Sequences in Dendrons and Dendrimers

Article abstract of DOI:10.1021/jo049878p

Sequential incorporation of a variety of functional groups forms the basis for specificity in biomacromolecules. Introduction of such diversity and sequencing ability in artificial macromolecules is fundamentally interesting. In this paper, three different synthetic approaches have been used to build dendrons and dendrimers in which all the monomer units are different from each other. The synthetic strategies described in this paper involve the use of (i) an ABB_p monomer, (ii) an ABB′ monomer, and (iii) an ABB _m monomer. The complementarity and the versatility of these synthetic approaches should render them useful for a variety of applications.

Full text of DOI:10.1021/jo049878p

Sequ en ces in Den d r on s a n d Den d r im er s
Kulandaivelu Sivanandan, Britto S. Sandanaraj, and S. Thayumanavan*
Department of Chemistry, University of Massachusetts, 701 LGRT-A, 710 North Pleasant Street,
Amherst, Massachusetts 01003
thai@chem.umass.edu
Received J anuary 21, 2004
Sequential incorporation of a variety of functional groups forms the basis for specificity in
biomacromolecules. Introduction of such diversity and sequencing ability in artificial macromolecules
is fundamentally interesting. In this paper, three different synthetic approaches have been used
to build dendrons and dendrimers in which all the monomer units are different from each other.
The synthetic strategies described in this paper involve the use of (i) an ABBp monomer, (ii) an
ABB′ monomer, and (iii) an ABBm monomer. The complementarity and the versatility of these
synthetic approaches should render them useful for a variety of applications.
In tr od u ction
molecule is an excellent choice for biomimicry.5 Several
reports exist on the use of a dendrimer as an effective
mimic of nature from an encapsulation standpoint.6 The
propensity of dendrimers to adopt a globular conforma-
tion at high generations also suggests that these mol-
ecules could be pursued as possible globular protein
mimics.7 Dendrimers are composed mainly of three
structural components: a core, branching units, and
peripheral units. All of these structural components are
important for the dendrimers’ ability to bind guest
molecules. For example, it has been shown that the
The wealth of information storage and function through
the ability to sequence polymers is obvious from the
versatility of nature’s polymers in biology. Proteins and
nucleic acids use only few (20 and 4, respectively)
different monomers to bring about their impressive
structural complexities and functions. With a desire to
further expand the scope of these biopolymers in both
structure and function, several labs seek to expand
functional group variety by manipulating nature’s ma-
chinery.1 An alternate pathway to obtaining diversity in
macromolecules is a bottom-up approach, in which custom-
designed polymers are synthesized with a high degree
of control. Nature’s functional versatility has served as
inspiration to design biomimetic structures for several
years.2 However, most of these structures are small-
molecule-based. Although there are a few examples of
macromolecular biomimetics, the number is surprisingly
low.3
(4) (a) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendrimers
and Dendrons: Concepts, Syntheses, Applications, 2nd ed.; Wiley-
VCH: New York, 2001. (b) Bosman, A. W.; J anssen, H. M.; Meijer, E.
W. Chem. Rev. 1999, 99, 1665-1688. (c) Fischer, M.; Vo¨gtle, F. Angew.
Chem., Int. Ed. 1999, 38, 884-905. (d) Fre´chet, J . M. J . Science 1994,
263, 1710-1715. (e) Matthews, O. A.; Shipway, A. N.; Stoddart, J . F.
Prog. Polym. Sci. 1998, 23, 1-56. (f) Moore, J . S. Acc. Chem. Res. 1997,
30, 402-413. (g) Newkome, G. R.; He, E.; Moorefield, C. N. Chem. Rev.
1999, 99, 1689-1746. (h) Tomalia, D. A. Adv. Mater. 1994, 6, 529-
539. (i) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III. Angew.
Chem., Int. Ed. Engl. 1990, 29, 138-175. (j) Dendrimers II: Architec-
ture, Nanostructure and Supramolecular Chemistry; Vo¨gtle, F., Ed.;
Springer: Berlin, 2000; Vol. 210. (l) Zeng, F.; Zimmerman, S. C. Chem.
Rev. 1997, 97, 1681-1712.
(5) (a) Diederich, F.; Felber, B. Proc. Nat. Acad. Sci. U.S.A. 2002,
59, 4778-4781. (b) Baars, M. W. P. L.; Meijer, E. W. Top. Curr. Chem.
2000, 210, 131-182. (c) Zimmerman, S. C.; Lawless, L. J . Top. Curr.
Chem. 2001, 217, 95-120. (d) Thayumanavan, S.; Bharathi, P.;
Sivanandan, K.; Vutukuri, D. R. C. R. Acad. Sci., Ser. IIc: Chim. 2003,
6, 767-778.
