Modular Approach to the Accelerated Convergent Growth of Laser Dye-Labeled Poly(aryl ether) Dendrimers Using a Novel Hypermonomer

Article abstract of DOI:10.1021/jo990776m

The synthesis of novel dendrimers functionalized with laser dyes both at the periphery and at the core, along with all relevant model compounds necessary for accurate photophysical studies, is described. The utilized synthetic strategy involves a modular approach in which a variety of peripheral and core moieties can be placed on a dendritic structure bearing electrophilic peripheral groups and a nucleophilic core. Specifically, the target macromolecules required functionalization with the laser dyes coumarin 2 (periphery) and coumarin 343 (core) due to the possibility of energy transfer from the former to the latter dye. In addition, the preparation of a novel, highly soluble and reactive hypermonomer utilized in the rapid and efficient synthesis of high-generation dye-labeled dendrimers and model compounds is outlined.

Full text of DOI:10.1021/jo990776m

7474
J . Org. Chem. 1999, 64, 7474-7484
Mod u la r Ap p r oa ch to th e Acceler a ted Con ver gen t Gr ow th of
La ser Dye-La beled P oly(a r yl eth er ) Den d r im er s Usin g a Novel
Hyp er m on om er
Sylvain L. Gilat,† Alex Adronov, and J ean M. J . Fre´chet*
Department of Chemistry, University of California at Berkeley, Berkeley, California 94720-1460
Received May 12, 1999
The synthesis of novel dendrimers functionalized with laser dyes both at the periphery and at the
core, along with all relevant model compounds necessary for accurate photophysical studies, is
described. The utilized synthetic strategy involves a modular approach in which a variety of
peripheral and core moieties can be placed on a dendritic structure bearing electrophilic peripheral
groups and a nucleophilic core. Specifically, the target macromolecules required functionalization
with the laser dyes coumarin 2 (periphery) and coumarin 343 (core) due to the possibility of energy
transfer from the former to the latter dye. In addition, the preparation of a novel, highly soluble
and reactive hypermonomer utilized in the rapid and efficient synthesis of high-generation dye-
labeled dendrimers and model compounds is outlined.
In tr od u ction
dendrimers12 and showed that they can be readily
surface-functionalized12,13 in high yields by nucleophilic
attack of either an alcohol or an amine. However, the
electron-withdrawing character of the appended carbonyl
As the field of dendrimers rapidly grows,1 a few key
architectures clearly stand out as the most attractive and
best documented ones within the highly diverse pool of
branched polymers described so far. Poly(aryl ether)
dendrimers belong to this class: the simplicity, reliability,
and flexibility of their convergent synthesis,2 together
with the commercial availability of the monomer itself,
strongly contribute to the prominent role of this structure
within the dendrimer literature. Indeed, poly(aryl ether)
dendritic macromolecules have been widely used by
independent groups for a variety of applications,3,4 and
their chemistry5-9 and properties10 are now well estab-
lished.
In the course of our work on energy transfer in dye-
labeled poly(aryl ether) dendrimers,11 we experienced the
need for an alternative structure with orthogonal focal
and terminal functionalities. The design of our dendritic
antenna molecules connects the nucleophilic amino group
of coumarin 2 and the electrophilic acid group of cou-
marin 343 to the chain ends and focal point of the
dendrimer, respectively (Table 1). In contrast, with the
“classical” convergent approach to poly(aryl ether) den-
drimers,2 it is the terminal group that bears the electro-
philic functionality, whereas the focal point displays a
nucleophilic coupling site (Table 1).
(3) (a) J iang, D.-L.; Aida, T. Nature 1997, 388, 454-456. (b) Kawa,
M.; Fre´chet, J . M. J . Chem. Mater. 1998, 10, 286-296. (c) Karthaus,
O.; Ijiro, K.; Shimomura, M.; Hellmann, J .; Irie, M. Langmuir 1996,
12, 6714-6716. (d) J unge, D. M.; McGrath, D. V. Chem. Commun.
1997, 857-858. (e) Stewart, G. M.; Fox, M. A. J . Am. Chem. Soc. 1996,
118, 4354-4360. (f) Serroni, S.; Campagna, S.; J uris, A.; Venturi, M.;
Balzani, V.; Denti, G. Gazz. Chim. Ital. 1994, 124, 423-427. (g)
Kremers, J . A.; Meijer, E. W. J . Org. Chem. 1994, 59, 4262-6266. (h)
Hudson, S. D.; J ung, H.-T.; Percec, V.; Cho, W.-D.; J ohansson, G.;
Ungar, G.; Balagurusamy, V. S. Science 1997, 278, 449-452. (i)
Amabilino, D. B.; Ashton, P. R. Balzani, V.; Brown, C. L.; Credi, A.;
Fre´chet, J . M. J .; Leon, J . W.; Raymo, F. M.; Spencer, N.; Stoddart, J .
F.; Venturi, M. J . Am. Chem. Soc. 1996, 118, 12012-12020. (j)
Zimmerman, S. C.; Zeng, F. W.; Reichert, D. E. C.; Kolotuchin, S. V.
Science 1996, 271, 1095-1098. (k) Butz, T.; Murer, P.; Seebach, D.
Polym. Mater. Sci. Eng. 1997, 77, 132-133. (l) Seebach, D.; Lapierre,
J .-M.; Greiveldinger, G.; Skrobridis, K. Helv. Chim. Acta 1994, 77,
1673-1688. (m) Hawker, C. J .; Wooley, K. L. Fre´chet J . M. J . J . Chem.
Soc., Chem. Commun. 1994, 925. (n) Ferguson, G.; Gallagher, J . F.;
McKervey, M. A.; Madigan, E. J . Chem. Soc., Perkin Trans. 1 1996,
599-602. (o) Camps, X.; Scho¨nberg, H.; Hirsch, A. Chem. Eur. J . 1997,
3, 561-567. (p) Klopsch, R.; Franke, P.; Schlu¨ter, A.-D. Chem. Eur. J .
1996, 2, 1330-1334. (q) Wooley, K. L.; Hawker, C. J .; Fre´chet, J . M.
J .; Wudl. F.; Srdanov, G.; Shi, S.; Li, C.; Kao, M. J . Am. Chem. Soc.
