd for
C
F igu r e 3. UV-vis absorption spectra of pyrene at concentra-
tions of 0.77, 1.16, 1.54, 1.92, and 2.31 × 10-5 M in 2.80 ×
10-3 M aqueous dendrimer 1 at pH 3.0.
10H10Br2O2 319.9, found 321, 323, 325 [M + H]+.
Ester 6. A solution of 3.34 g (8.1 mmol) of phenol 4, 1.30 g
(4.04 mmol) of bromide 5, and 1.66 g (12.0 mmol) of K2CO3 in
38 mL of THF was stirred under nitrogen at 65 °C for 24 h.
The mixture was concentrated, and 20 mL of water (20 mL)
was added. The mixture was extracted with chloroform,
washed with 1% aqueous Na2CO3 and water, and dried over
MgSO4. Flash chromatography (MeOH/CHCl3, 2:98) afforded
3.03 g (77%) of 6 as a colorless thick oil: IR (film on NaCl)
νmax 1730, 1638, 1596 cm-1; 1H NMR (CDCl3, δ) 3.3-3.4 (2 br
s, 6H each), 3.4-3.8 (4 br s, 4H each), 3.95 (s, 3H), 5.18 (s,
4H), 7.08 (s, 2H), 7.12 (s, 4H), 7.72 (s, 1H), 8.08 (s, 2H); 13C
NMR (CDCl3, δ) 45.37, 49.86, 52.49, 59.02, 69.61, 70.54, 70.94,
114.60, 118.49, 128.40, 130.76, 131.21, 137.62, 138.52, 158.38,
166.59, 171.22; LSIMS (m/z) calcd for C50H72N4O16 984.5, found
984 [M]+.
Am id e 7. A solution of 3.20 g (3.25 mmol) of ester 6 in 6
mL of methanol and 18 mL of 40% aqueous MeNH2 was stirred
at room temperature for 24 h. The mixture was concentrated,
acidified to pH 4 using 2% aqueous HCl, and extracted with
CHCl3. The CHCl3 solution was washed with water, dried over
Na2SO4, concentrated, and flash chromatographed (MeOH/
CHCl3, 2:98) to give 2.12 g (71%) of 7 as a colorless thick oil:
IR (film on NaCl) νmax 3359, 1637, 1595 cm-1; 1H NMR (CDCl3,
δ) 2.96 (d, 3H), 3.3-3.4 (2 br s, 6H each), 3.4-3.8 (4 br s, 4H
each), 5.18 (s, 4H), 7.18 (6H), 7.59 (s, 1H), 7.82 (s, 2H); 13C
NMR (CDCl3, δ) 26.51, 44.93, 49.39, 58.56, 69.32, 70.07, 70.45,
114.31, 118.01, 125.63, 128.70, 135.40, 137.09, 138.05, 157.94,
167.22, 170.77; LSIMS (m/z) calcd for C50H73N5O15 983.5, found
983 [M+], 984 [M + H]+.
Exp er im en ta l Section
All starting materials were from Aldrich and were used as
received unless otherwise stated. THF was freshly distilled
from sodium. Pyridine and triethylamine were dried over 3 Å
molecular sieves and freshly distilled. All glassware was dried
at 170 °C before use. 1H NMR spectra at 400 or 300 MHz NMR
spectra and 13C NMR spectra at 100.6 or 75.4 MHz were
recorded with the solvent proton signal as the reference. Liquid
secondary ion mass spectra (LSIMS) were obtained using a
25 keV primary Cs+ ion beam and 3-nitrobenzyl alcohol as the
matrix. Electrospray mass spectra were acquired by infusing
the samples in water:acetonitrile:acetic acid (50:50:0.5) at a
flow rate of 1 µL min-1. Calculated m/z values for all mass
spectra are for the lowest mass isotopomer. Analytical TLC
was performed on Kodak thin-layer chromatography plates
with silica gel GF254. Preparative TLC was performed on
Aldrich silica gel GF plates (1000 µm thick), and the plates
were pre-developed with 2% trimethylamine in CH2Cl2 and
activated at 60 °C for 6 h. Baker silica gel (40 µm) was used
for flash chromatography. HPLC was carried out with a
reversed-phase C18 column, 50/50 methanol/chloroform as
solvent, and UV detection at 350 nm.