(6) (a) Hecht, S.; Fre´chet, J . M. J . Angew. Chem., Int. Ed. 2001, 40,
74-91. (b) Gorman, C. B.; Smith, J . C. Acc. Chem. Res. 2001, 34, 60-
71. (c) Stone, D. L.; Smith, D. K.; McGrail, P. T. J . Am. Chem. Soc.
2002, 124, 856-864. (d) Smith, D. K.; Diederich, F. Top. Curr. Chem.
2000, 210, 183-227. (e) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.;
Yeung, L. K. Acc. Chem. Res. 2001, 34, 181-190.
(7) (a) Smith, D. K.; Diederich, F. Chem. Eur. J . 1998, 4, 1353-
1361. (b) Dandliker, P. J .; Diederich, F.; Gisselbrecht, J . P.; Louati,
A.; Gross, M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2725-2728. (c)
Mattei, S.; Wallimann, P.; Kenda, B.; Amrein, W.; Diederich, F. Helv.
Chim. Acta 1997, 80, 2391-2417. (d) Habicher, T.; Diederich, F.;
Gramlich, V. Helv. Chim. Acta 1999, 82, 1066-1095. (e) Wallimann,
P.; Mattei, S.; Seiler, P.; Diederich, F. Helv. Chim. Acta 1997, 80, 2369-
2390. (f) J iang, D. L.; Aida, T. Chem. Commun. 1996, 1523-1524. (g)
Bharathi, P.; Zhao, H.; Thayumanavan, S. Org. Lett. 2001, 3, 1961-
1964.
Dendrimers are the only class of artificial macromol-
ecules that can be obtained in high molecular weights in
a monodisperse form.4 Therefore, the branched macro-
(1) (a) Wang, L.; Brock, A.; Herberich, B.; Schultz, P. G. Science
2001, 292, 498-500. (b) Wang, P.; Tang, Y.; Tirrell, D. A. J . Am. Chem.
Soc. 2003, 125, 6900-6906. (c) Wang, L.; Zhang, Z.; Brock, A.; Schultz,
P. G. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 56-61. (d) Kwon, I.;
Kishenbaum, K.; Tirrell, D. A. J . Am. Chem. Soc. 2003, 125, 7512-
7513. (e) Hohsaka, T.; Ashizuka, Y.; Sasaki, H.; Murakami, H.; Sisido,
M. J . Am. Chem. Soc. 1999, 121, 12194-12195. (f) Anderson, R. D.,
III; Zhou, J .; Hecht, S. M. J . Am. Chem. Soc. 2002, 124, 9674-9675.
(2) (a) Lehn, J .-M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304-
1319. (b) Conn, M. M.; Rebek, J . Chem. Rev. 1997, 97, 1647-1668. (c)
Rebek, J . Acc. Chem. Res. 1999, 32, 278-286. (d) Breslow, R.; Dong,
S. D. Chem. Rev. 1998, 98, 1997-2011. (e) Breslow, R. Acc. Chem. Res.
1995, 28, 146-153. (f) Nowick, J . S. Acc. Chem. Res. 1999, 32, 287-
296.
(3) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (b) Hill,
D. J .; Mio, M. J .; Prince, R. B.; Hughes, T. S.; Moore, J . S. Chem. Rev.
2001, 101, 3893-4012. (c) Liu, L.; Rozenman, M.; Breslow, R. J . Am.
Chem. Soc. 2002, 124, 12660-12661. (d) Liu, L.; Breslow, R. J . Am.
Chem. Soc. 2003, 125, 12110-12111. (e) Liu, L.; Breslow, R. J . Am.
Chem. Soc. 2002, 124, 4978-4979.
10.1021/jo049878p CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/26/2004
J . Org. Chem. 2004, 69, 2937-2944
2937

Sivanandan et al.
length of the alkyl chain at the core of an amphiphilic
dendrimer could dictate the location of the hydrophobic
guest molecule.8 Similarly, the solubility of dendrimers
is dependent on the nature of the peripheral functional-
ities, which are therefore crucial for binding events based
on solvophobic forces. Although there has been much
work on varying the core and the periphery of dendrim-
ers, the effect of functional group incorporations within
the branching units has not been studied in detail.
However, it has been noted that the functionalities
present in the branching units have significant effects
on binding or catalysis by the dendrimer.9 The ability to
introduce sequences within dendrimers provides the
opportunity to systematically vary the core, periphery,
and branching units. Also, sequencing methodologies
should provide the possibility of presenting a diverse set
of functional groups in all these locations. Sequencing
dendrimers will open up a number of possibilities for
dendrimers in molecular recognition, especially in bio-
mimetics and catalysis. We believe that the synthetic
methods outlined here will provide the fundamental tools
necessary for those possibilities.