1993, 115, 9836-9837. (r) Gitsov, I.; Fre´chet, J . M. J . Macromolecules
1993, 26, 6536-6546.
(4) (a) Sadamoto, R.; Tomioka, N.; Aida, T. J . Am. Chem. Soc. 1996,
118, 3978-3979. (b) J iang, D.-L.; Aida, T. J . Chem. Soc., Chem.
Commun. 1996, 1523-1524. (c) Tomoyose, Y.; J iang, D.; J in, R.;. Aida,
T.; Yamashita, T.; Horie, K.; Yashima, E.; Okamoto, Y. Macromolecules
1996, 29, 5236-5238. (d) J in, R. H.; Aida, T.; Inoue, S. J . Chem. Soc.,
Chem. Commun. 1993, 1260-1262. (e) Pollak, K. W.; Leon, J . W.;
Fre´chet, J . M. J .; Maskus, M.; Abrun˜a, H. D. Chem. Mater. 1999, 10,
30-38. (f) Pollak, K. W.; Leon, J . W.; Fre´chet, J . M. J . Polym. Mater.
Sci. Eng. 1995, 73, 333-334.
To remedy this potential shortcoming and also provide
easy access to a wider range of surface functionalities,
we later introduced ester-terminated poly(aryl ether)
* Corresponding author. Phone: (510) 643-3077. Fax: 643-3079
E-mail: frechet@cchem.berkeley.edu.
(5) (a) Hawker, C. J .; Fre´chet, J . M. J . Macromolecules 1990, 23,
4726-4729. (b) Wooley, K. L.; Hawker, C. J .; Fre´chet, J . M. J . J . Chem.
Soc., Perkin Trans. 1 1991, 1059-1076.
† Current address: Bell Laboratories, 600 Mountain Avenue, Room
1D-246, Murray Hill, NJ 07974. Phone: (908) 582-4604. Fax: (908)
582-3609. E-mail: sgilat@bell-labs.com.
(6) Lochman, L.; Wooley, K. L.; Ivanova, P. T.; Fre´chet, J . M. J . J .
Am. Chem. Soc. 1993, 115, 7043-7044.
(1) (a) Fre´chet, J . M. J .; Hawker, C. J . In Synthesis and Properties
of Dendrimers and Hyperbranched Polymers, Comprehensive Polym.
Sci., 2nd Suppl.; Aggarwal, S. L., Russo, S., Eds.; Pergamon Press:
Oxford, 1996; p 140. (b) Fre´chet, J . M. J . Science 1994, 263, 1710-
1715. (c) Issberner, J .; Moors, R.; Vo¨gtle, F. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2413-2420.
(2) (a) Fre´chet, J . M. J .; J iang, Y.; Hawker, C. J .; Philippides, A. E.
Preprints of the IUPAC International Symposium of Functional
Polymers; The Polymer Society of Korea: Seoul, 1989; p 19. (b) Hawker,
C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112, 7638-7647.
(7) (a) Wooley, K. L.; Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem.
Soc. 1991, 113, 4252-4261. (b) Spindler, R.; Fre´chet, J . M. J . J . Chem.
Soc., Perkin Trans. 1 1993, 913-918.
(8) L’Abbe´, G.; Forier, B.; Dehaen, W. J . Chem. Soc., Chem.
Commun. 1996, 2143-2144. Kawaguchi, T.; Walker, K. L.; Wilkins, C.
L.; Moore, J . S. J . Am. Chem. Soc. 1995, 117, 2159-2165.
(9) (a) Sanford, E. M.; Fre´chet, J . M. J .; Wooley, K. L.; Hawker, C.
J . Polym. Prepr. 1993, 34, 654-655. (b) Wooley, K. L.; Hawker, C. J .;
Fre´chet, J . M. J . Angew. Chem., Int. Ed. Engl. 1994, 33, 82-85.
10.1021/jo990776m CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/11/1999

Laser Dye-Labeled Poly(aryl ether) Dendrimers
J . Org. Chem., Vol. 64, No. 20, 1999 7475
Ta ble 1. Com p a r ison of P er ip h er a l a n d Cor e Gr ou p s in
Cla ssica l a n d “Rever sed ” Den d r on s
group may well affect the electronic properties of the
attached chain-end moieties. For example, amidation of
the coumarin 2 laser dye would significantly reduce the
magnitude of the intramolecular charge transfer which
is at the origin of its excellent optical properties. In turn,
this would affect our ability to predict the position of
absorption and emission maxima, the magnitude of the
molar extinction coefficient, and the fluorescence quan-
tum yield.
F igu r e 1. Distribution of the reactive groups in the “classical”
and “reversed” poly(aryl ether) dendrimers.
Another possible option for attaching the dyes onto the
dendritic backbone without altering their optical proper-
ties involves utilization of appropriately functionalized
spacer groups. However, this possibility was eliminated
since a key requirement of an efficient dendritic antenna
operating through a Fo¨rster mechanism is that the
interacting chromophores be kept at a minimum dis-
tance.11 Moreover, the increased flexibility resulting from
the presence of any spacer might lead to undesired
interactions such as aggregation, excimer formation, and
dye self-quenching between the numerous terminal groups.
A little known strategy (Figure 1) that still makes use
of the efficient coupling reactions that we first introduced
with the convergent method but “reverses” focal and
terminal functionalities was described by Hanson and co-
workers, along with a later variant by Ho¨ger.14 This
“reversed” strategy provides an additional entry to poly-
(aryl ether) dendritic macromolecules, thus adding even
more flexibility to the general convergent synthesis of this
type of architecture. Although the poly(aryl ether) struc-
tures resulting from the two strategies are different
(Figure 1), it may reasonably be expected that their
chemical stability, solubility, and some of their other
properties, with the notable exception of the “antenna”
effect,3a,b will be closely related.10
By contrast, this minor skeletal variation results in two
surprisingly different synthetic schemes: foremost, the
monomer used to build the reversed dendritic structure
should be a protected 3,5-bis(bromomethyl)phenol, in-
stead of the widely used 3,5-dihydroxybenzyl alcohol2
(Figure 1). In the case of the reversed strategy, the
additional need to first synthesize the monomer (as
opposed to obtaining it directly from commercial sources)
is balanced by the great variety of commercially available
phenols and amines, which, in turn, provides easy access
to a wide range of surface functionalities. The use of a
protecting group at the focal point of the growing den-
drons is an additional feature that allows the activation
step of the classical convergent growth to be replaced by
a simple deprotection reaction. The protecting group may
be chosen among the numerous phenol protecting groups
reported in the literature15 to ensure that its cleavage is
regioselective and compatible with the various function-
alities on the dendron. In addition, the absence of a
benzyl alcohol functionality either on the monomer or on
the dendron (Figure 1) allows for the use of bases
stronger than K2CO3 for the coupling step, as long as the
phenol protecting group is stable under these conditions.
