Synthesis, electrochemistry, and interactions with β-cyclodextrin of dendrimers containing a single ferrocene subunit located 'off-center'

Article abstract of DOI:10.1021/jo991973o

Two series of dendrimers containing a single ferrocene unit located in the focal point of these macromolecules have been synthesized and characterized. The first series of dendrimers has considerable lipophilic character, with tert-butyl ester groups located in their peripheral regions. In contrast, the second series of dendrimers was obtained by the hydrolysis of these peripheral ester groups, yielding water-soluble dendrimers with carboxylic acid groups in their surfaces. The electrochemical properties of these macromolecules were strongly affected by the dendritic groups attached to the ferrocene subunits. Host-guest interactions between the water-soluble dendrimers and the well-known receptor β-cyclodextrin were also investigated. The dendritic groups were found to hamper markedly the formation of inclusion complexes between the cyclodextrin receptor and the dendrimer's ferrocene unit.

Full text of DOI:10.1021/jo991973o

J . Org. Chem. 2000, 65, 1857-1864
1857
Syn th esis, Electr och em istr y, a n d In ter a ction s w ith â-Cyclod extr in
of Den d r im er s Con ta in in g a Sin gle F er r ocen e Su bu n it Loca ted
“Off-Cen ter ”
Claudia M. Cardona,† Tracy Donovan McCarley,‡ and Angel E. Kaifer*,†
Center for Supramolecular Science and Department of Chemistry, University of Miami,
Coral Gables, Florida 33124-0431, and Choppin Laboratories of Chemistry, Louisiana State University,
Baton Rouge, Louisiana 70803-1804
Received December 28, 1999
Two series of dendrimers containing a single ferrocene unit located in the focal point of these
macromolecules have been synthesized and characterized. The first series of dendrimers has
considerable lipophilic character, with tert-butyl ester groups located in their peripheral regions.
In contrast, the second series of dendrimers was obtained by the hydrolysis of these peripheral
ester groups, yielding water-soluble dendrimers with carboxylic acid groups in their surfaces. The
electrochemical properties of these macromolecules were strongly affected by the dendritic groups
attached to the ferrocene subunits. Host-guest interactions between the water-soluble dendrimers
and the well-known receptor â-cyclodextrin were also investigated. The dendritic groups were found
to hamper markedly the formation of inclusion complexes between the cyclodextrin receptor and
the dendrimer’s ferrocene unit.
In tr od u ction
groups are usually located at3 or very near3b the center
of the dendrimer. In some cases, more than one inner
redox group is incorporated inside the dendrimer,3g,n but
in such a way that the structure maintains its overall
branching symmetry.
The covalent incorporation of redox-active groups into
dendrimers1 is a very active area of chemical research.
Numerous reports on dendrimers functionalized with
peripheral2 or core3 redox groups have been published
in the past few years. All these reports focus on es-
sentially symmetric macromolecular structures. For in-
stance, peripheral redox groups are normally attached
to every branch2 of the dendrimer structure. Core redox
The molecular weight and size of dendrimers has
elicited comparisons to proteins.3i Therefore, redox-active
dendrimers may be measured up, at least formally, to
redox proteins. The former have a clear advantage over
the latter; that is, dendrimers are robust molecules that
do not denature, unlike proteins, in response to certain
environmental conditions. On the other hand, although
some heme-containing dendrimers exhibit oxygen and
carbon monoxide binding affinities that compare favor-
ably to those of hemoglobin and myoglobin,4 many redox
proteins have properties that current dendrimers do not
match, such as directional reactivity and selectivity in
their electron-transfer reactions.5 We reasoned that these
* To whom correspondence should be addressed. Tel: (305) 284-
3468. Fax: (305) 444-1777 (preferred) or (305) 284-4571. E-mail:
akaifer@umiami.ir.miami.edu.
† University of Miami.
‡ Louisiana State University.
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99, 1689.
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M.-M.; Arakawa, R. Angew. Chem., Int., Ed. Engl. 1996, 35, 76. (i)
Valerio, C.; Fillaut, J .-L.; Ruiz, J .; Guittard, J .; Blais, J .-C.; Astruc, D.
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Alonso, B.; Mora´n, M.; Losada, J .; Belsky, V. J . Am. Chem. Soc. 1997,
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G. R.; Walker, A. K.; MacDonnell, F. M. J . Am. Chem. Soc. 1997, 119,
10364. (l) Takada, K.; D´ıaz, D. J .; Abrun˜a, H. D.; Cuadrado, I.; Casado,
C. M.; Alonso, B.; Mora´n, M.; Losada, J J . Am. Chem. Soc. 1997, 119,
10763. (m) Serroni, S.; J uris, A.; Venturi, M.; Campagna, S.; Resino,
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(n) Newkome, G. R.; He, E. J . Mater. Chem. 1997, 7, 1237. (o) Wang,
C.; Bryce, A.; Batsanov, A. S.; Goldenberg, L. M.; Howard, J . A. K. J .
Mater. Chem. 1997, 7, 11189. (p) Gonza´lez, B.; Casado, C. M.; Alonso,
B.; Cuadrado, I.; Mora´n, M.; Wang, Y.; Kaifer, A. E. Chem. Commun.
1998, 2569. (q) Storrier, G.; Takada, K.; Abrun˜a, H. D. Langmuir 1999,
15, 872.
(3) (a) Dandliker, P. J .; Diederich, F.; Gross, M.; Knobler, C. B.;
Louati, A.; Sadford, E. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1739.