Diversity in functional group display within dendrim-
ers can be achieved through both divergent and conver-
gent approaches. Newkome, Majoral, and others have
reported the incorporation of a few different functional-
ities in dendrimers using divergent methods.10 The
inherent nature of the divergent approach does not allow
precise control over the extent and position of functional
group incorporation. However, this approach is syntheti-
cally much less strenuous and therefore is useful for
certain applications. Since excellent control in the place-
ment of functional groups is desirable for biomimetic
possibilities, the convergent approach is preferred.11 In
fact, convergent synthesis has been used to incorporate
a controlled number of functionalities in the periphery
of dendrimers.12 This was achieved by the stepwise
incorporation of functionalities, where the desired mono-
substituted product in the first step would be obtained
as a statistical mixture with the corresponding undesired
disubstituted product. This approach has its obvious
drawbacks. To introduce sequences within a dendrimer,
F IGURE 1. Strategy to obtain sequenced dendrimers.
the convergent methodology should have the capability
of differentiating the two “B” functionalities in an AB2
monomer as shown in Figure 1.
Because sequenced dendrimers with different sets of
backbone functionalities and connectivities are likely to
emerge in the literature, availability of several comple-
mentary methodologies is desirable. We have introduced
two complementary methods for the synthesis of den-
drons in which the functionalities in the periphery are
different from one another:13 (i) through the stepwise
incorporation of two different functional groups to an
ABBp monomer and (ii) through an ABB′ monomer, in
which the reactivities of B and B′ are different. These
two methodologies can be used to synthesize dendrimers
in which each monomer unit is different. In addition, we
also introduce here a third complementary synthetic
method using ABBm building block. In this paper, we
utilize these methodologies to introduce sequences within
dendrimers. To our knowledge, this is the first report in
which each monomer unit is different from the other
within a dendrimer. The dendrimers reported here are
based on arylalkyl ether dendrimers, since one of our
long-term goals is to incorporate various functionalities
in specific locations of the benzyl ether based amphiphilic
dendrimers that we previously reported.7g It should be
noted, however, that the conceptual aspects of these
methodologies could be applied to any set of backbone
functionalities.
(8) Watkins, D. M.; Sayed-Sweet, Y.; Klimash, J . W.; Turro, N. J .;
Tomalia, D. A. Langmuir 1997, 13, 3136-3141.
(9) For examples, see: (a) Daniel, M. C.; Ruiz, J .; Astruc, D. J . Am.
Chem. Soc. 2003, 125, 1150-1151. (b) Piotti, M. E., J r.; F. R.; Bond,
R.; Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1999, 121, 9471-
9472. (c) Koenig, S.; Mu¨ller, L.; Smith, D. K. Chem. Eur. J . 2001, 7,
979-986.
Resu lts a n d Discu ssion
Ba sed on a n ABBp Mon om er . In this approach, one
of the B functionalities is protected with an easily
removable protecting group. To synthesize a G-1 dendron
in which all three monomer units are different from each
other, three steps are involved: (i) reaction of the first
monomer with the unprotected B, (ii) deprotection of the
Bp moiety, and (iii) reaction of the second monomer with
the newly liberated B. In the case of dihydroxybenzyl
alcohol, one of the phenolic groups is protected. The
protecting groups that have been used include allyl,
benzoyl, and methoxymethyl ether moieties. We have
(10) (a) Newkome, G. R.; Weis, C. D.; Moorefield, C. N.; Baker, G.
R.; Childs, B. J .; Epperson, J . Angew. Chem., Int. Ed. 1998, 37, 307-
310. (b) Newkome, G. R.; Kim, H. J .; Moorefield, C. N.; Maddi, H.;
Yoo, K.-S. Macromolecules 2003, 36, 4345-4354. (c) Newkome, G. R.;
Yoo, K. S.; Hwang, S.-H.; Moorefield, C. N. Tetrahedron 2003, 59,
3955-3964. (d) Larre´, C.; Donnadieu, B.; Caminade, A.-M.; Majoral,
J .-P. J . Am. Chem. Soc. 1998, 120, 4029-4030. (e) Latigue, M.-L.;
Slany, M.; Caminade, A.-M.; Majoral, J .-P. Chem. Eur. J . 1996, 2,
1417-1426. (f) Woller, E. K.; Walter, E. D.; Morgan, J . R.; Singel, D.
J .; Cloninger, M. J . J . Am. Chem. Soc. 2003, 125, 8820-8826.
(11) Grayson, S. M.; Fre´chet, J . M. J . Chem. Rev. 2001, 101, 3819-
3868.
(12) (a) Wooley, K. L.; Hawker, C. J .; Fre´chet, J . M. J . J . Chem.
Soc., Perkin Trans. 1 1991, 1059-1076. (b) Bo, Z.; Scha¨fer, A.; Franke,
P.; Schlu¨ter, A. D. Org. Lett. 2000, 2, 1645-1648. (c) Ganesh, R. N.;
Shraberg, J .; Sheridan, P. G.; Thayumanavan, S. Tetrahedron Lett.
2002, 43, 7217-7220. (d) For differential substitutions in layer by
layer, see: Freeman, A. W.; Chrisstoffels, L. A. J .; Fre´chet, J . M. J . J .