(10) (a) Hawker, C. J .; Malmstro¨m, E. E.; Frank, C. W.; Kampf, J .
P. J . Am. Chem. Soc. 1997, 119, 9903-9904. (b) T. H. Mourey, T. H.;
Turner, S. R.; Rubinstein, M.; Fre´chet, J . M. J .; Hawker, C. J .; Wooley,
K. L. Macromolecules 1992, 25, 2401-2406. (c) Hawker, C. J .; Wooley,
K. L.; Fre´chet, J . M. J . J . Am. Chem. Soc. 1993, 115, 4375-4376. (d)
Wooley, K. L.; Klug, C. A.; Tasaki, K.; Schaefer, J . J . Am. Chem. Soc.
1997, 119, 53-58. (e) Wooley, K. L.; Hawker, C. J .; Fre´chet, Pochan,
J . M.; J . M. J . Macromolecules 1993, 26, 1514-1519. (f) Saville, P. M.;
White, J . W.; Hawker, C. J .; Wooley, K. L.; Fre´chet, J . M. J . J . Phys.
Chem. 1993, 97, 293-294. (g) Saville, P. M.; Reynolds, P. A.; White,
J . W.; Hawker, C. J .; Fre´chet, J . M. J .; Wooley, K. L.; Penfold, J .;
Webster, J . R. P. J . Phys. Chem. 1995, 99, 8283-8289. (h) Hawker, C.
J .; Farrington, P. J .; Mackay, M. E.; Wooley, K. L.; Fre´chet, J . M. J . J .
Am. Chem. Soc. 1995, 117, 4409-4410.
(11) (a) Gilat, S. L.; Adronov, A.; Fre´chet, J . M. J . Polym. Mater.
Sci. Eng. 1997, 77, 91-92. (b) Gilat, S. L.; Adronov, A.; Fre´chet, J . M.
J . Angew. Chem., Int. Ed. Engl. 1999, 38, 1422-1427.
(12) Leon, J . W.; Kawa, M.; Fre´chet, J . M. J . J . Am. Chem. Soc. 1996,
118, 8847-8859.
Resu lts a n d Discu ssion
Several multistep syntheses of protected 3,5-bis(halo-
genomethyl)phenols involving protecting groups such as
(13) (a) Leduc, M. R.; Hayes, W.; Fre´chet, J . M. J . J . Polym. Sci.
Part A: Polym. Chem. 1998, 36, 1-10. (b) Hayes, W.; Leduc, M. R.;
Leon, J . W.; Fre´chet, J . M. J . Polym. Mater. Sci. Eng. 1997, 77, 143-
144.
(14) (a) Tyler, T. L.; Hanson, J . E. Polym. Mater. Sci. Eng. 1995,
73, 356-357. (b) Ho¨ger, S. Synthesis 1997, 20-21.
(15) (a) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991. (b) Kocienski,
P. J . In Protecting Groups: Thieme Foundations of Organic Chemistry
Series; Endres, D., Noyori, R., Trost, B. M., Eds.; Georg Thieme
Verlag: Stuttgart, 1994.

7476 J . Org. Chem., Vol. 64, No. 20, 1999
Gilat et al.
-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride24 (EDC) and a catalytic amount of (dimethylamino)-
pyridine (DMAP), afforded the first-generation (G-1) dye-
labeled dendron 7 in 93% yield (Scheme 1). The same
esterification reaction was also carried out with the
commercial 3,5-dimethylphenol to afford model com-
pound 8, the analogue of 7 lacking the donor (coumarin
2) chromophores (Scheme 1). In these and other esteri-
fication reactions, EDC was preferred to dicyclohexyl-
carbodiimide (DCC), since the urea byproduct is water
soluble and therefore easier to remove.24 The use of
DPTS, the 1:1 molecular complex between DMAP and
para-toluenesulfonic acid (PTSA), touted as an efficient
catalytic system for esterification reactions,25 afforded
only low yields of product in our case.
Following a standard convergent strategy,2 coupling of
the phenol 6 to the methyl ether protected monomer 3,
under typical Williamson ether synthesis conditions (K2-
CO3 and 18-crown-6 in refluxing acetone), afforded the
dye-labeled, methyl ether protected second-generation (G-
2) dendron 9 in 81% yield (Scheme 2). However, all our
attempts to obtain the corresponding G-2 phenol 10 using
BBr3 under a number of reaction conditions failed. The
lack of regioselectivity for cleavage of the methyl ether
focal point versus the benzyl ethers of the dendritic
structure led to the recovery of only the phenol 6.
Additionally, the use of lithium diphenylphosphine26 to
effect this deprotection proved unsuccessful. Therefore,
the methyl ether protecting group is only useful in the
preparation of the G-1 dendron 7, and an alternative
protecting group had to be found for the synthesis of dye-
labeled dendrons of higher generation.
F igu r e 2. Structure of the current, lipophilic hypermonomer
(A) and its previous, hydrophilic analogue (B).
methyl,16 octadecyl,17 or tert-butyldimethylsilyl18 (TB-
DMS) ethers and mesylate or hexadecanesulfonate have
been described.14 The single-step synthesis of 3,5-bis-
(bromomethyl)anisole (3) by bromination of 3,5-dimethyl-
anisole 1 (Figure 2) with NBS has also been described,19
although characterization of the obtained product is poor
and even inconsistent with previous literature data.16 In
fact, more recent work on the bromination of methyl-
substituted anisoles with NBS20 shows that this reaction
may be accompanied by side reactions in which ring
bromination is favored over side-chain bromination. In
the case of 3,5-dimethylanisole 1, reaction with 2 equiv
of NBS under irradiation did not afford the expected 3,5-
bis(bromomethyl)anisole (3), but gave 4-bromo-3-(bro-
momethyl)-5-methylanisole instead.