(b) Newkome, G. R.; Guther, R.; Moorefield, C. N.; Cardullo, F.;
Echegoyen, L.; Perez-Cordero, E.; Luftmann, H. Angew. Chem., Int.,
Ed. Engl. 1995, 34, 2023. (c) Dandliker, P. J .; Diederich, F.; Gissel-
brecht, J .-P.; Louati, A.; Gross, M. Angew. Chem., Int. Ed. Engl. 1995,
34, 2725. (d) Chow, H.-F.; Chan, I. Y.-K.; Chan, D. T. W.; Kwok, R. W.
M. Chem. Eur. J . 1996, 2, 1085. (e) Sadamoto, R.; Tomioka, N.; Aida,
T. J . Am. Chem. Soc. 1996, 118, 3978. (f) Bhyrappa, P.; Young, J . K.;
Moore, J . S.; Suslick, K. S. J . Am. Chem. Soc. 1996, 118, 5708. (g)
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L.; Su, W. Y.; Chen, K.-Y. J . Am. Chem. Soc. 1997, 119, 1141. (i)
Dandliker, P. J .; Diederich, F.; Zingg, A.; Gisselbrecht, J . P.; Gross,
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Chem. Res. 1998, 31, 26. (k) Selby, T. D.; Blacstock, S. C. J . Am. Chem.
Soc. 1998, 120, 12155. (l) Pollak, K. W.; Leon, J . W.; Fre´chet, J . M. J .;
Maskus, M.; Abrun˜a, H. D. Chem. Mater. 1998, 10, 30. (m) Vo¨gtle, F.;
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Marchis, V.; Venturi, M.; Balzani, V. J . Am. Chem. Soc. 1999, 121,
6290. (n) Newkome, G. R.; Patri, A. K.; God´ınez, L. A. Chem. Eur. J .
1999, 5, 1445. (o) Gorman, C. B.; Smith, J . C.; Hager, M. W.; Parkhurst,
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10.1021/jo991973o CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/02/2000

1858 J . Org. Chem., Vol. 65, No. 6, 2000
Cardona et al.
desirable properties would be more easily expressed in
unsymmetric redox dendrimers, that is, dendrimers that
contain a single redox-active group unsymmetrically
located in their structures. By positioning the redox
subunit “off center”, the overall structure loses symmetry,
and this lack of symmetry should naturally lead to more
directional electron transfer reactivity. In this paper, as
a first step in this direction, we describe the synthesis,
characterization, and electrochemistry of two new series
of unsymmetric dendrimers containing a single ferrocene
group covalently attached “off center”. The first series of
dendrimers (compounds 1-3) is hydrophobic,6 while the
second one is hydrophilic (4-6). For the second series of
dendrimers, we also report data on their binding interac-
tions in aqueous solution with â-cyclodextrin (â-CD), a
well-established molecular receptor for ferrocene deriva-
tives.7
Resu lts a n d Discu ssion
Syn th esis. The first generation dendrimer 1 was
prepared by direct coupling between chlorocarbonylfer-
rocene and Behera’s amine.8 Although 2 and 3 can be
prepared from 1 using Newkome’s divergent approach,8
we elected to prepare second- and third-generation build-
ing block analogues of Behera’s amine and react them
directly with chlorocarbonylferrocene to yield 2 and 3.
The preparation of the second-generation building block
amine 10 is shown in Scheme 1. Briefly, hydrolysis of
the nitrotriester 7, which is the precursor of Behera’s
amine and has also been described by Newkome and co-
workers,8 leads to the nitrotriacid 8. Treatment of this
compound with 3 equiv of Behera’s amine yields the
nitrononaester 9, which can be reduced with Raney Ni
to produce the desired aminononaester 10. The third-
generation building block amine 11 was prepared using
a similar procedure, that is, reaction of nitrotriacid 8 with
3 equiv of 10 followed by reduction to give 11 in 77%
yield. In all cases, ferrocene was introduced at the end
by coupling the corresponding dendritic amine with
chlorocarbonylferrocene to produce the tert-butyl ester
dendrimers 1-3 in moderate yields. Hydrolysis of the
peripheral esters in dendrimers 1-3 led to the corre-
sponding carboxylic acid dendrimers 4-6. All these
compounds were characterized by 1H and 13C NMR, UV-
vis and FT-IR spectroscopy, and MALDI-TOF mass
spectrometry.
The purity and degree of monodispersity of the ferro-
cenyl-functionalized dendrimers depends primarily on
the purity and monodispersity of the amine building
blocks. The MALDI-TOF spectrum of dendrimer 3 (re-
corded in an anthracene matrix) is shown in Figure 1
(top) as an illustrative example. Notice that the molecular
peak (M+) is the only significant spectral feature for m/z
values up to 12 000. The molecular ion is probably formed
by an electron-transfer mechanism.9 For comparison, the
MALDI-TOF spectrum of the hydrolyzed analogue 6 is
shown in Figure 1 (middle). In this case, 2,5-dihydroxy-
benzoic acid (DHB) was selected as the matrix because
the greater polar character of this dendrimer precluded
the use of anthracene. The main spectral feature ob-
served is again the molecular peak (M + H)+. The only
sign of incomplete hydrolysis of the tert-butyl esters of 3
is a tiny peak at m/z 3267 that could correspond to the
dendrimer with one residual tert-butyl ester. There is no
spectral indication of any other hydrolytic failure se-
quences. There is also a series of peaks at lower m/z
values that may correspond to sequential losses of water
from (M + H)+ and a cluster of small peaks between m/z
2964 and 3030, which correspond to loss of the ferrocene
(5) We have recently reported strong molecular orientation effects
on the electrochemistry of some of the dendrimers described in this
work using gold electrodes covered with cystamine monolayers: Wang,
Y.; Cardona, C. M.; Kaifer, A. E. J . Am. Chem. Soc. 1999, 121, 9756.