Org. Chem. 2000, 65, 7612-7617. (e) For synthesis of dendrimers using
different branching structures in one pot, see: Okaniwa, M.; Takeuchi,
K.; Asai, M.; Ueda, M. Macromolecules 2002, 35, 6224-6231; 6232-
6238.
(13) (a) Sivanandan, K.; Vutukuri, D.; Thayumanavan, S. Org. Lett.
2002, 4, 3751-3753. (b) Vutukuri, D.; Sivanandan, K.; Thayumanavan,
S. Chem. Commun. 2003, 796-797. (c) Simanek and co-workers
reported a methodology in which the differential reactivities of di-,
mono-, and unsubstituted cyanuric chloride have been utilized. See:
Zeng, W.; Nowlan, D. T., III; Thomson, L. M.; Lackowski, W. M.;
Simanek, E. E. J . Am. Chem. Soc. 2001, 123, 8914-8922.
2938 J . Org. Chem., Vol. 69, No. 9, 2004

Sequences in Dendrimers
SCHEME 1
SCHEME 2
hydride followed by benzyl bromide affords the product
8 in 93% yield. The allyl functionality of 8 was then
converted to hydroxypropyl by hydroboration to afford
9. Conversion of the hydroxyalkyl group to the corre-
sponding bromomethyl moiety was achieved using triph-
enylphosphine and NBS. Further elaboration to higher
generations can be carried out by repeating these steps
with different sets of monomer units.
developed facile deprotection strategies for all these
protecting groups. An example is shown in Scheme 1, in
which a methoxymethyl ether (MOM) functionality is
used as the protecting group. Treatment of 1 with
m-bromobenzyl bromide in the presence of potassium
carbonate provides the monosubstituted product 2. Treat-
ment of 2 with Dowex resin in methanol resulted in the
cleavage of the MOM group, and the reaction of the
resulting phenolic compound 3 with a second electrophile,
decyl iodide, provides the unsymmetrically substituted
first generation dendron 4. The ester moiety in 4 was
reduced to the alcohol 5 using borane-dimethyl sulfide
complex. The overall yield of 5 from 1 was 90%. Note that
the intermediates shown in this scheme were not iso-
lated. The overall yield of the 3-mer from the ABBp
monomer compares favorably with the classical synthesis
of reacting 2 equiv of benzyl bromide with 3,5-dihydroxy-
benzyl alcohol.14 The hydroxymethyl group of compound
5 was converted to a bromomethyl moiety using triph-
enylphosphine and N-bromosuccinimide (NBS) to afford
5-Br in 87% yield.
Ba sed on a n ABB′ Mon om er . The inherently dif-
ferential reactivities of two different functional groups
within a monomer unit under certain reaction conditions
can also be used to achieve multifunctional dendrons. In
this approach, the active form of A can readily react with
B under a set of reaction conditions. Under this condition,
B′ is either unreactive or much less reactive. This affords
the selective incorporation of the first monomer unit on
to B. Incorporation of the second monomer unit is then
carried out under a different set of conditions in which
B′ is reactive with A. An example is outlined in Scheme
2, where the differential reactivity of the phenolic and
the hydroxyalkyl functionalities toward the alkyl halide
electrophiles is exploited. Treatment of 6 with m-meth-
ylbenzyl bromide with potassium carbonate as the base
affords the monosubstituted product 7 in 79% yield.
Under these conditions, the hydroxymethyl group is
unreactive toward the alkyl halide electrophile. Treat-
ment of the monosubstituted compound 7 with sodium
Ba sed on a n ABBm Mon om er . In this approach, the
B or B′ moiety is masked as a different functionality until
the first reaction between A and B is completed. This
allows for flexibility in the reaction conditions that could
be used to react A with the first B. The second B moiety
is then unmasked to install the second monomer unit.
An example of this approach is outlined in Scheme 3. To
demonstrate the possibility, we utilized the monomer 10
as the starting material. Treatment of 10 with potassium
carbonate and an electrophilic alkyl halide provided the
monosubstituted product 11 in 85% yield. The allyl
moiety was then hydroborated in order to unmask it as
a hydroxyalkyl group. The resultant product 12 was then
treated with sodium hydride and a second alkyl halide
to afford the unsymmetrically substituted product. The
ester moiety of this compound was then reduced to the
corresponding hydroxymethyl moiety to obtain 13. Ela-
boration of this dendron to higher generation could
then be carried out through the benzyl alcohol moiety
of 13.
Com p a r ison of th e Th r ee Meth od ologies. It is
immediately obvious that the number of steps involved
in all three methodologies described above is more than
the classical synthesis of dendrimers. However, we
rationalized that if the synthetic steps are achieved in
high yields, then the benefits of being able to differentiate
each monomer within a dendrimer far outweigh the
rather small increase in the number of synthetic steps.