Using 1.8 equiv of NBS in refluxing CCl4 under
irradiation and in the presence of trace amounts of
benzoyl peroxide, we obtained both 3-bromomethyl-5-
methyl-anisole21 (2) and 3,5-bis(bromomethyl)anisole (3)
in 18% and 35% yield, respectively (Scheme 1). The two
products can be separated by column chromatography,
and their characterization is consistent with the assigned
structures and literature data.16 Though 3,5-bis(bromo-
methyl)anisole is our main target, the product of mono-
bromination, 2, might also prove useful in the prepara-
tion of dendrimers bearing a single terminal dye at the
periphery. Reaction of the bis(bromomethyl)anisole (3)
with 3 equiv of coumarin 2 in refluxing acetonitrile for 3
days, using potassium carbonate as a base,22 afforded the
dye-labeled anisole 4 in 85% yield (Scheme 1). A hydroly-
sis byproduct, the anisole bearing a single coumarin 2
and a hydroxymethyl group at the 5 position (5), was also
isolated in 6% yield.
We consequently employed the hexadecanesulfonate
protecting group, since it has been shown14 that it can
be readily cleaved by strong bases without altering the
poly(aryl ether) dendritic structure. Moreover, the hexa-
decane chain introduces a large difference in polarity
between the starting phenol and the protected product,
facilitating their chromatographic separation, even at
higher generations.14 An added advantage of this protect-
ing group is the extra crystallinity it imparts on all the
protected products, allowing their ready isolation and
purification. Although coumarins were chosen as the focal
and terminal chromophores because of their relatively
good solubility, in addition to their excellent optical
properties,11 the solubility enhancement provided by the
long alkyl chain represented a decisive advantage since
many other dye derivatives tend to be extremely insoluble
and hence difficult to use.
Cleavage of the methyl ether protecting group of 4 to
afford the corresponding phenol 6 was achieved regiose-
lectively in 99% yield by reaction with boron tribromide
in dichloromethane23 (Scheme 1). Finally, acylation of the
phenol 6 with an excess of coumarin 343, using 1-(3-
Protected monomer 14 was obtained by first reacting
the commercially available dimethyl 5-hydroxyisophtha-
late 11 with 1-hexadecanesulfonyl chloride to give 12 in
91% yield27 (Scheme 3). Mild reduction of the ester
functionalities with KBH4, in dry THF and in the
presence of anhydrous LiCl,28 afforded the bis(hydroxy-
methyl) protected phenol 13 in 82% yield. No cleavage
(16) (a) Dewey, T. M.; Du Bois, J .; Raymond, K. N. Inorg. Chem.
1993, 32, 1729-1738. (b) Zimmerman, H. E.; J ones, G., II. J . Am.
Chem. Soc. 1970, 92, 2753-2761. (c) Boekelheide, V.; Griffin, R. G.,
J r. J . Org. Chem. 1969, 34, 1960-1961.
(17) Murray, M. M.; Kaszynski, P.; Kaisaki, D. A.; Chang, W.;
Dougherty, D. A. J . Am. Chem. Soc. 1994, 116, 8152-8161.
(18) Huck, W. T. S.; van Veggel, F. C. J . M.; Kropman, B. L.; Blank,
D. H. A.; Keim, E. G.; Smithers, M. M. A.; Reinhoudt, D. N. J . Am.
Chem. Soc. 1995, 117, 8293-8294.
(19) Karlin, K. D.; Nasir, M. S.; Cohen, B. I.; Cruse, R. W.; Kaderli,
S.; Zuberbu¨hler, A. D. J . Am. Chem. Soc. 1994, 116, 1324-1336.
(20) Gruter, G.-J .; Akkerman, O. S.; Bickelhaupt, F. J . Org. Chem.
1994, 59, 4473-4481.
(24) (a) Sheehan, J . C.; Cruickshank, P. A.; Boshart, G. L. J . Org.
Chem. 1961, 26, 2525-2528. (b) Sheehan, J . C.; Preston, J .; Cruick-
shank, P. A. J . Am. Chem. Soc. 1965, 87, 2492-2493. (c) Desai, M. C.;
Stephens Stramiello, L. M. Tetrahedron Lett. 1993, 34, 7685-7688.
(25) Moore, J . S.; Stupp, S. I. Macromolecules 1990, 23, 65-70.
(26) Ireland, R. E.; Walba, D. M. Org. Synth. 1967, IV, 567-570.
(27) Crossland, R. L.; Servis, K. L. J . Org. Chem. 1970, 35, 3195-
3196.
(21) Kuck, D.; Paisdor, B.; Gru¨tzmacher, H.-F. Chem. Ber. 1987, 120,
589-595.
(22) Bencini, A.; Burguete, M. I.; Garcia-Espana, E.; Luis, S. V.;
Miravet, J . F.; Soriano, C. J . Org. Chem. 1993, 58, 4749-4753.
(23) (a) Grieco, P. A.; Nishizawa, M.; Oguri, T.; Burke, S. D.;
Marinovic, N. J . Am. Chem. Soc. 1977, 99, 5773-5780. (b) Demuynck,
M.; De Clercq, P.; Vandewalle, M. J . Org. Chem. 1979, 44, 4863-4866.
(28) Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J .
Org. Chem. 1987, 52, 1252-1255.

Laser Dye-Labeled Poly(aryl ether) Dendrimers
J . Org. Chem., Vol. 64, No. 20, 1999 7477
Sch em e 1
Sch em e 2
Sch em e 3
were then converted to the corresponding benzyl bromide
functionalities using CBr4 and PPh3 in dry THF2 to afford
the hexadecanesulfonate protected monomer 14 in 90%
yield. The dye-labeled phenol (c2)2-[G-1]-OH 6 could
again be obtained using this new monomer: reaction of
14 with coumarin 2 afforded the dye-labeled hexadecane-
sulfonate protected phenol 15 in 67% yield, which was
of the sulfonate group during the reductive step could
be detected by H NMR. The two benzyl alcohol groups
1

7478 J . Org. Chem., Vol. 64, No. 20, 1999
Gilat et al.