(6) For
a preliminary report on this series of compounds, see:
Cardona, C. M.; Kaifer, A. E. J . Am. Chem. Soc. 1998, 120, 4023.
(7) Kaifer, A. E. Acc. Chem. Res. 1999, 32, 62 and references cited
therein.
(8) Newkome, G. R.; Behera, R. K.; Moorefield, C. N.; Baker, G. R.
J . Org. Chem. 1991, 26, 7162.
(9) McCarley, T. D.; McCarley, R. L.; Limbach, P. A. Anal. Chem.
1998, 70, 4376.

Dendrimers Containing a Single Ferrocene Subunit
J . Org. Chem., Vol. 65, No. 6, 2000 1859
Sch em e 1. Syn th esis of th e Secon d -Gen er a tion Bu ild in g Block Am in e
group. These peaks seem to result from fragmentation
and not from impurities, as peaks for the building block
amine 11 were not detected in the spectrum of the
precursor dendrimer 3.10 The spectrum of 6 also shows a
small peak corresponding to the m/z value expected for
a dimer, which forms in the gas phase probably due to
hydrogen bonding between the carboxylic acid “faces” of
this dendrimer. The spectrum of the nonaacid, second-
generation dendrimer 5 (DHB matrix, Figure 1 (bottom))
is again clearly dominated by the molecular peak.
The synthetic methodology described here affords a
series of three dendritic amine building blocks (Behera’s
amine plus 10 and 11) that can be utilized to prepare in
straightforward one-step reactions a variety of unsym-
metrically functionalized dendrimers (Scheme 2). In this
work, as represented in the scheme, the attachment of
the functional group to the dendrimer structure is done
via condensation reactions of the amines with acid
chloride functions. However, the highly reactive character
of amines should make the coupling scheme work equally
well with a number of other functional groups, such as
activated acids, aldehydes, isocyanides, and coordinately
unsaturated metal centers. These amine dendrons may
thus find a number of applications for the preparation
of dendrimer systems containing a single functional
group.
Electr och em istr y. The voltammetric behavior of the
ferrocene-containing dendrimers was investigated in
CH2Cl2/0.2 M TBAPF6 (compounds 1-3) and in 0.1 M
NaCl aqueous solution (compounds 4-6) buffered at pH
7 with 0.05 M Tris. As anticipated, the electrochemistry
of the dendrimers was dominated by the one-electron,
reversible oxidation of the ferrocene nucleus. The experi-
mental cyclic voltammograms were fitted to digital
simulated ones (see Figure 2 for an example) in order to
obtain the voltammetric parameters that describe the
electrochemical behavior of each dendrimer. The results
are given in Table 1. Representative voltammograms for
the 4-6 series are also shown in Figure 3. In both series
of dendrimers, the diffusion coefficients (Do) and the
standard rate constants for heterogeneous electron trans-
fer (k°) decrease with dendrimer generation. Qualita-
(10) Amine 11 gives a well-defined molecular peak when analyzed
in an anthracene matrix. If unreacted or residual 11 were present in
our samples of 3, we should see peaks from this compound in the
MALDI-TOF spectra recorded in anthracene matrix.

1860 J . Org. Chem., Vol. 65, No. 6, 2000
Cardona et al.
H2O, respectively) contrasts with the differing trends
seen in the half-wave potentials (E1/2, see Table 1). While
the E1/2 value for ferrocene oxidation decreases with
increasing dendrimer generation in the 1-3 series (in
CH2Cl2/0.2 M TBAPF6), the trend is exactly the opposite
in the water-soluble series 4-6 (in 0.1 M NaCl buffered
at pH 7 with 0.05 M Tris). The potential variation in the
latter series is likely to be determined by the relative ease
of hydration of the oxidized form of the redox couple, the
positively charged ferrocenium. Dendrimer growth ap-
pears to interfere with ferrocenium solvation by water
molecules, probably because the dendrimer branches
start to surround the ferrocene group in the second and
in the third generation compounds (5 and 6). This
interference or hindrance on hydration processes is
responsible for the shift to more positive values, which
is observed in the half-wave potentials. However, the
magnitude of this shift is rather modest, as the total
potential change from compound 4 to 6 is +30 mV. In
contrast to this, the observed potential shifts are in the
opposite direction and larger in magnitude for the series
of hydrophobic, tert-butyl ester dendrimers; the total
potential shift from compound 1 to 3 is -90 mV. This
finding means that the generation of positive charge is
thermodynamically favored in this dendrimer series by
the growth of the dendron covalently attached to one of
the cyclopentadienyl rings of the ferrocene residue, a
result that cannot be described as intuitive. Other groups
have observed comparable potential trends in dendrimers
with electroactive cores. The most relevant example is
the porphyrin-containing dendrimers, prepared by Dieder-
ich and co-workers, that possess similar dendritic
structures.3a,i A clear rationalization of this potential
trend in dendrimers 1-3 is not yet available.
F igu r e 1. Representative MALDI-TOF mass spectra. (Top)
dendrimer 3, anthracene matrix. (Middle) dendrimer 6, 2,5-
dihydroxybenzoic acid matrix. (Bottom) dendrimer 5, 2,5-
dihydroxybenzoic acid matrix.
We have also performed some isolated electrochemical
measurements with ultramicroelectrodes in order to
verify the quality of the parameters given in Table 1. For
instance, we used platinum ultramicroelectrodes (4-µm
radius) to record current-potential curves corresponding
to the electrochemical oxidation of dendrimers 1 and 2
in CH2Cl2/0.2 M TBAPF6 solution. The results were
analyzed according to the convenient method described
by Mirkin and Bard,11 yielding values of 0.20 ( 0.05 cm/s
for 1 and 0.023 ( 0.007 cm/s for 2. These k° values are
in reasonable agreement with those given in Table 1. We
could not extend these measurements to the remaining
systems as we found highly irreproducible behavior and/
or problems associated with adsorptive behavior in some
ultramicroelectrode experiments.