Note also that even the well-known syntheses of polypep-
tides involve protection-deprotection strategies to intro-
duce an appropriate sequence. Within the three methods
described above, the ABB′ method is capable of providing
the products with one less step per iteration. In the
particular set of functionalities that we have chosen, it
requires two steps to unmask the functionality A from
an ester moiety to a bromomethyl group. This is mainly
due to our particular interest in arylalkyl ether dendrim-
(14) Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112,
7638-7647.
J . Org. Chem, Vol. 69, No. 9, 2004 2939

Sivanandan et al.
SCHEME 3
SCHEME 4
ers for the reasons mentioned above. However, note that
with a judicial choice of functionalities, it is easily
imaginable to reduce the number of unmasking steps to
one. Despite one more step per iteration in the other two
methodologies, those approaches are useful complements
to the ABB′ methodology.
The difference between the ABBp and ABBm method-
ologies is subtle. In the former case, the two B function-
alities are the same and one of them is protected. In the
latter case, the only requirement is that both B and the
unmasked form of Bm are reactive toward A. The two B
functionalities (from B and the unmasked form of Bm)
can be exactly the same or different. In the particular
example outlined above, the reactivity of the unmasked
form Bm is very different from that of B.
The preference for which methodology one should
choose for sequencing a dendrimer depends on a few
factors. If one prefers identical linkages between the
monomer units and if efficient protection-deprotection
strategies have been developed, then the ABBp monomer-
based methodology is the preferred approach. If differ-
ences in linkages could be tolerated or if the number of
steps per iteration is an important criteria, then the ABB′
method should be chosen. If different linkages could be
tolerated but two different reaction conditions in which
B and B′ react with A could not be identified, then the
preferred method should be based on an ABBm monomer.
Additionally, the choice of the method will depend on the
nature of the linkages that connect the building blocks,
other functional groups present in various monomers,
and the compatibility of the dendrimer assembly reaction
conditions to those functional groups. Considering the
variables that could dictate the choice, the availability
of three complementary synthetic methodologies should
prove useful.
ferent 3-mer dendrons are needed, and they have been
assembled using the methodologies described above. For
example, the 3-mer dendron 16 was assembled using the
ABB′ methodology, as outlined in Scheme 4. The starting
material 14 was synthesized from dihydroxybenzyl al-
cohol and bromoethanol. Treatment of this compound
with potassium carbonate and p-bromobenzyl bromide,
followed by sodium hydride and o-methylbenzyl bromide,
affords the unsymmetrically substituted product 15 with
75% overall yield. Note that these two alkylation steps
above were carried out in one pot, although the alkylation
conditions are very different from each other. Reduction
of the ester moiety of 15 affords the 3-mer dendron 16 in
96% yield.
Treatment of the benzoyl-protected monomer unit 17
with potassium carbonate and the G-1 dendron 18
afforded the corresponding 4-mer dendron 19. The syn-
thesis of the 3-mer dendron 18 was achieved using an
ABB′ repeating unit. Reaction of 19 with BH3‚DMS
provided the corresponding benzyl alcohol while simul-
taneously deprotecting the benzoyl protecting group to
afford 20. Because of some inseparable impurities in 19
and 20, these compounds were taken to the next step
without further characterization. Reaction of compound
20 with potassium carbonate and the bromomethyl
version of the 3-mer dendron 16 provided the 7-mer
dendron 21 in 49% overall yield. The hydroxymethyl
group at the focal point of 21 was converted to the
corresponding bromomethyl moiety using triphenylphos-
phine and NBS to afford the compound 22. The synthetic
protocol is outlined in Scheme 5.
Synthesis of the 7-mer dendron 25 was achieved using
a reaction sequence similar to that outlined in Scheme
5. The 3-mer dendrons used in this case were the
bromoalkyl versions of 5 and 9. The bromoalkyl com-
pounds were synthesized from the corresponding hy-
droxymethyl compounds using triphenylphosphine and
NBS as the reagent. The core unit for this dendron was
Sequ en cin g Den d r on s. A G-3 monodendron in which
each monomer unit is different from the other has been
synthesized. To assemble this macromolecule, four dif-
2940 J . Org. Chem., Vol. 69, No. 9, 2004

Sequences in Dendrimers
SCHEME 5
derived from the monomer 23, which was easily synthe-
sized from 3,5-dihydroxybenzoic acid.
G-1, G-2, and G-3 dendrons are shown in Figure 3, to
illustrate that these molecules are clean and monodis-
perse macromolecules.