Sch em e 4
then regioselectively deprotected in 82% yield with sodi-
um hydroxide in refluxing absolute ethanol (Scheme 3).29
The utility of the hexadecanesulfonate protected mono-
mer 14 clearly emerges in the synthesis of the second-
and third-generation dendrons. Following a standard
convergent strategy,2 phenol 6 was first coupled to
monomer 14, again under standard Williamson ether
synthesis conditions, to afford the protected G-2 dendron
16 in 86% yield (Scheme 4). Separation of the product
from the starting phenol proved to be facile as a result
of the long alkyl chain introduced by the protecting group.
Compound 16 was regioselectively deprotected to the
corresponding phenol 10 in 91% yield, using NaOH in
refluxing absolute ethanol.29 Finally, acylation of 10 with
coumarin 343, under conditions similar to those used for
7, afforded the fully labeled G-2 dendron 17 in 85% yield
(Scheme 4).
applications. As a consequence, several attempts to
accelerate the synthesis of poly(aryl ether) dendrimers
have been described,7-9 including the use of a “hyper-
monomer” of the AB4 type,8,9 which allows for the growth
of two generations in a single activation/coupling se-
quence.
Acceler a ted Syn th esis of High er Gen er a tion Den -
d r on s. Our approach to the accelerated synthesis of laser
dye-labeled dendrons involved the novel tetrabromide
hypermonomer 20 (Scheme 4). Deprotection of precursor
13 using NaOH in refluxing ethanol afforded the bis-
(hydroxymethyl)phenol30 18 in 82% yield, which was then
coupled to the protected monomer 14 obtained previously
from the same parent compound. The second-generation
dendron 19 was thus obtained in 97% yield. Conversion
to the tetrabromide 20 was achieved with CBr4 and PPh3
in dry THF (71% yield). In this scheme, all three products
18, 19, and the hypermonomer 20 itself were isolated by
crystallization.
In principle, analogous dendrons of higher generation
could further be elaborated using monomer 14 in a
standard convergent strategy. However, the time-con-
suming stepwise synthesis of dendrimers represents a
major drawback for this type of polymer architecture and
has somewhat hampered their widespread use and
Because of the very nature of the “reversed” strategy,
this novel hypermonomer 20 displays five lipophilic
groups and is therefore extremely soluble in common
organic solvents. In contrast, the corresponding hyper-
(29) Looker, J . H.; Thatcher, D. N. J . Am. Chem. Soc. 1954, 76,
4-788.
(30) Lee, S. M.; Fre´chet, J . M. J .; Willson, C. G. Macromolecules
1994, 27, 5154-5159.

Laser Dye-Labeled Poly(aryl ether) Dendrimers
J . Org. Chem., Vol. 64, No. 20, 1999 7479
Sch em e 5
monomer (Figure 2, B) used in the classical convergent
strategy presents an array of five hydrophilic groups and,
not surprisingly, was found to display poor solubility in
organic solvents. As a consequence, its synthesis and
handling were reported to be relatively difficult.9
The ready availability of the versatile hypermonomer
20 enables a simple modular approach to a great variety
of dendrons of various generations bearing different
surface functionalities. For example, Scheme 5 outlines
the single-step preparation of a broad array of generation
2 dendrons from hypermonomer 20. Functionalization of
the four benzyl bromide functionalities by phenol under
standard Williamson ether synthesis conditions afforded
the phenyl-terminated dendron 21 in 98% yield. Com-
pound 21 could easily be deprotected to the corresponding
phenol 22 (78% yield) and coupled to coumarin 343 using
EDC and DMAP to give the second-generation model
dendron 23 (87%) containing the acceptor dye, but no
donors. Reaction of the hypermonomer 20 with the
hydroxyisophthalate 11 afforded the ester-terminated
second-generation dendron 24 (88% yield). As demon-
strated previously in the case of the classical poly(aryl
ether) structure, ester-terminated dendrimers are of
great significance since they provide easy access to a
number of surface functionalities (namely, carboxylic
acid, acid chloride, benzyl alcohols, amides, and other
esters by transesterification).12,13 Most importantly, func-
tionalization of the four benzyl bromide groups by cou-
marin 2, under strictly anhydrous conditions and using
CaH2 as a base,22 afforded the dye-labeled second-
generation dendron 16 in 76% yield (Scheme 5), previ-
ously obtained in three steps from monomer 14.

7480 J . Org. Chem., Vol. 64, No. 20, 1999
Gilat et al.
Sch em e 6
Finally, coupling of the deprotected G-2 phenol 10 to
hypermonomer 20 quickly afforded the protected fourth-
generation (G-4) dendron 26 (77%, Scheme 6), thus
demonstrating the accelerating effect generated by the
use of the hypermonomer in this modular approach.
Similarly, reaction of the G-1 phenol 6 with hypermono-
mer 20 gave the protected third-generation (G-3) dendron
25 in 81% yield (Scheme 6).
In line with the results obtained for the previous
generations, deprotection of the G-3 dendron 25 with
NaOH proceeded smoothly to yield the corresponding
phenol 27 (77%, Scheme 7). However, starting at genera-
tion 4, cleavage of the sulfonate protecting group using
the same conditions proved to be more difficult. At this
stage, the protected dendron 26, bearing 16 laser dyes
on its periphery, turned out to be completely insoluble
in refluxing ethanol. All our attempts to achieve the
deprotection in this solvent or in higher alcohols, using
different bases in excess, failed. One possible explanation
for this lack of reactivity is the collapse of the dendrimer
on its focal point, prohibiting access of the base to the
buried sulfonate. Alternatively, since a nucleophilic base
is required for the deprotection, attack at the lactone
rings of the multiple and accessible coumarins may be
more likely than at the single sulfonate group of the focal
point. By trying a variety of solvents to “expand” the
dendritic structure, while also monitoring the disappear-
ance of the starting material and the appearance of the
deprotected product by MALDI-TOF spectrometry, the
best conditions for the deprotection were found to involve
the addition of a NaOH solution in ethanol to a DMF
solution of the dendrimer. Though clearly not ideal, this
process could be used to transform the G-4 dendron 26
into the corresponding phenol 28 in 30% yield (Scheme
8). Evidence for lactone ring opening on the peripheral
coumarins was observed through color changes from light
yellow to darker yellow-brown upon addition of base,
which may account for the poor yield of the reaction.