Bin d in g In ter a ction s w ith â-CD. Ferrocene is a
well-known guest for binding inside the cavity of the
â-CD host.7 Therefore, we decided to investigate the
binding interactions between the ferrocene containing
dendrimers described here and â-CD (see Scheme 3). This
investigation was constrained to dendrimers 4-6, since
compounds 1-3 are not water-soluble. The host-guest
interactions can be conveniently monitored by voltam-
metric techniques taking advantage of the electroactive
character of the ferrocene nucleus. Similar methodology
has been utilized in the past by our group12 and others13
with simpler CD inclusion complexes. Figure 4A shows
tively, these findings agree with other reports on the
electrochemical behavior of dendrimers having an elec-
troactive core.3 The diffusion coefficients decrease with
generation due to the anticipated increase in the den-
drimer molecular weights and radii. The trend observed
with the k° values probably results from the increasing
isolation of the electroactive core from the outer surface
as the dendrimer grows. The higher the generation of the
dendrimer, the further away the dendritic bulk keeps the
ferrocene subunit from the electrode surface. As the
average ferrocene-electrode distance of maximum ap-
proach increases with generation, the observed electron-
transfer rate decreases. Notice that the k° values are
similar for dendrimers of the same generation in the two
different media surveyed. For instance, the proximity of
the k° values for the pairs 1 and 4, 2 and 5, and 3 and 6,
respectively, is noticeable. Since the electron-transfer rate
constants are determined by the average ferrocene-
electrode distance, a reasonable interpretation for this
experimental finding is that the additional steric bulk
introduced by the tert-butyl groups in the periphery of
1, 2, and 3 may be compensated by a more extended, open
structure (driven by the solvation of the carboxylates by
the water molecules) in 4, 5, and 6. Overall, our data
clearly indicate that dendrimer growth extending from
one of the cyclopentadienyl rings of the electroactive
ferrocene core tends to hinder kinetically the heteroge-
neous electron-transfer reactions of these dendrimers
with the electrode.
(11) Mirkin, M. V.; Bard, A. J . Anal. Chem. 1992, 64, 2293.
(12) (a) Mirzoian, A.; Kaifer, A. E. Chem. Eur. J . 1997, 3, 1052. (b)
Wang, Y.; Mendoza, S.; Kaifer, A. E. Inorg. Chem. 1998, 37, 317.
(13) Matsue, T.; Evans, D. H.; Osa, T.; Kobayashi, N. J . Am. Chem.
Soc. 1985, 107, 3411.
The similar variation of the Do and k° values observed
for the two series of dendrimers (soluble in CH2Cl2 and

Dendrimers Containing a Single Ferrocene Subunit
J . Org. Chem., Vol. 65, No. 6, 2000 1861
Sch em e 2. On e-Step Syn th esis of Un sym m etr ica lly F u n ction a lized Den d r im er s
Ta ble 1. Str u ctu r a l a n d Electr och em ica l P a r a m eter s for
th e F er r ocen e-Con ta in in g Den d r im er s 1-6 a t 25 °C
E1/2
(V vs
Do
ko
MW
(106
×
(103
×
(amu)
medium
Ag/AgCl) cm2‚s-1
)
R
cm‚s-1
)
1
2
3
4
5
6
627.6 CH2Cl2
1652.0 CH2Cl2
4725.0 CH2Cl2
459.3 H2O (pH 7)
1147.0 H2O (pH 7)
3210.1 H2O (pH 7)
0.63
0.60
0.54
0.39
0.41
0.42
9.5 ( 1.0 0.5 80 ( 20
4.0 ( 0.5 0.5 17 ( 3
2.3 ( 0.3 0.4
5 ( 1
3.5 ( 0.4 0.5 70 ( 30
2.2 ( 0.2 0.5 20 ( 4
0.8 ( 0.1 0.5
6 ( 1
apparent half-wave potential to more positive values and
causes a considerable decrease on the currents associated
with the ferrocene/ferrocenium wave. Both effects clearly
reveal the formation of an inclusion complex between
â-CD and the ferrocene nucleus. The shift of the E1/2 value
in the positive direction reflects the more pronounced CD-
induced stabilization of ferrocene compared to that
experienced by ferrocenium. The current decrease results
from the lower diffusion coefficient of the inclusion
complex relative to that of the uncomplexed ferrocene
derivative. Similar results have been obtained with many
F igu r e 2. Cyclic voltammetric response (continuous line) on
glassy carbon (0.018 cm2) of a 1.0 mM solution of 4 in 0.1 M
NaCl buffered at pH 7 with 0.05 M Tris. Scan rate: 0.2 V/s.
The circles represent a simulated voltammogram obtained
with the parameters given in Table 1.
the changes observed in the cyclic voltammetric response
of the first generation dendrimer 4 upon addition of 7
equiv of â-CD. The presence of the host shifts the

1862 J . Org. Chem., Vol. 65, No. 6, 2000
Cardona et al.
F igu r e 4. Cyclic voltammetric responses on glassy carbon
(0.018 cm2) of 1.0 mM solutions of (A) 4, (B) 5, and (C) 6 in 0.1
M NaCl buffered at pH 7 with 0.05 M Tris. The voltammo-
grams were recorded in the absence (continuous line) and in
the presence (open circles) of 7.0 mM â-CD. Scan rate: 0.1
V/s.
