Dendrimers based on a three-dimensionally disposed AB4 monomer

Article abstract of DOI:10.1021/ol049147b

(Matrix Presented) Design and synthesis of a novel class of dendrons based on an AB₄ monomer are described. These dendrons have been evaluated by using dendritic encapsulation of a redox active core. The electrochemical properties of symmetric

Full text of DOI:10.1021/ol049147b

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2547-2550
Dendrimers Based on a
Three-Dimensionally Disposed AB4
Monomer
K. Natarajan Jayakumar, Pandi Bharathi, and S. Thayumanavan*
Department of Chemistry, UniVersity of Massachusetts, Amherst, Massachusetts 01003
thai@chem.umass.edu
Received May 10, 2004
ABSTRACT
Design and synthesis of a novel class of dendrons based on an AB4 monomer are described. These dendrons have been evaluated by using
dendritic encapsulation of a redox active core. The electrochemical properties of symmetric ferrocene-cored dendrimers show that significant
alterations in redox potential and heterogeneous electron-transfer rate constants could be achieved even at lower generations.
The study of dendrimers has been a topic of considerable
interest in recent years for a variety of applications.1 Syn-
theses of dendrimers are achieved by using ABn monomers,
where “n” represents the degree of branching. Most reported
dendrimers are based on AB2 or AB3 building block units.1,2
Understandably, increasing the magnitude of n results in a
rapid assembly of high molecular weight dendrimers.2
Herein, we wish to report on the dendrons and dendrimers
based on a biaryl-based AB4 monomer 5.
That molecular design is based on the twist that is commonly
observed in biaryls, which should provide an interesting
three-dimensional spatial disposition of the phenolic moieties
with respect to the hydroxymethyl functionality in 5. A
space-filling model of a tetrabenzyl-substituted AB4 mono-
mer 7, energy-minimized using MM2 calculations (shown
in the abstract), supports the presumed spatial arrangement
of the dendritic branches. We hypothesized that the three-
dimensional disposition of the branches should provide
dendritic microenvironments at the core of the dendrimer or
the focal point of the dendrons at lower generations. Such
features can be investigated by studying the effectiveness
of these dendrimers in encapsulating electroactive units.4 In
this vein, we have unsymmetrically (monodendrons) and
symmetrically (didendrons) attached dendrons based on the
biaryl monomer 5 to ferrocene. Here, we report on the
syntheses, characterization, and electrochemical studies of
these dendrimers.
The biaryl monomer design is based on our monomer
design for uniformly functionalized amphiphilic dendrimers.3
(1) (a) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendrimers and
Dendrons: Concepts, Syntheses, Applications; Wiley-VCH: New York,
2001. (b) Dendrimers and Other Dendritic Polymers; Fre´chet, J. M. J.,
Tomalia, D. A., Eds.; John Wiley & Sons: New York, 2002. (c) Bosman,
A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999, 99, 1665. (d)
Fischer, M.; Vo¨gtle, F. Angew. Chem., Int. Ed. 1999, 38, 884. (e) Zeng, F.;
Zimmerman, S. C. Chem. ReV. 1997, 97, 1681. (f) Grayson, S. M.; Fre´chet,
J. M. J. Chem. ReV. 2001, 101, 3819.
(2) (a) Dukeson, D. R.; Ungar, G.; Balagurusamy, V. S. K.; Percec, V.;
Johansson, G. A.; Glodde, M. J. Am. Chem. Soc. 2003, 125, 15974. (b)
Elemans, J. A. A. W.; Boerakker, M. J.; Holder, S. J.; Rowan, A. E.; Cho,
W.-D.; Percec, V.; Nolte, R. J. M. Proc. Natl. Acad. Sci. 2002, 99, 5093.
(c) Ohta, M.; Fre´chet, J. M. J. J. Macromol. Sci., Pure Appl. Chem. 1997,
A34, 2025. (d) Scott, D. A.; Kru¨lle, T. M.; Finn, M.; Fleet, G. W. J.
Tetrahedron Lett. 2000, 41, 3959.
The AB4 monomer 5 was synthesized from compounds 1
and 2, as shown in Scheme 1. Compounds 1 and 2 were
synthesized from 1-bromo-3,5-dimethoxybenzene and 4-bro-
(3) Bharathi, P.; Zhao, H.; Thayumanavan, S. Org. Lett. 2001, 3, 1961.
10.1021/ol049147b CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004