5-Acetoxy-1,3-bis[N,N-bis(2-m eth oxyeth yl)]ben zen ed i-
ca r boxa m id e (3). A mixture of 6.01 g (33.0 mmol) of 5-hy-
droxyisophthalic acid, 10.80 g (138.0 mmol) of acetyl chloride,
and 10 mL of toluene was stirred under reflux for 6 h. Thionyl
chloride (11.02 g, 92.0 mmol) was added, and the mixture was
stirred for 7 h under reflu, and concentrated under reduced
pressure. The oily residue 2 was dissolved in 10 mL of THF.
A solution of 9.06 g (68.0 mmol) of bis(2-methoxyethyl)amine
in 15 mL of THF and triethylamine (8.10 g, 80.0 mmol) was
added slowly with stirring at 0 °C, and the mixture was stirred
for 30 min at 0 °C and 4 h at room temperature, added to 30
mL of water, extracted with CHCl3 (2 × 50 mL), washed with
water, dried over MgSO4, and evaporated to a light yellow oil,
which was eluted through a short column chromatography
(SiO2, MeOH/CHCl3 2:98) to give 10.11 g (67%) of 3 as a thick
Am in e 8. A suspension of 98 mg (2.58 mmol) of LiAlH4 and
16 mL of THF under nitrogen was cooled to 0 °C, and 998 mg
(1.01 mmol) of 7 in 4 mL of THF was added slowly with
stirring at 0 °C. The mixture was stirred at 70 °C for 24 h,
cooled, and slowly poured into 20 mL of saturated aqueous
Na2SO4 solution at 0 °C. The mixture was acidified to pH 1
using 6 M aqueous HCl, washed with Et2O (2 × 5 mL), added
to 10 M aqueous NaOH to pH 12, and extracted with Et2O (3
× 15 mL). The organic solution was washed with water, dried
over K2CO3, evaporated, and dried under vacuum to give 722
oil: IR (film on NaCl) νmax 1738, 1638, 1595 cm-1
;
1H NMR
mg (80%) of 8 as a thick oil: IR (film on NaCl) νmax 1593 cm-1
;
(CDCl3, δ) 2.36 (s, 3H), 3.3-3.4 (2 br s, 6H each), 3.4-3.8 (4
br s, 4H each), 7.22 (s, 2H), 7.40 (s, 1H); 13C NMR (CDCl3, δ)
20.47, 44.70, 49.09, 58.22, 69.65, 70.14, 120.75, 122.46, 137.48,
149.58, 168.09, 169.76; LSIMS (m/z) calcd for C22H34N2O8
454.2, found 455 [M + H]+.
1H NMR (CDCl3, δ) 2.49 (s, 3H), 2.76 (t, 16H), 3.34 (s, 24H),
3.48 (t, 16H), 3.68 (s, 8H), 5.18 (s, 4H), 6.87 (s, 2H), 6.92 (s,
4H), 7.36-7.46 (m, 3H); 13C NMR (CDCl3, δ) 36.01, 53.60,
55.79, 58.61, 59.48, 69.63, 71.15, 113.51, 121.74, 125.25,
126.73, 137.55, 140.81, 140.85, 158.77; ESIMS (m/z) calcd for
5-Hyd r oxy-1,3-bis[N,N-bis(2-m eth oxyeth yl)]ben zen e-
d ica r boxa m id e (4). Acetate 3 (10.00 g, 22.0 mmol), 10 mL
of methanol, and 20 mL of 40% aqueous MeNH2 were stirred
for 8 h at room temperature. The mixture was concentrated
on a rotary evaporator, acidified to pH 4-5 using 2% aqueous
HCl, and extracted with CHCl3. The CHCl3 solution was
C .