Ta ble 2. P a r a m eter s for th e Associa tion of
F er r ocen e-Con ta in in g Den d r im er s a n d th e â-CD Host a t
25 °C in Aqu eou s Solu tion
F igu r e 3. Cyclic voltammetric responses on glassy carbon
(0.018 cm2) of 1.0 mM solutions of (A) 4, (B) 5, and (C) 6 in 0.1
M NaCl buffered at pH 7 with 0.05 M Tris. Scan rates: 0.1,
0.5, and 1.0 V/s.
dendrimer
Dc (106 × cm2‚s-1
)
K (L‚mol-1
)
4
5
6
2.0 ( 0.2
1.8 ( 0.2
0.2 ( 0.1
950 ( 140
250 ( 50
50 ( 10
Sch em e 3. Associa tion Equ ilibr iu m betw een
F er r ocen e-Con ta in in g Den d r im er a n d â-CD
implicit recognition that electron transfer does not take
place from the inclusion complex; that is, the complex
must first dissociate before the electrochemical oxidation
reaction.12-14
Figure 4B,C shows the corresponding â-CD-induced
changes observed with the second and third generation
compounds (5 and 6). The voltammetric responses in the
presence of â-CD can also be simulated using the CE
mechanism proposed above. From the optimization of the
fit between the simulated and experimental voltammo-
grams, the equilibrium binding constant (K) for the
complexation process, and the diffusion coefficient of the
complex (Dc) can be estimated. The resulting values are
given in Table 2. As anticipated from the simple inspec-
tion of the voltammetric results of Figure 4, the equilib-
rium binding constant between the dendrimer and â-CD
quickly decreases as the dendrimer grows. The first-
generation compound exhibits a K value that is in the
low end of the normal range for â-CD complexes of
ferrocene derivatives. The K value is substantially lower
for the second-generation compound, while the binding
becomes very weak for the third-generation dendrimer.
These results strongly suggest that the growth of the
dendrimer interferes with the approach to the ferrocene
residue and inclusion by the CD host. This finding is in
excellent agreement with the variation of E1/2 values
observed in this series of dendrimers, which reveals that
the ferrocene subunit is at least partially surrounded by
the growing dendron in compounds 5 and 6. It is this
steric crowding effect that is responsible for the low
stability of the corresponding â-CD inclusion complexes.
Con clu sion s. We present here a synthetic method for
the preparation of dendrimers containing a single ferro-
cenyl residue positioned “off center” in the dendrimer
structure. This method can be easily extended to the
preparation of other unsymmetric dendrimers containing
different functional groups at their focal points. The
dendron attached to the ferrocene residue has a pro-
other ferrocene derivatives.13,14 The electrochemical oxi-
dation of ferrocene derivatives in the presence of â-CD
is widely accepted to proceed through a mechanism of
the type
â-CD•Fc a â-CD + Fc
Fc a Fc+ + e
(1)
(2)
In electrochemical terms, this is a CE mechanism
(electron-transfer preceded by a chemical step). Notice
that the adoption of this mechanism carries along the
(14) Isnin, R.; Salam, C.; Kaifer, A. E. J . Org. Chem. 1991, 56, 35.

Dendrimers Containing a Single Ferrocene Subunit
J . Org. Chem., Vol. 65, No. 6, 2000 1863
MALDI-TOF MS: 1439.13 (100, M+, calcd 1439.91), 1461.23
(M + Na+), 1383.1 (MH+ - tBuH).
nounced effect on its electrochemical properties and in
its ability to function as an effective guest for inclusion
complexation by â-CD. Our data suggests that in the
third-generation dendrimers (3 and 6) the dendritic
growth is enough to wrap around and isolate to some
extent the ferrocene group from solvent and environmen-
tal effects.
27 Cascade/(2-Azaeth ylidyn e)/(3-Oxo-2-azapen tylidyn e)/
(3-Oxo-2-a za p en tylid yn e)/ter t-Bu tyl P r op a n oa te (11). Tri-
acid 8 (0.25 g, 0.90 mmol) was reacted with the second-
generation building block amine 10 (4.04 g, 2.81 mmol) in the
presence of DCC (0.79 g, 3.8 mmol) and 1-HOBT (0.19 g, 1.4
mmol). The mixture was stirred in 75 mL of dry THF under
N2 for 6 days at room temperature. The urea byproduct was
filtered off, and after evaporation of the solvent, the residue
was purified by column chromatography (SiO2, 5:1 CH2Cl2/
EtOAc followed by EtOAc). The recovered product was reduced
in a Parr Hydrogenator, 55 psi H2, 60 °C, with 23.0 g of
activated Raney nickel. The catalyst was filtered, and the
solvent was removed under reduced pressure and chased with
hexane to procure a white solid in a 77% yield (3.12 g). FT-IR
(KBr): 3312.77 (ν(N-H)) cm-1; 1732.13 (ν(CdO)) cm-1; 1652.20
Exp er im en ta l Section
All chemicals employed were reagent grade (Aldrich or
Across) and were used as received. Solvents, such as THF and
DMF, were freshly distilled. Column chromatography was
performed with Scientific Adsorbents silica gel (63-200 µm).
1H and 13C NMR spectra were recorded on a Varian VXR-400
spectrometer; all the chemical shift (δ) values are reported in
ppm. MALDI-TOF mass spectra were recorded at the LSU
Mass Spectrometry Facility.