procedure.5 This bromoarene was then subjected to a
bromine-lithium exchange followed by treatment with
trimethyl borate and hydrolysis to obtain the aryl boronic
acid 1. Compound 2 was synthesized from 4-bromo-3,5-
dihydroxybenzoic acid, by converting the acid to an ester
followed by methylation of the phenolic groups. A key step
in the synthesis of target monomer is the aryl-aryl bond-
forming reaction to obtain 3. Since Suzuki coupling has been
reported to give reasonably good yields of hindered biaryls,
we have utilized this reaction for aryl-aryl coupling.6 The
biaryl compound 3 was synthesized by the palladium-
catalyzed coupling of the boronic acid 1 and the bromoarene
2 in anhydrous DME in the presence of potassium phosphate
in 72% yield. We also attempted Stille coupling reaction
conditions for the synthesis of 3. This methodology afforded
the desired product in only about 45% yield. Demethylation
of 3 with BBr3 resulted in the tetraphenolic compound 4 in
84% yield. Lithium aluminum hydride reduction of the ester
4 afforded the target AB4 monomer 5 in 82% yield.
Scheme 1. Synthesis of AB4 Monomer and Dendrons
The assembly of dendrons from the AB4 monomer was
achieved by using the protocols developed for AB2 arylalkyl
ethers.7 Monomer 5 was treated with slightly more than 4
equiv of benzyl bromide in the presence of K2CO3 and 18-
crown-6 to afford the first generation monodendron 7.
However, the yield was only about 50% and the product was
accompanied by a few unidentified less polar compounds.
To circumvent this complication, we attempted the alkylation
of ester 4 with benzyl bromide, where the product 6 was
obtained in 95% yield. Compound 6 was then reduced with
LAH to afford the first generation alcohol 7 in 84% yield.
The alcohol 7 was converted to bromide 8 upon treatment
with NBS/PPh3. Reaction of 4 with slightly more than 4
equiv of bromomethyl compound 8 followed by reduction
with LAH afforded the second generation dendron 10 in 71%
overall yield.
Syntheses of unsymmetrical and symmetrical ferrocene-
cored dendrimers are shown in Scheme 2. Ferrocene was
chosen as the redox active core mainly because of its simple
and well-studied one-electron redox feature. Benzylferrocene
carboxylate (11) and benzylferrocene-1,1′-dicarboxylate (12)
were synthesized as the control for the unsymmetrical and
symmetrical dendrimers, respectively. Compounds 11 and
12 were synthesized by the EDC/DMAP mediated coupling
of benzyl alcohol with ferrocenecarboxylic acid and 1,1′-
ferrocenedicarboxylic acid, respectively. Unfortunately, the
same reaction conditions afforded poor yield of the desired
product in the reaction with the dendritic alcohol 7. There-
fore, we employed fluorocarbonylferrocene or ferrocenyl-
1,1′-diacid fluoride8 as the electrophilic species. Reaction
of fluorocarbonylferrocene with the dendritic alcohols 7 and
10 in the presence of DMAP resulted in the unsymmetrical
dendrons 13 and 14 in 88% and 75% yields, respectively,
as shown in Scheme 2. Similarly, treatment of 7 and 10 with
ferrocenyl-1,1′-diacid fluoride afforded symmetrical den-
mo-3,5-dihydroxybenzoic acid, respectively. The former
bromoarene was synthesized from the commercially available
3,5-dimethoxybenzoic acid, using a previously reported
(4) (a) Diederich, F.; Felber, B. Proc. Natl. Acad. Sci. 2002, 99, 4778.
(b) Dandliker, P. J.; Diederich, F.; Gisselbrecht, J. P.; Louati, A.; Gross,
M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2725. (c) Jiang, D. L.; Aida, T.
Chem. Commun. 1996, 1523. (d) Gorman, C. B.; Smith, J. C.; Hager, M.
W.; Parkhurst, B. L.; Sierzputowska-Gracz, H.; Haney, C. A. J. Am. Chem.
Soc. 1999, 121, 9958. (e) Chasse, T. L.; Sachdeva, R.; Li, Q.; Li, Z.; Petrie,
R. J.; Gorman, C. B. J. Am. Chem. Soc. 2003, 125, 8250. (f) Cardona, C.
M.; Mendoza, S.; Kaifer, A. E. Chem. Soc. ReV. 2000, 29, 37. (g) Hecht,
S.; Fre´chet, J. M. J. Angew. Chem., Int. Ed. 2001, 40, 74. (h) Newkome,
G. R.; Gu¨ther, R.; Moorefield, C. N.; Cardullo, F.; Echegoyen, L.; Pe´rez-
Cordero, E.; Luftmann, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2023.
(i) Balzani, V.; Campagna, S.; Denti, G.; Juris, A.; Serroni, S.; Venturi, M.
Acc. Chem. Res. 1998, 31, 26.
(5) Dol, G. C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Eur. J. Org.
Chem. 1998, 359.
(6) (a) Hoye, T. R.; Chen, M. J. Org. Chem. 1996, 61, 7940. (b) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(7) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
2548
Org. Lett., Vol. 6, No. 15, 2004