Laser Dye-Labeled Poly(aryl ether) Dendrimers
J . Org. Chem., Vol. 64, No. 20, 1999 7481
Sch em e 7
Finally, acylation of the dendritic phenols 27 and 28 with
coumarin 343 afforded the fully dye-labeled dendrons 29
and 30, in 95% and 85% yield, respectively.
tachment of two G-3 deprotected dendrons 27 to the 3,5-
bis(bromomethyl)benzyl alcohol 32, obtained in three
steps from the commercially available diethyl-5-meth-
oxyisophthalate (Scheme 8), afforded the G-4 protected
dendron 33. Deprotection of 33 proceeded smoothly with
TBAF to yield the alcohol 34 in 60% yield (Scheme 8).
This molecule could be coupled to coumarin 343 using
the same EDC/DMAP conditions, to yield the slightly
modified G-4 fully dye-labeled dendrimer 35 in 76% yield.
Compound 35 is extremely similar to 30 and is altered
only by the presence of a methylene group at the core.
Preliminary steady-state fluorescence measurements
indicate that energy transfer from the peripheral donor
coumarins (coumarin 2) to the core acceptor (coumarin
343) is highly efficient. Energy-transfer efficiencies at
each dendrimer generation were calculated by studying
fluorescence quenching of the donor dyes in the presence
of the acceptor. It was found that, for the first three
generations, energy transfer is greater than 97% efficient.
Alter n a tive P r otectin g Gr ou p . The low yield of the
deprotection step in the fourth generation demonstrates
the difficulty in balancing the need for a highly reactive
nucleophile for core deprotection with the need for
preserving the somewhat fragile coumarin dyes at the
periphery. The poor yield achieved in the deprotection
step prompted us to look for an alternative strategy for
the assembly of the G-4 dendron. We eventually chose
to use the more classical tert-butyldiphenylsilyl (TBDPS)
protecting group, since its deprotection with tetrabutyl-
ammonium fluoride (TBAF) is well documented and
highly selective.15 However, to implement this protecting
group, a significant change in the dendrimer focal point
had to be made. The protected phenolic core functionality
was replaced by a protected benzyl alcohol that confers
greater stability to the chosen protecting group.15a At-

7482 J . Org. Chem., Vol. 64, No. 20, 1999
Gilat et al.
Sch em e 8
With the larger fourth-generation dendrimer, this ef-
ficiency of energy transfer drops to approximately 90%
as a result of increased distance between donor and
acceptor dyes.31 However, to fully quantify the photopro-
cesses occurring in these dendritic assemblies, it is
necessary to carry out careful quantum yield calculations,
as well as time-resolved measurements. These measure-
ments will be presented in a subsequent publication.32
egy allows for the utilization of the previously described
high-yielding Williamson ether synthesis reactions to
assemble dendrimers with appropriate functionality for
coupling nucleophilic peripheral chromophores and an
electrophilic core chromophore. The hexadecanesulfonate
protecting group was found to have several advantages,
namely, improved solubility, crystallinity, and ease of
purification. However, its usefulness is greatly reduced
at the fourth generation, where solubility problems
hampered its efficient removal. The optical properties,
including the light-harvesting and energy-transfer capac-
ity, of the various dendrimers described in this article
will be reported separately.32
Con clu sion
To carry out accurate photophysical studies on multi-
chromophoric macromolecules, it is necessary to gain
access to a variety of model compounds in order to
deconvolute the contribution of each individual type of
chromophore. In the case of dendrimers, it is also
necessary to identify the effects of increasing the den-
drimer generation. Hence, to carry out the necessary
studies on dendritic systems, a large number of different
structures are required. Our modular approach to the
synthesis of multichromophoric dendrimers, involving a
novel and versatile hypermonomer, allows for the prepa-
ration of not only the target molecules but also the
necessary model compounds. This novel, “reversed” strat-
Exp er im en ta l Section
All reagents were used as received and without further
purification, unless otherwise noted. THF was distilled under
N2 over sodium/benzophenone immediately prior to use. NBS
was recrystallized in water, and 3,5-dimethylanisole was
distilled prior to use. Coumarin 2 and coumarin 343 (laser
grade) were purchased from Acros. Potassium carbonate and
lithium chloride were ground and dried in an oven (170 °C)
overnight. Column chromatography was carried out with
Merck silica gel for flash columns, 230-400 mesh. Preparative
TLC plates were 1 or 2 mm thick Merck silica gel 60 F254 glass
backed plates. Spinning band chromatography was done using
rotors coated with 1 or 2 mm thick TLC grade silica (Aldrich)
layers. IR spectra were recorded on a Mattson Genesis Series
FTIR. NMR spectra were recorded on a Bruker AMX-300,
(31) T. Fo¨rster, Z. Naturforsch. 1949, 4A, 319-27. Fo¨rster, T.
Discuss. Faraday Soc. 1959, 27, 7-17. Stryer, L. Annu. Rev. Biochem.
1978, 47, 819-846.
(32) Adronov, A.; Gilat, S. L.; Fre´chet, J . M. J . Manuscript in
preparation.

Laser Dye-Labeled Poly(aryl ether) Dendrimers
J . Org. Chem., Vol. 64, No. 20, 1999 7483
Bruker AMX-400, or Bruker DRX-500 instrument with TMS
or solvent carbon signal as the standards. Matrix-assisted laser
desorption ionization time-of-flight (MALDI-TOF) mass spec-
trometry was performed on a PerSeptive Biosystems Voyager-
DE spectrometer using delayed extraction mode and with an
acceleration voltage of 20 keV. Samples were prepared33 by
using a 1:20 ratio of analyte (5 mg/mL in THF) to matrix
solution (trans-indoleacrylic acid, 10 mg/mL in THF). Fluo-
rescence spectra were recorded on an SPEX/ISA Fluorolog 3.22
equipped with double excitation and emission monochromators
and a digital photon-counting photomultiplier. Excitation
correction was achieved with a solid-state silicon photodiode.
UV/vis spectra were recorded in toluene (maximum OD < 0.2)
on a Uvicon 933 spectrophotometer, using standard 1 cm
quartz UV cells. Samples for fluorescence measurements were
degassed by bubbling N2 through the solution for 5 min.