(ν(amide-I, CdO)) cm-1; 1542.13 (ν(amide II, N-H)) cm-1
;
1
1154.94 (ν(C-O)) cm-1. H NMR (400 MHz, CDCl3) δ: 1.4 (s,
CH3, 243 H); 1.7-2.4 (m, CH2CH2, 156 H); 6.2 (sb, NH, 9H)
gen 3; 6.85 (sb, NH, 3H) gen 2. 13C NMR (400 MHz, CDCl3) δ:
28.13 (CH3); 29.81 (CH2CH2) gen 3; 31.52 (CH2CH2) gen 2;
57.37 (C(CH2CH2)3) gen 3; 80.37 (C(CH3)) gen 3; 172.68
(COOtBu). MALDI-TOF MS: 4513.44 (100, M+, calcd 4512.94).
3 Ca sca d e/F er r ocen e[1]/(3-Oxo-2-a za p r op yld yn e)/ter t-
Bu tyl P r op a n oa te (1). Ferrocene carboxylic acid (0.372 g,
1.62 mmol) was dissolved in 8.1 mL of 0.2 N NaOH and
filtered, and the water was removed under vacuum to complete
dryness. The residue was mixed with 5 mL of oxalyl chloride
and 20 mL of dry benzene and stirred for 1 h under N2. After
removal of the solvent in vacuo, the residue was mixed with
Behera’s amine (0.687 g, 1.65 mmol) and Et3N (1.65 mmol,
0.230 mL) in 25 mL of THF. The reaction mixture was stirred
at room temperature for 3 days under N2. Removal of the
solvent under vacuum procured a brown residue that was
dissolved in 75 mL of CHCl3. The organic layer was then
extracted with 0.2 N NaOH, 10% HCl, and brine and dried
over Na2SO4. Purification was accomplished by column chro-
matography (SiO2, CHCl3), and yellow crystals were obtained
(0.363 g, 36%) after recrystallization from CHCl3/hexane
mixture. FT-IR (CH2Cl2): 1727, 1654 (ν(CdO)) cm-1. 1H NMR
(CDCl3) δ: 1.42 (s, CH3, 27H); 2.0-2.3 (m, CH2, 12H, J ) 7.9
Hz); 4.2 (s, Fc C5H5, 5H); 4.3-4.7 (m, Fc CH, 4H, J ) 1.7 Hz);
6.2 (bs, NH, 1H). 13C NMR δ: 28.1 (CH3); 30.0, 30.41 (CH2CH2);
57.5 (C(CH2CH2)3); 68.1, 70.2 (Fc CHCH); 69.6 (Fc C5H5); Fc
C-quaternary is under the solvent signal, CDCl3; 80.7 (C(CH3)3;
169.6 (CONH); 173.1 (COOtBu). UV-vis [λmax, nm (ꢀ, M-1
cm-1), CH2Cl2]: 303 (1002.1); 337 (shoulder); 445 (202.9).
MALDI-TOF MS: 627.433 (100, M+, calcd 627.60), 650.441
(M + Na+), 666.431 (M + K+).
The electrochemical behavior of the dendrimers was studied
with a Bioanalytical Systems 100 B/W workstation controlled
by a 100 MHz Pentium PC, which was also employed to run
the Digi-Sim 2.1 software for the digital simulation work. The
voltammetric experiments were performed in a 1.0-mL cell
equipped with a glassy carbon electrode (0.0078 cm2 for the
esters and 0.018 cm2 for the acids), a platinum counter
electrode, and a Ag/AgCl reference electrode. The esters were
dissolved (0.001 M) in HPLC grade dichloromethane contain-
ing tetrabutylammonium hexafluorophosphate (Fluka, >99%)
as the supporting electrolyte (0.2 M). Prior to its use, this
material had been recrystallized twice from an ethanol/H2O
(80:20) mixture. The acids were dissolved (0.001 M) in Tris
(Across Reagent ACS) buffer prepared in 0.1 M NaCl (Strem
Chemicals, 99.999%). A nitrogen atmosphere was maintained
over the solutions throughout the electrochemical experiments.
Cyclic voltammetry (CV) was the primary technique em-
ployed to obtain the reported electrochemical parameters.
Typical scan rate values of 0.100, 0.200, 0.500, 1.000, and 2.000
V/s were used. The k° and D values were obtained by fitting
digital simulations (Digi-Sim 2.1) to the experimental voltam-
mograms throughout the entire range of scan rates surveyed.
IR compensation as implemented in the BAS 100 B/W poten-
tiostat was used throughout the experiments and every effort
was made to minimize capacitive currents and uncompensated
resistance. Osteryoung Square Wave voltammetry was mainly
used to verify the half-wave potential values and the purity
of the compounds.
The electrochemical titrations with â-cyclodextrin (â-CD)
were monitored only at 0.100 V/s except for the ferrocene
triacid 4 that was also followed at 0.500, 1.0, 5.0, and 10.0
V/s. Voltammograms taken at â-CD concentrations of 0.001,
0.003, 0.005, and 0.007 M were fitted by digital simulations
(Digi-Sim 2.1) to obtain the corresponding binding parameters
(equilibrium association constant, K, and diffusion coefficient
for the complex, Dc).
9 Ca sca d e/F er r ocen e[1]/(3-Oxo-2-a za p r op ylid yn e)/(3-
Oxo-2-a za p en tylid yn e)/ter t-Bu tyl P r op a n oa te (2). Start-
ing with ferrocene carboxylic acid (0.164 g, 0.710 mmol), the
acid chloride was prepared as described in the procedure
above. Then, it was mixed with the second-generation building
block amine 10 (1.02 g, 0.706 mmol) and Et3N (0.72 mmol,
0.10 mL) in 20 mL of THF and stirred for 4 days at room
temperature under N2. After evaporation of the solvent, the
residue was dissolved in 75 mL of CHCl3 and extracted with
0.2 N NaOH, 10% HCl, and brine. The organic layer was then
dried over Na2SO4. After removal of the solvent, purification
was accomplished by column chromatography (SiO2, 3:1
CHCl3/EtOAc) and an orange foam was obtained (0.36 g, 31%).