Scheme 2. Synthesis of Symmetrical and Unsymmetrical Ferrocene-Cored Dendrimers
drimers 15 and 16 in 85% and 72% yields, respectively
Experimental cyclic voltammograms were simulated by using
Digisim to determine diffusion coefficients (Do) and hetero-
geneous electron-transfer rate constants (k0) (see Figure 1).
Diffusion coefficients, estimated by using the Randles-
Sevcik equation {iP ) (2.69 × 105)ACD1/2V1/2}, were used
as the starting point for the simulation. The E1/2 and the k0
values are shown in Table 1. The redox potentials of the
unsymmetrical dendrons 13 and 14 are essentially unchanged
compared to those of the control ferrocene carboxylic ester
11. This suggests that the difference between the stability
(Scheme 2). All dendrimers were characterized by 1H NMR,
13C NMR, and MALDI-ToF spectrometry. The dendrimers
were also analyzed with GPC as an additional check for
purity.
Electrochemical measurements were performed with 0.2
M tetrabutylammonium hexafluorophosphate as a supporting
electrolyte in CH2Cl2. Electrochemical data for compounds
11-16 are given in Table 1. Half-wave potentials (E1/2) were
measured relative to Fc/Fc+, using square wave voltammetry.
Org. Lett., Vol. 6, No. 15, 2004
2549