Sequ en cin g Den d r im er s. In addition to synthesizing
multifunctional monodendrons, the synthetic approaches
outlined above can also be used to bring about functional
group diversity in didendrons and tridendrons. To dem-
onstrate this possibility, we synthesized didendrons or
tridendrons with different monomer units. To synthesize
a didendron, we used 4,4′-biphenol as the core unit. The
sequential introduction of two different monodendrons
onto the biaryl core was accomplished using the protec-
tion-deprotection methodology. One of the phenolic groups
of 4,4′-biphenol was protected with a MOM group to
afford the core unit 28. Treatment of 28 with potassium
carbonate and 25 afforded the corresponding monosub-
stituted 8-mer compound in 96%yield. The MOM group
was then deprotected using catalytic amount of PTSA in
The 15-mer dendron 27 was synthesized using the
protocols similar to those outlined in Scheme 5. The
7-mer dendron 22 was treated with 26 in the presence
of potassium carbonate to afford the corresponding 8-mer
dendron.15 Reduction followed by the incorporation of the
second 7-mer dendron 25 afforded the 15-mer dendron
27 in 90% yield. All 15 monomer units within the G-3
dendron 27 are different from each other. The variations
within the monomer units is due either to the functional-
ity present in the aryl ring or to the linker that is used
to attach to the next monomer unit. The different
monomer units within the dendron 27 are identified with
different colors for each monomer unit in Figure 2. The
size exclusion chromatography (SEC) elution profiles of
(15) Compound 26 was obtained from 5-bromo-resorcinol, which was
synthesized from 3,5-dimethoxybenzoic acid using the procedures
reported in: Dol, G. C.; Kamer, P. C. J .; van Leeuwen, P. W. N. M.
Eur. J . Org. Chem. 1998, 359, 9-364.
F IGURE 2. Structure of a multifunctional 15-mer monoden-
dron.
J . Org. Chem, Vol. 69, No. 9, 2004 2941

Sivanandan et al.
SCHEME 6
methanol and dioxane in 80% yield. The resultant
product was then treated with the 7-mer dendron 22 to
afford the didendron 29 in 89% yield, as outlined in
Scheme 6.
trifunctional core), 33 (two dendrons installed) and 34
(tridendron) are shown in Figure 4.
Su m m a r y
To synthesize a tridendron, we need to introduce three
different monodendrons sequentially on to a central core
unit. The core unit chosen was ethyl-3-hydroxy-5-hy-
droxymethylbenzoate (30). Here, we used both the dif-
ferential reactivity of phenolic and hydroxyalkyl func-
tionalities along with the unmasking of another hydroxy-
alkyl group from an ester functionality. The phenolic
moiety of 30 was first reacted with a 3-mer dendron 31
to afford the corresponding 4-mer 32.16 Compound 32 was
then treated with sodium hydride followed by the bro-
momethyl version of the 3-mer dendron 16 to afford the
corresponding 7-mer 33. Reduction of the ester moiety
with BH3‚DMS followed by the alkylation of the resultant
hydroxymethyl moiety with the 3-mer dendron 34 af-
forded the 10-mer tridendron 35 in 74% yield. The
synthetic approach is outlined in Scheme 7. The SEC
elutions of compounds 32 (one dendron installed on the
Three complementary synthetic strategies for differ-
entially substituting B units of an AB2 monomer are
reported. These methodologies encompass the variations
that are desirable for designing dendrimers with different
sets of functional groups and connectivities. These meth-
odologies were then used to introduce sequences in
dendrons. We have also demonstrated that dendrons can
be sequentially introduced onto a core to synthesize
didendrons and tridendrons. Note that these methodolo-
gies are not limited to tridendrons, since the combination
of the above-mentioned strategies do provide the op-
portunity to introduce several dendrons onto a multi-
functional core. The ability to vary the monomer units
within dendrimers provides the opportunity to introduce
a variety of functional groups within these macromol-
ecules with excellent control. Such capabilities should
have implications in a variety of areas, especially in
biomimetics. The ability of proteins to selectively bind
guest molecules is often attributed to its ability to
converge multiple functionalities that are complementary
to those present in the guest molecule. The methodologies
outlined here could provide the basis for synthesizing
artificial macromolecules with the controlled spatial
disposition of functional groups.17 Efforts toward such
goals are part of the ongoing studies in our laboratories.
Exp er im en ta l Section
This section describes the general procedures for the key
steps involved in sequencing the dendrimers. Each general
procedure is followed by an example. Details of synthesis and
(16) Synthesis of 31 is illustrated in Scheme 11 within Supporting
Information.
(17) For an interesting example in which copies of the same
functionality are incorporated in the dendritic interior, see: Zimmer-
man, S. C.; Wendland, M. S.; Rakow, N. A.; Zharov, I.; Suslick, K. S.
Nature 2002, 418, 399-403. (b) Zimmerman, S. C.; Zharov, I.;
Wendland, M. S.; Rakow, N. A.; Suslick, K. S. J . Am. Chem. Soc. 2003,
125, 13504-13518.
F IGURE 3. Elution profiles in size exclusion chromatography
for G-1, G-2, and G-3 monodendrons.
2942 J . Org. Chem., Vol. 69, No. 9, 2004

Sequences in Dendrimers
F IGURE 4. Elution profiles in size exclusion chromatography for mono-, di-, and tridendrons.