9 Ca sca d e/(2-Aza eth ylid yn e)/(3-Oxo-2-a za p en tylid in e)/
ter t-Bu tyl P r op a n oa te (10). The nitrotriester 7, precursor
of Behera’s amine, was hydrolyzed by stirring in 10 mL of 96%
formic acid. The formed triacid 8 (2.5 g, 9.0 mmol) was coupled
to Behera’s amine (11.2 g, 27.0 mmol) in the presence of DCC
(5.60 g, 27.1 mmol) and 1-HOBT (1.2 g, 9.1 mmol). The mixture
was stirred in 100 mL of dry THF for 6 days at room
temperature. The product was filtered, and after evaporation
of the solvent, the residue was purified by column chroma-
tography (2:1 CH2Cl2/EtOAc). A portion (7.1 g) of the isolated
product (10.1 g, 76%) was reduced (50 psi H2, 60 °C) with 18.0
g of activated Raney nickel. After filtration of the catalyst, the
solvent was evaporated and traces of it were chased with
hexane to procure the product as a white solid (6.0 g, 86%).
1
FT-IR (CH2Cl2): 1726, 1663 (ν(CdO)) cm-1. H NMR (CDCl3)
δ: 1.4 (s, CH3, 81H); 1.9-2.2 (m, CH2, 36H, J ) 8 Hz); 2.0-
2.3 (m, CH2, 12H, J ) 7.3 Hz); 4.2 (s, Fc C5H5, 5H); 4.3-4.8
(m, Fc CH, 4H, J ) 1.7 Hz); 6.1 (bs, NH, 3H); 8.2 (bs, NH,
1H). 13C NMR δ: 28.1 (CH3); 29.9, 30.1 (CH2CH2) gen2; 32.1,
32.7 (CH2CH2) gen1; 57.5 (C(CH2CH2)3) gen2; 57.9 (C(CH2-
CH2)3) gen1; 68.5, 70.4 (Fc CHCH); 69.6 (Fc C5H5); Fc C-
quaternary is under the solvent signal, CDCl3; 80.6 (C(CH3)3);
171.1 (CONH) gen1; 172.7 (CO2tBu); 173.1 (CONH) gen2. UV-
vis [λmax, nm (ꢀ, M-1 cm-1), CH2Cl2]: 304 (1059.1); 335
(shoulder); 444 (216.6). MALDI-TOF MS: 1652.74 (100, M+,
calcd 1651.95).
1
FT-IR (CH2Cl2): 1724,1674 (ν(CdO)) cm-1. H NMR (CDCl3)
δ: 1.41 (s, CH3, 81H); 1.55-2.15 (m, CH2CH2, 12H, J ) 8.9
Hz); 1.85-2.20 (m, CH2CH2, 36H, J ) 8 Hz); 6.05 (sb, NH,
3H). 13C NMR δ: 28.1 (CH3); 29.9, 30.0 (CH2CH2) gen 2; 31.6,
35.3 (CH2CH2) gen 1; 52.7 (C(CH2CH2)) gen 1; 57.4 (C(CH2-
CH2)) gen 2; 80.7 (C(CH3)3); 172.5 (CONH); 172.7 (COOtBu).

1864 J . Org. Chem., Vol. 65, No. 6, 2000
Cardona et al.
(27 Ca sca d e/Fer r ocen e[1]/(3-Oxo-2-a za p r op ylid yn e)/(3-
Oxo-2-a za p en tylid yn e)(3-Oxo-2-a za p en tylid yn e)/ter t-Bu -
tyl P r op a n oa te (3). Ferrocene acyl chloride (prepared from
ferrocenecarboxylic acid, 0.060 g, 0.26 mmol) was combined
with the third generation building block amine 11 (1.0 g, 0.22
mmol) in the presence of Et3N (0.28 mmol, 0.040 mL) in 5 mL
of dry THF. The reactants are stirred for 4 days under N2 at
room temperature. The resulting mixture was filtered. The
filtrate was chromatographed (SiO2, CH2Cl2 followed by 1:1
CH2Cl2/EtOAc) to procure an orange foam after evaporatiion
of all the solvent and drying under vacuum (0.60 g, 49%). FT-
5 mL) was stirred at 25 °C for 24 h. The solvent was removed
in vacuo, and the remaining formic acid was chased with
acetone followed by methylene chloride. After the residue was
dried under vacuum at 80 °C overnight, an orange powder
(0.20 g, 95%) was obtained. FT-IR (KBr): 3300-2500 (ν(O-
H)) cm-1; 3348.01 (ν(N-H)) cm-1; 1716.84 (ν(CdO)) cm-1
;
1652.2 (ν(amide-I, CdO)) cm-1; 1540.49 (ν(amide II, N-H))
1
cm-1; 1291.19 (ν(C-O)) cm-1. H NMR (400 MHz, DMSO-d6)
δ: 1.6-2.20 (m, CH2CH2, 48H) gen 1 & 2; 4.15 (s, FcC5H5, 5H);
4.30-4.80 (m, FcCHCH, 4H); 7.30 (sb, NH, 3H); 7.40 (sb, NH,
1H); 12.10 (sb, COOH, 9H). 13C NMR (400 MHz, DMSO-d6) δ:
28.07, 29.11 (CH2CH2) gen 2; 30.26, 30.71 (CH2CH2) gen 1;
56.28 (C(CH2CH2)3) gen 2; 57.04 (C(CH2CH2)3) gen 1; 68.17,
69.57 (FcCHCH); 69.17 (FcC5H5); 77.71 (FcCCONH); 168.0
(CONH) gen 1; 172.05 (CONH) gen 2; 174.05 (COOH). MALDI-
TOF MS: 1147.76 (100, M+, calcd 1146.98); 1170.96 (M + Na+).