attenuation in the rate. Also, compound 16 exhibits a
significant decrease in the reversibility of the electrochemical
reactions, especially at higher scan rates.
Table 1. Electrochemical Data for Dendrimersa
b
E1/2
D0
hydrodynamic
radiusc (nm)
k0
The rate of electron transfer decreases steadily and slowly
in the case of monodendrons 13 and 14. This could be
attributed to the steric inhibition of electron transfer. In the
symmetrical dendrimer 15 also, a decrease in the electron-
transfer rate was observed. A larger decrease accompanied
by irreversibility in the cyclic voltammogram was observed
with the dendrimer 16. This suggests that ferrocene is
reasonably well-encapsulated in the second generation den-
drimer.9 The fact that the monodendrons do not provide
sufficient encapsulation to vary the microenvironment of the
ferrocene at the focal point is not surprising, because one
side of the ferrocene unit is likely to be significantly exposed
to the bulk solvent. However, it is noteworthy that even the
first generation symmetrical dendrimer 15 was able to
provide a sufficiently different microenvironment for the
ferrocene at the core that there is a change in the redox
potential.9 The observed increase in potential suggests that
the ferrocenium ion is less stabilized in the first generation
dendrimer. The destabilization is understandably enhanced
in the second generation. Alterations in the microenvironment
of ferrocene are likely to be due to encapsulation by the
dendritic backbone. Since the polarity of the backbone should
be less than that of the solvent electrolyte, it is not surprising
that the more charged ferrocenium species is less stabilized.
Three-dimensional shielding of the electroactive species
seems to be necessary for altering the redox potential of the
ferrocene core. The fact that the first generation symmetrical
dendrimer affords a noticeable alteration in the redox po-
tential provides supporting evidence for the presumed three-
dimensional arrangement of the branches in these biaryl
dendrimers. Investigations in the area of encapsulating cata-
lysts to achieve substrate selectivity are part of the ongoing
efforts in our laboratories with these dendrimers.
compd
(mV)
(10-6 cm2/s)
(10-4 cm/s)
unsymmetrical dendrimers
11
13
14
264
264
268
4.5 ( 0.5
2.0 ( 0.1
1.0 ( 0.1
1.08
2.43
5.11
46 ( 7
31 ( 7
21 ( 2
symmetrical dendrimers
12
15
16
496
508
528
5.5 ( 2.5
1.4 ( 0.1
irr.
0.88
3.47
irr.
45 ( 14
28 ( 5
7 ( 0d
-
a Carried out with 0.2 M TBA+PF6 in CH2Cl2 at 25 °C. See the
Supporting Information for other experimental details. b Half-wave potentials
(E1/2) were measured relative to Fc/Fc+, using square wave voltammetry.
c Determined by using the Stokes-Einstein equation. d k0 for 16 was
approximated by inputting the D0 value of 15.
Figure 1. A typical experimental CV and the simulation (com-
pound 13).
Acknowledgment. We are grateful to National Science
Foundation for a CAREER award.
Supporting Information Available: Synthetic procedures
and characterization data for all new compounds. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
of ferrocene and the ferrocenium species is similar in 11,
13, and 14. These unsymmetrical monodendrons exhibit
steady, but small decreases in the electron-transfer rate
constants. Compared to the control molecule 11, with k0 )
4.6 × 10-3 cm/s, the biaryl dendrons 13 and 14 exhibit k0
of 3.1 × 10-3 and 2.1 × 10-3 cm/s, respectively.
OL049147B
(8) Galow, T. H.; Rodrigo, J.; Cleary, K.; Cooke, G.; Rotello, V. M. J.
Org. Chem. 1999, 64, 3745.
Interestingly, the symmetrical biaryl dendrimers 15 and
16 exhibit a different behavior. These molecules exhibit a
steady increase in the redox potential of 508 and 528 mV,
respectively, compared to the 496 mV for the control
molecule 12. With respect to electron-transfer rate constants,
compound 15 exhibits a slight decrease in k0 relative to 12,
while the second generation dendrimer 16 exhibits a large
(9) Compare these results to a rather insensitive behavior of arylalkyl
ether dendrimers based on the AB2 monomer, 3,5-dihydroxybenzyl
alcohol: (a) Toba, R.; Quintela, J. M.; Peinador, C.; Roma´n, E.; Kaifer, A.
E. Chem. Commun. 2001, 857. (b) Smith, D. K. J. Chem. Soc., Perkin Trans.
2 1999, 1563. For related reports, see: (c) Stone, D. L.; Smith, D. K.;
McGrail, P. T. J. Am. Chem. Soc. 2002, 124, 856. (d) Cardona, C. M.;
Kaifer, A. E. J. Am. Chem. Soc. 1998, 120, 4023. (e) Ong, W.; Kaifer, A.
E. J. Am. Chem. Soc. 2002, 124, 9358.
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Org. Lett., Vol. 6, No. 15, 2004