SCHEME 7
characterization of all other compounds are outlined in Sup-
porting Information.
Gen er a l P r oced u r e for Eth er Syn th esis u sin g P h en ol
a n d Alk yl Ha lid es. A mixture of phenol (1.00 equiv), ap-
propriate bromomethyl compound (1.0-1.2 equiv), dry K2CO3
(3.00 equiv), and 18-crown-6 (0.1 equiv) in acetone or THF
(THF was the solvent of choice in the presence of benzoyl
protecting groups) was heated at reflux and stirred vigorously
under nitrogen for 12 h. The reaction mixture was allowed to
cool, and solvent was evaporated to dryness. The residue was
J . Org. Chem, Vol. 69, No. 9, 2004 2943

Sivanandan et al.
partitioned between water and CH2Cl2. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layer was dried over Na2SO4 and
evaporated to dryness. The crude product was purified by silica
gel column chromatography.
reaction was monitored by TLC. The reaction mixture was
slowly added to aqueous ammonium chloride solution and was
extracted twice with dichloromethane. The combined organic
layer was dried over Na2SO4 and evaporated to dryness. The
crude product was purified by silica gel column chromatogra-
phy.
Syn th esis of 3-(m -Meth ylben zyloxy)-5-a llyloxy-ben zyl
Alcoh ol (7). Phenol 613a (1.84 g, 10.22 mmol), 3-methylbenzyl
bromide (1.6 mL, 12.2 mmol), K2CO3 (1.14 g, 30.0 mmol), 18-
crown-6 (0.27 g, 1.0 mmol), and acetone (30 mL) were refluxed
under nitrogen for 12 h. The reaction mixture was allowed to
cool, and solvent was evaporated to dryness. The residue was
partitioned between water and CH2Cl2. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organic layer was dried over Na2SO4 and
evaporated to dryness. The crude product was isolated by silica
gel column chromatography using ethyl acetate /hexane
(30:70). Yield 2.30 g (79%). 1H NMR (400 MHz, CDCl3): δ
7.32-7.14 (m, 4H), 6.62 (bs, 1H), 6.56 (bs, 1H), 6.50 (t, J )
2.2 Hz, 1H), 6.11-6.00 (m, 1H), 5.41 (m, 1H), 5.29 (m, 1H),
5.01 (s, 2H), 4.52 (m, 2H), 2.38 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 160.1, 159.8, 143.3, 138.2, 136.6, 133.0, 128.7, 128.4,
128.2, 124.6, 117.7, 105.5, 105.4, 101.07, 70.0, 68.8, 65.2, 21.3.
EI/MS m/z(relative intensity): 284(M+, 17), 106(11), 105(100),
81(8), 79(6), 77(6), 69(15).
Gen er a l P r oced u r e for Rea ction of Hyd r oxya lk yl
Gr ou p s w ith Alk yl Ha lid es. To a stirred solution of NaH
(2.0 equiv) in dry THF was added appropriate benzyl alcohol
in THF under nitrogen atmosphere. The reaction mixture was
stirred at room temperature for 15 min. A mixture of 18-
crown-6 (0.1 equiv) and appropriate bromomethyl compound
(1-1.2 equiv) in dry THF was added dropwise to the above
solution. The reaction was monitored by TLC (thin-layer
chromatography). After completion of the reaction, the reaction
mixture was quenched by slow addition of water and extracted
with ether. The organic layer was washed with brine and dried
over Na2SO4. The organic layer was evaporated and purified
by silica gel column chromatography.
Syn th esis of 3-m er Alcoh ol 16. The ester 15 (0.5 g, 1.1
mmol) was treated with 2.0 M solution of BH3:SMe2 (2.9 mL,
6.0 mmol) and refluxed overnight in THF (20 mL) to obtain
the corresponding alcohol. The reaction mixture was added
to a cold solution of ammonium chloride and extracted with
CH2Cl2. The crude mixture was purified by silica gel column
chromatography using ethyl acetate/hexane (20:80) as the
1
eluent. Yield 0.5 g (96%). H NMR (400 MHz, CDCl3): δ 7.44
(s, 1H), 7.42 (s, 1H), 7.32 - 7.12 (m, 6H), 6.50 (bs, 1H), 6.47
(bs, 1H), 6.39 (t, J ) 2.2 Hz, 1H), 4.85 (s, 2H), 4.55 (s, 2H),
4.48 (s, 2H), 4.03 (t, J ) 4.6 Hz, 2H), 3.74 (t, J ) 4.6 Hz, 2H),
2.73 (bs, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
159.8, 159.4, 143.4, 136.6, 135.7, 135.5, 131.4, 130.1, 128.9,
128.5, 127.7, 125.5, 121.6, 105.3, 105.2, 100.7, 71.5, 68.9, 68.2,
67.2, 64.6, 18.6. EI/MS m/z(relative intensity): 459(M + 3, 25),
458(M + 2, 25), 457(M + 1,6), 456(M+, 25), 170(97), 168(100),
105(92), 91(14), 90(10).