IR (KBr): 3365.63 (ν(N-H)) cm-1; 1732.77 (ν(CdO)) cm-1
;
1653.82 (ν(amide-I, CdO)) cm-1; 1540.83 (ν(amide II, N-H))
cm-1; 1154.59 (ν(C-O)) cm-1. 1H NMR (CDCl3) δ: 1.4 (s, CH3,
243); 1.9-2.2 (m, CH2, 156H, J ) 7.8 Hz); 4.2 (s, Fc C5H5, 5H);
4.3-4.9 (m, Fc CH, 4H, J ) 1.7 Hz); 6.3 (bs, NH, 9H); 6.8 (bs,
NH, 3H); 8.0 (bs, NH, 1H. 13C NMR δ: 28.15 (CH3); 29.8
(CH2CH2) gen 3; 31.6 (CH2CH2) gen 2; 57.4 (C(CH2CH2)3) gen
(27 Ca sca d e/F er r ocen e[1]/(3-Oxo-2-a za p r op ylid yn e)/
(3-Oxo-2-a za p en tylid yn e)/(3-Oxo-2-a za p en tylid yn e)/P r o-
p a n oic Acid (6). As described above, a solution (0.15 g, 0.032
mmol) of the tert-butyl ester dendrimer 3 in formic acid (96%,
5 mL) was stirred at 25 °C for 36 h. The solvent was removed
in vacuo, and the remaining formic acid was chased with DMF.
Some residual DMF could not be removed from the final
orange-brown product after drying it under vacuum at 80 °C
overnight (0.098 g, 98%). FT-IR (KBr): 3300-2500 (ν(O-H))
cm-1; 3349.27 (ν(N-H)) cm-1; 1720.12 (ν(CdO)) cm-1; 1649.68
3; 69.8 (Fc C5H5); 80.4 (C(CH3)3); 172.7 (CO2tBu). UV-vis [λmax
,
nm (ꢀ, M-1 cm-1), CH2Cl2]: 300 (shoulder), 335 (shoulder), 439
(231.2). MALDI-TOF MS: 4726.29 (100, M+, calcd 4724.98).
(3 Ca sca d e/F er r ocen e[1]/(3-Oxo-2-a za p r op ylid yn e)/(3-
Oxo-2-a za p en tylid yn e)/P r op a n oic Acid (4). A solution
(0.307 g, 0.489 mmol) of the tert-butyl triester dendrimer 1 in
formic acid (96%, 5 mL) was stirred at 25 °C for 24 h. The
solvent was removed in vacuo, and the remaining formic acid
was chased with acetone followed by methylene chloride. The
product recovered in 95% yield may be further purified if
required by dissolving it in 0.2 N NaOH and reprecipitating
with conc HCl. A yellow powder was obtained after drying the
product in a vacuum at 80 °C (0.20 g, 90%). FT-IR (KBr):
3300-2500 (ν(O-H)) cm-1; 3427.31 (ν(N-H)) cm-1; 1714.44
(ν(CdO)) cm-1; 1621.93 (ν(amide-I, CdO)) cm-1; 1526.91
(ν(amide II, N-H)) cm-1; 1293.42 (ν(C-O)) cm-1. 1H NMR (400
MHz, DMSO-d6) δ: 1.9-2.25 (m, CH2CH2, 12H); 4.15 (s,
FcC5H5, 5H); 4.30-4.85 (m, FcCHCH, 4H); 6.75 (sb, NH, 1H);
12.10 (sb, COOH, 3H). 13C NMR (400 MHz, DMSO-d6) δ:
28.18, 29.10 (CH2CH2); 56.98 (C(CH2CH2)3); 68.31, 69.67
(FcCHCH); 69.14 (FcC5H5); 77.45 (FcCONH); 168.54 (CONH);
174.52 (COOH). MALDI-TOF MS: 460.889 (100, M+, calcd
459.28); 482.847 (M + Na+).
(ν(amide-I, CdO)) cm-1; 1546.45 (ν(amide II, N-H)) cm-1
;
1294.49 (ν(C-O)) cm-1. 1H NMR (400 MHz, DMSO-d6) δ: 1.6-
2.40 (m, CH2CH2, 156H) gen 1, 2 & 3; 4.1 (s, FcC5H5, 5H);
4.30-4.80 (m, FcCHCH, 4H); 7.30 (sb, NH, 13H); 12.10 (sb,
COOH, 27H). 13C NMR (400 MHz, DMSO-d6) δ: 28.27, 29.19
(CH2CH2) gen 3; 30.26, 30.75 (CH2CH2) gen 2; 56.29 (C(CH2-
CH2)3) gen 3; 69.31 (FcC5H5); 172.18 (CONH) gen 2; 174.66
(COOH). MALDI-TOF MS: 3211.62 (100, M+, calcd 3210.07);
6418.1 (dimer).
Ack n ow led gm en t. We gratefully acknowledge the
support of this research by the NSF (to A.E.K., CHE-
9633434 and CHE-9982014). C.M.C. thanks the NIH for
a predoctoral fellowship. We thank Dr. Patrick Griffin
(Merck Corp.) for running some MALDI-TOF mass
spectra of dendrimer samples.
9 Ca sca d e/F er r ocen e[1]/(3-Oxo-2-a za p r op ylid yn e)/(3-
Oxo-2-a za p en tylid yn e)/P r op a n oic Acid (5). Following the
procedure described above, a solution of the tert-butyl nano-
ester dendrimer 2 (0.303 g, 0.183 mmol) in formic acid (96%,
J O991973O