50H83N5O10 913.6, found 914.8 [M + H]+, 457.9 [M + 2H]2+
Tetr a ester 11. A mixture of 2.10 g (10.0 mmol) of dimethyl
5-hydroxyisophthalate (9), 1.29 g (4.90 mmol) of R,R′-dibromo-
p-xylene (10), 2.21 g (16.0 mmol) of K2CO3, 0.10 g of 18-crown-6
ether, and 38 mL of THF was stirred under nitrogen at 65 °C
for 24 h. The mixture was concentrated, and 20 mL of 1%

Dendrimers with Alternating Amine and Ether Generations
J . Org. Chem., Vol. 64, No. 23, 1999 8593
aqueous Na2CO3 was added at 0 °C. The solid was collected,
washed with water and ether, and dried under vacuum at 50
°C to give 2.31 g (90%) of 11 as a white powder: mp 186-188
ν
max 1590 cm-1; 1H NMR (CDCl3, δ) 2.18 (s, 9H), 2.76 (t, 48H),
3.34 (s, 72H), 3.46 (t, 48H), 3.58 (m, 12H), 3.68 (s, 24H), 5.18
(s, 12H), 6.84 (m, 18H), 7.2-7.5 (m, 9H); 13C NMR (CDCl3, δ)
44.98, 53.58, 58.70, 59.50, 69.63, 69.78, 71.10, 113.80, 113.94,
122.10, 125.64, 125.71, 127.90, 128.07, 137.52, 137.78, 140.81,
158.99; ESIMS (m/z) calcd for C159H255N15O30 2854.9, found
°C; IR (KBr) νmax 1730, 1602, 1459, 1346, 1246, 1040, 755 cm-1
;
1H NMR (CDCl3, δ) 3.96 (s, 12H), 5.19 (s, 4H), 7.50 (s, 4H),
7.84 (d, 4H), 8.32 (t, 2H); 13C NMR (CDCl3, δ) 52.40, 70.08,
120.22, 123.38, 127.95, 131.94, 136.25, 158.83, 166.23; LSIMS
(m/z) calcd for C28H26O10 522.2, found 523 [M + H]+.
1429.2 [(M + 2H)]2+
.
Den d r im er 16. By the method for dendrimer 14, 548 mg
(0.600 mmol) of amine 8, 4.0 mL of DMF, 70 mg (0.13 mmol)
of 13, and 60 mg (0.59 mmol) of triethylamine gave 280 mg
(54%) of 16 as a light yellow thick oil: IR (film on NaCl) νmax
Tetr a ca r boxylic Acid 12. A solution of 1.02 g (1.95 mmol)
of ester 11, 10 mL of methanol, 450 mg (8.02 mmol) of KOH,
and 10 mL of water was stirred under nitrogen at 50-60 °C
for 48 h. The mixture was concentrated, and 6 M aqueous HCl
was added slowly at 0 °C. The precipitate was collected,
washed with water, and dried under vacuum to give 0.62 g
(68%) of acid 12 as a white solid: IR (KBr) νmax 3500-2500,
1648, 1597 cm-1; H NMR (CDCl3, δ) 2.76 (m, 64H), 2.8-3.1
1
(br, 12H), 3.34 (m, 96H), 3.50 (m, 64H), 3.78 (s, 32H), 4.4-4.9
(br, 8 H), 5.06 (m, 16H), 6.90 (m, 24H), 7.12-7.25 (m, 6H),
7.35-7.6 (m, 12H); 13C NMR (CDCl3, δ) 53.55, 58.70, 59.47,
69.58, 71.02, 113.82, 122.24, 126.32, 127.26, 127.95, 138.20,
140.83, 158.95; ESIMS (m/z:) calcd for C224H342N20O46 4048.5,
found 2026.4 [M + 2H]2+, 1351.2 [M + 3H]3+, 1014.0 [M +
1
1708, 1602 cm-1; H NMR (DMSO-d6, δ) 5.29 (s, 4H, CH2O),
7.58 (s, 4H), 7.81 (s, 4 H), 8.18 (s, 2H), 13.40 (br, 4H); 13C NMR
(DMSO-d6, δ) 69.7, 119.8, 122.8, 128.2, 133.0, 136.7, 158.9,
166.8.
4H]4+, 811.2 [M + 5H]5+, 676.0 [M + 6H]6+
.