Melting points were measured on a Gallenkamp melting point
apparatus. Elemental analyses were performed by MHW
laboratories. Electron impact (EIMS) mass spectra were
obtained using a VG Prospec mass spectrometer operated in
positive ion mode. Detailed NMR data for all compounds are
available in the Supporting Information.
brown powder obtained was recrystallized in ethyl acetate,
yielding a fine, yellowish powder (1.09 g, 95%). Method 2: To
a solution of (c2)2-[G-1]-OHds (15) (475 mg, 5.65 × 10-4 mol)
in 200 mL of absolute ethanol was added a solution of NaOH
(250 mg, 6.25 × 10-3 mol, 11 equiv) in 150 mL of absolute
ethanol. The mixture was stirred and heated to reflux for 3 h,
after which it was brought to pH 5 using dilute (2 M) HCl.
The solvent was evaporated in vacuo, and the residue was
taken up in CH2Cl2, filtered, and chromatographed on silica
gel (8:2 CH2Cl2/ethyl acetate). Yield: 257 mg (82%). MS (EI):
m/z 552 (M+), calcd m/z 552.67. Anal. Calcd for C34H36N2O5‚
H2O (570.68): C, 71.56; H, 6.71; N, 4.91. Found: C, 71.58; H,
6.92; N, 4.72.
(c2)2-[G-1]-C343 (7). An orange solution of (c2)2-[G-1]-OH
(100 mg, 0.181 mmol), coumarin 343 (2 equiv, 0.361 mmol,
103 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (EDC) (2.5 equiv, 0.454 mmol, 87.0 mg), and
(dimethylamino)pyridine (DMAP) (0.2 equiv, 36.19 mmol, 5.4
mg) in CH2Cl2 (2 mL) was stirred for 72 h at room temperature.
After addition of water (2 mL), the organic phase was
separated, washed with aqueous HCl (0.5N, 4 × 2 mL),
saturated NaHCO3 (4 × 2 mL), and water (2 × 2 mL), dried
over Na2SO4, and chromatographed twice on silica gel (pre-
parative TLC, 9:1 CH2Cl2/EtOAc, then 9:1 CH2Cl2/Et2O) to give
an orange powder (138 mg, 93%). MS (MALDI): m/z 816.9
(M+), calcd m/z 819.9. UV/vis (CH2Cl2): λmax (ꢀ) ) 343, 437 nm
3,5-Bis(br om om eth yl)a n isole (3). A yellow, heteroge-
neous solution of 3,5-dimethylanisole (5.01 g, 36.8 mmol),
N-bromosuccinimide (1.80 equiv, 66.2 mmol, 11.8 g), and traces
of benzoyl peroxide (0.04 mol %, 15.0 mmol, 3.50 mg) in CCl4
(90.0 mL) was heated at reflux with vigorous stirring for 14 h
under irradiation (120 W standard white bulb). The resulting
brownish heterogeneous mixture was filtered, and the filtrate
was washed with water (100 mL), saturated aqueous NaHCO3
(100 mL), and again with water (100 mL), dried on Na2SO4,
and concentrated in vacuo. Column chromatography on silica
gel (9:1 hexanes/chloroform) afforded two major products. After
evaporation of the solvent in vacuo, the first (Rf ) 0.35) was a
clear oil that crystallized slowly at room temperature to give
colorless crystals of 3-(bromomethyl)-5-methylanisole (1.46 g,
19% based on the anisole). The second product (Rf ) 0.2) was
a white powder, which was further recrystallized in cyclohex-
ane to yield 3,5-bis(bromomethyl)anisole (3.713 g, 35%): white
(25 000, 46 000, respectively). Anal. Calcd for C50H53N3O10
2H2O (855.98): C, 70.16; H, 6.24; N, 4.91. Found: C, 70.15;
H, 5.86; N, 4.91.
‚
3,5-Bis(b r om om et h yl)p h en ol h exa d eca n esu lfon a t e,
(Br )2-[G-1]-OHd s (14). Compound 13 (1.50 g, 3.39 mmol) and
CBr4 (2.5 equiv, 8.47 mmol, 2.25 g) were dissolved in dry THF
(50 mL), and triphenylphosphine (2.5 equiv, 8.47 mmol, 2.22
g) was added in two parts. The reaction mixture was stirred
at room temperature under N2 for 2 h. The solvent was
evaporated in vacuo and the residue was filtered over a short
plug of silica gel (eluted with 6:4 hexanes/CH2Cl2), affording
a white solid (1.636 g; 85%), mp 81-83 °C. HRMS (EI): m/z
calcd for C24H40O3S81Br2 570.1024, found 570.1016.
needles; mp 75-76 °C (lit.20 76-76.5 °C); Anal. Calcd for C9H10
Br2O (293.98): C, 36.77; H, 3.43. Found: C, 36.85; H, 3.60.
-
(c2)4-[G-2]-OHd s (16). Method 1: A yellow, heterogeneous
solution of 14 (0.905 g, 1.59 × 10-3 mol), 6 (1.90 g, 3.44 × 10-3
mol, 2.2 equiv), K2CO3 (1.33 g, 9.62 × 10-3 mol, 6.0 equiv),
and 18-crown-6 (0.255 g, 9.65 × 10-4 mol, 0.6 equiv) in acetone
(250 mL) was heated at reflux under Ar with vigorous stirring
for 20 h. The cooled solution was evaporated to dryness in
vacuo, taken up in CH2Cl2, and filtered. The light yellow
solution was then concentrated and purified by chromatogra-
phy on silica gel (9:1 CH2Cl2/ethyl acetate). Yield: 2.35 g (98%).
Method 2: The heterogeneous mixture of 20 (92.0 mg, 9.52 ×
10-5 mol), coumarin 2 (124 mg, 5.71 × 10-4 mol, 6 equiv), and
CaH2 (29 mg, 6.89 × 10-4 mol, 7.2 equiv) in 25 mL of dry CH3-
CN was stirred and heated to reflux for 85 h. The solution
was then cooled and filtered, and the solvent was evaporated
in vacuo. The resulting residue was taken up in CH2Cl2 and
purified by preparative TLC (95:5 CH2Cl2/ethyl acetate).
Yield: 109 mg (76%). MS (MALDI): m/z 1509.4 (M+), calcd
m/z 1511.96. Anal. Calcd for C92H110N4O13S (1511.96): C,
73.08; H, 7.33; N, 3.71. Found: C, 72.85; H, 7.48; N, 3.55.