Gen er a l P r oced u r e for Con ver sion of Ben zylic Alco-
h ol in to Cor r esp on d in g Br om id e. To a stirred solution of
the appropriate benzyl alcohol (1.00 equiv) and PPh3 (1.1-1.3
equiv) in minimal dry THF was added N-bromosuccinimide
(1.1-1.3 equiv) under nitrogen atmosphere. The reaction
mixture was stirred at room temperature and was monitored
by TLC (all reactions completed within 1-5 min). The reaction
mixture was treated with water and extracted two times with
CH2Cl2. The combined organic layer was dried over Na2SO4
and evaporated to dryness. The crude product was purified
by silica gel column chromatography.
Syn th esis of Br om om eth yl Der iva tive of 16. Alcohol 16
(0.4 g, 1.0 mmol) was dissolved in THF (10 mL) followed by
addition of PPh3 (0.3 g, 1.2 mmol). After 5 min, NBS (0.2 g,
1.2 mmol) was added. After completion of the reaction, the
reaction mixture was quenched with water and extracted with
CH2Cl2. The crude mixture was purified by silica gel column
chromatography using ethyl acetate/hexane (2:98) as the
Syn th esis of 3-m er Den d r on 8. To a stirred solution of
NaH (0.61 g, 15.3 mmol) in dry THF was added 7 (2.18 g, 7.66
mmol) in THF under nitrogen atmosphere. The reaction
mixture was stirred at room temperature for 15 min. A mixture
of 18-crown-6 (0.22 g, 0.7 mmol) and benzyl bromide (1.1 g,
mL, 9.2 mmol) in dry THF was added dropwise to the above
solution. The reaction was monitored by TLC. After completion
of the reaction, the reaction mixture was quenched by slow
addition of water and extracted with ether. The organic layer
was washed with brine and dried over Na2SO4. The organic
layer was evaporated and purified by silica gel column chro-
matography using ethyl acetate/hexane (10:90) as the eluent.
1
eluent. Yield 0.4 g (77%). H NMR (400 MHz, CDCl3): δ 7.35
(s, 1H), 7.33 (s, 1H), 7.19 (d, J ) 7.2 Hz, 1H), 7.14-7.00 (m,
5H), 6.44 (d, J ) 2.0 Hz, 1H), 6.43 (d, J ) 2.0 Hz, 1H), 6.32 (t,
J ) 2.2 Hz, 1 H), 4.77 (s, 2H), 4.46 (s, 2H), 4.23 (s, 2H), 3.95
(t, J ) 4.8 Hz, 2H), 3.65 (t, J ) 4.8 Hz, 2H), 2.21 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 159.8, 159.4, 139.5, 136.6, 135.6,
135.4, 131.4, 130.1, 128.9, 128.4, 127.7, 125.5, 121.7, 107.8,
107.8, 101.7, 71.6, 69.0, 68.2,67.3, 33.4, 18.6. EI/MS m/z(rela-
tive intensity): 521(M + 3, 7), 519(M + 1, 15), 517(M+, 7), 170-
(97), 168(100), 105(96), 91(24), 90(11).
1
Yield 2.65 g (93%). H NMR (400 MHz, CDCl3): δ 7.37-7.11
(m, 9H), 6.61 (bs, 1H), 6.55 (bs, 1H), 6.49 (t, J ) 2.4 Hz, 1H).
6.09-5.98 (m, 1H), 5.39 (m, 1H), 5.26 (m, 1H), 4.98 (s, 2H),
4.53 (s, 2H), 4.50 (t, J ) 1.6 Hz, 2H), 4.51-4.48 (m, 2H), 2.36
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.6, 159.7, 140.6,
138.2, 138.1, 136.6, 133.1, 128.7,128.4, 128.3, 128.2, 127.7,
127.6, 124.6, 117.6, 106.4, 106.3, 101.1, 71.9, 71.9, 70.0, 68.7,
21.3. EI/MS m/z(relative intensity): 374(M+, 2), 268(56), 147-
(26), 105(100), 91(32).
Ack n ow led gm en t. This work is supported by the
NIGMS of the National Institutes of Health (GM-
065255-01). Part of this work was carried out at Tulane
University.
Gen er a l P r oced u r e for Con ver sion of Ester to Alcoh ol
a n d Dep r ot ect ion of Ben zoyl Gr ou p . To the ester (1.00
equiv) in dry THF was added borane-dimethyl sulfide complex
(4.00-8.00 equiv), and the resulting mixture was stirred at
refluxing condition under nitrogen atmosphere for 8 h. The
Su p p or tin g In for m a tion Ava ila ble: Synthesis and spec-
tral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O049878P
2944 J . Org. Chem., Vol. 69, No. 9, 2004