Tetr a ca r boxylic Acid Ch lor id e 13. A mixture of 400 mg
(0.850 mmol) of acid 12, 4 mL of toluene, and 4 mL of SOCl2
was stirred under nitrogen at 70-75 °C for 48 h. The
precipitate was collected, washed with ether (2 × 3 mL), and
dried under vacuum to give 250 mg (54%) of 13 as a light
yellow solid: mp 189-192 °C; IR (KBr) νmax 1765, 1597, 1304,
Den d r im er 1. By the method for amine 8, 38 mg (1.00
mmol) of LiAlH4, 17 mL of THF, and 220 mg (0.0543 mmol) of
16 gave 169 mg (78%) of 1 as a thick oil: IR (film on NaCl)
ν
max 1591 cm-1; 1H NMR (CDCl3, δ) 2.19 (s, 12H), 2.76 (t, 64H),
3.34 (s, 96H), 3.46 (t, 64H), 3.53-3.62 (m, 16H), 3.67 (s, 32H),
5.08 (s, 16H), 6.85-7.05 (m, 32H), 7.40-7.48 (m, 14H); 13C
NMR (CDCl3, δ) 41.93, 53.60, 58.70, 59.52, 61.81, 62.19, 69.81,
71.10, 113.83, 122.07, 125.77, 127.88, 136.81, 137.58, 140.84,
159.07; ESIMS (m/z) calcd for C224H350N20O42 3992.6, found
1
681 cm-1; H NMR (DMSO-d6, δ) 5.25 (s, 4H, CH2O), 7.58 (s,
4H), 7.78 (s, 4H), 8.10 (s, 2H); 13C NMR (DMSO-d6, δ) 69.49,
119.64, 122.60, 127.97, 132.74, 136.46, 159 (br), 166.49.
Den d r im er 14. To a solution of 645 mg (0.706 mmol) of
amine 8 in 4.0 mL of DMF were added 60 mg (0.23 mmol) of
1,3,5-benzenetricarboxylic acid chloride and 63 mg (0.80 mmol)
of pyridine, and the mixture was stirred under nitrogen at 60
°C for 24 h. DMF was removed under reduced pressure. The
residue was dissolved in 1.5 M aqueous HCl and washed with
ether (2 × 5 mL). Aqueous 5 M NaOH was added to pH 11 at
0 °C. The aqueous mixture was extracted with ether (3 × 10
mL), and the combined organic solution was washed with
water, dried over potassium carbonate, and concentrated to
an oil. The crude product was purified on trimethylamine-
pretreated preparative silica gel plates (trimethylamine/
methanol/chloroform, 0.5:2.5:97) to give 300 mg (45%) of 14
as a light yellow thick oil: IR (film on NaCl) νmax 1641, 1590
cm-1; 1H NMR (CDCl3, δ): 2.78 (m, 48H), 2.81-3.14 (m, 9H),
3.31 (s, 72H), 3.50 (m, 48H), 3.70 (s, 24H), 4.5-4.84 (br, 6H),
5.06 (s, 12H), 6.91 (br s, 18H), 7.2-7.7 (m, 9H); 13C NMR
(CDCl3, δ): 45.31, 53.57, 58.64, 59.47, 64.07, 69.46, 69.66,
71.14, 113.56, 113.63, 121.89, 125.58, 126.35, 127.81, 137.55,
138.26, 139.66, 140.95, 141.06, 158.96; ESIMS (m/z) calcd for
1998.8 [M + 2H]2+, 1332.8 [M + 3H]3+, 1000.0 [M + 4H]4+
,
800.0 [M + 5H]5+, 666.8 [M + 6H]6+, 571.6 [M + 7H]7+
.
Solu bility Mea su r em en ts. Solubilities of the dendrimers,
and of pyrene in dendrimer solutions, were tested by adding
4-5 mg of the sample into 1.0 mL of the solvent or aqueous
solution in a 4 mL vial and stirring magnetically for 15 min.
The sample was judged soluble if a clear solution formed,
slightly soluble if a cloudy solution formed, and insoluble if
the oil or solid remained unchanged.
Ack n ow led gm en t. We thank the U.S. Army Re-
search Office for support of this research and the
Phillips Petroleum Co. for a fellowship to Y.P. Funds
for the 400 MHz spectrometer of the Oklahoma State-
wide Shared NMR Facility were provided by the Na-
tional Science Foundation (BIR-9512269), the Oklahoma
State Regents for Higher Education, the W. M. Keck
Foundation, and Conoco, Inc.
C
159H249N15O33 2896.8, found 1450.4 [M + 2H]2+, 967.2 [M +
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra and mass spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
3H]3+, 725.6 [M + 4H]4+, 580.4 [M + 5H]5+
.
Den d r im er 15. By the procedure for amine 8, 38 mg (1.0
mmol) of LiAlH4, 17 mL of THF, and 250 mg (0.0862 mmol) of
14 gave 216 mg (88%) of 15 as a thick oil: IR (film on NaCl)
J O991042C