(Br )4-[G-2]-OHd s (20). The solution of 19 (1.000 g, 1.399
mmol) and CBr4 (6 equiv, 8.392 mmol, 2.783 g) in dry THF
(50 mL) was cooled to 0 °C, and PPh3 (6 equiv, 8.392 mmol,
2.201 g) was added in two parts. The reaction mixture was
stirred at room temperature under N2 for 4 h. The pH was
then adjusted to 7 with saturated Na2CO3 (5 mL), and brine
(50 mL) was added. The aqueous phase was extracted with
CH2Cl2 (3 × 100 mL), and the organic fractions were combined
and concentrated in vacuo. The concentrate was loaded on a
short plug of silica, washed with hexanes (300 mL), and eluted
with 8:2 hexanes/ethyl acetate (300 mL). The product was then
crystallized in hexanes, yielding white crystals (960 mg; 71%),
mp 78-79 °C. Anal. Calcd for C40H54Br4O5S (966.54): C, 49.71;
H, 5.63. Found: C, 49.79; H, 5.52.
3,5-Bis(N-(4,6-dim eth yl-7-eth ylam in ocou m ar in )m eth yl)-
a n isole (or (c2)2-[G-1]-OMe) (4). 3,5-Bis(bromomethyl)-
anisole (690 mg, 2.35 mmol) in CH3CN (10 mL) was added
over 4 h to a mixture of 4,6-dimethyl-7-ethylaminocoumarin
(coumarin 2, 3 equiv, 7.04 mmol, 1.53 g) and K2CO3 (6 equiv,
14.08 mmol, 1.95 g) in CH3CN (60 mL). The reaction mixture
was heated at reflux under argon with vigorous stirring for 3
days. The cooled solution was then filtered, evaporated to
dryness in vacuo, taken up in CH2Cl2, and chromatographed
on silica gel (20:1 CH2Cl2/ethyl acetate), first affording re-
covered coumarin 2 (530 mg, 1.04 equiv, 35%), then (c2)2-
[G-1]-OMe as a white powder (1.14 g, 85%), and finally
3-hydroxymethyl-5-(N-(4,6-dimethyl-7-ethylaminocoumarin)-
methyl)anisole (52.0 mg, 6%). An analyticalsample of (c2)2-
[G-1]-OMe was provided by recrystallization in acetonitrile:
white crystals, mp 195-196 °C; MS (EI) m/z 566 (M+), calcd
m/z 566.69. Anal. Calcd for C35H38N2O5 (566.69): C, 74.18; H,
6.76; N, 4.94. Found: C, 73.93; H, 6.55; N, 4.85.
3,5-Bis(N-(4,6-d im eth yl-7-eth yla m in ocou m a r in )m eth -
yl)p h en ol (or (c2)2-[G-1]-OH) (6). Method 1: To a clear,
homogeneous solution of 3,5-bis(N-(4,6-dimethyl-7-ethylami-
nocoumarin)methyl)anisole (1.18 g, 2.08 mmol) in CH2Cl2 (100
mL) was added dropwise under an Ar atmosphere a solution
of BBr3 in CH2Cl2 (1.0 M, 20.0 mL, 20.0 mmol, 10 equiv). The
solution initially turned green and then pale yellow, with a
white precipitate. After 2 h of vigorous stirring at room
temperature, the mixture was carefully poured in water (200
mL). The clear, colorless organic phase was washed with
NaHCO3 (200 mL) and water (200 mL) and then dried over
Na2SO4. The solvent was evaporated in vacuo, and the yellow-
(c2)8-[G-3]-OHd s (25). The mixture of 20 (0.380 g, 3.93 ×
10-4 mol), 6 (1.00 g, 1.811 × 10-3 mol, 4.6 equiv), K2CO3 (0.691
g, 5.00 × 10-3 mol, 12.7 equiv), and 18-crown-6 (0.150 g,
(33) (a) Leon, J . W.; Fre´chet, J . M. J . Polym. Bull. 1995, 35, 449.
(b) Hayes, W.; Freeman, A.; Fre´chet, J . M. J . Polym. Mater. Sci. Eng.
1997, 77, 136-137.

7484 J . Org. Chem., Vol. 64, No. 20, 1999
Gilat et al.
5.675 × 10-4 mol, 1.4 equiv) in 25 mL of dry acetone was
stirred and heated at reflux under argon for 24 h. It was then
cooled and evaporated to dryness in vacuo to yield a yellow
powder that was taken up in CH2Cl2, filtered, and purified by
chromatography on silica gel (8:2 CH2Cl2/ethyl acetate).
Yield: 0.910 g (81%). MS (MALDI): m/z 2849.0 (M+), calcd
m/z 2853.57. Anal. Calcd for C176H194N8O25S‚4H2O (2925.63):
C, 72.26; H, 6.96; N, 3.83. Found: C, 72.33; H, 7.24; N, 3.77.
(c2)16-[G-4]-OHd s (26). The heterogeneous mixture of 20
(0.226 g, 2.34 × 10-4 mol), 10 (1.30 g, 1.06 × 10-3 mol, 4.5
equiv), K2CO3 (0.394 g, 2.85 × 10-3 mol, 12 equiv), and 18-
crown-6 (0.076 g, 2.88 × 10-4 mol, 1.2 equiv) in dry acetone
(150 mL) was stirred and heated to reflux under argon for 40
h. The reaction mixture was cooled and evaporated to dryness
in vacuo. The residue was then taken up in CH2Cl2, filtered,
and concentrated. The product was purified by column chro-
matography on silica gel (100:4 CH2Cl2/methanol) yielding a
light yellow solid (1.00 g, 77%). MS (MALDI): m/z 5530.3 (M+),
calcd m/z 5536.79. Anal. Calcd for C344H362N16O49S (5536.79):
C, 74.62; H, 6.59; N, 4.05. Found: C, 75.00; H, 6.51; N, 3.96.
Ack n ow led gm en t. The support from the AFOSR-
MURI program and a fellowship from the Kodak
Company (A.A.) are gratefully acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data for all compounds and full experimental details for
compounds 2, 5, 8-13, 15, 17-19, 21-24, and 27-35. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O990776M