Synthesis and characterisation of water-soluble poly(aryl ether) dendrimers for encapsulation of biomimetic active site analogues

Article abstract of DOI:10.1039/b002026p

Synthetic strategies to incorporate active site analogues of metalloenzymes at the core of water-soluble dendritic structures are explored. Synthesis of water-soluble aryl ether dendrimers containing tripyridyl metal-binding sites is successful when a con

Full text of DOI:10.1039/b002026p

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Synthesis and characterisation of water-soluble poly(aryl ether)
dendrimers for encapsulation of biomimetic active site analogues†
Michael J. Hannon,* Paul C. Mayers and Paul C. Taylor*
1
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, UK CV4 7AL.
Fax: ϩ 44 (0)24 7652 4112; E-mail: M.J.Hannon@warwick.ac.uk; P.C.Taylor@warwick.ac.uk
Received (in Cambridge, UK) 13th March 2000, Accepted 14th April 2000
Published on the Web 22nd May 2000
Synthetic strategies to incorporate active site analogues of metalloenzymes at the core of water-soluble dendritic
structures are explored. Synthesis of water-soluble aryl ether dendrimers containing tripyridyl metal-binding sites
is successful when a convergent, but not a divergent, strategy is employed.
design. Our target therefore is dendrimer systems with water-
Introduction
solubilising terminal groups and aryl-based interiors into the
centre of which might be incorporated a variety of different
active site mimics.
In the last 10–15 years, the synthesis of dendritic structures and
the investigation of their properties has been the subject of a
major research effort worldwide.1 Initial work focused on
developing the principles behind dendrimer synthesis,2 but
more recently efforts have been directed towards the prepar-
ation of systems which have some function or exhibit novel
properties, often at the borderline between polymer chemistry
and supramolecular chemistry.3 In particular, dendrimers
containing metal ions—metallodendrimers4—have formed the
basis of a good deal of work. Metal ion complexes have been
incorporated in dendrimers in many ways: as surface groups,5 as
connectors and branching centres6 and as dendrimer cores.7
We are interested in the development of dendritic systems
which contain, at their core, ligands for the coordination of a
variety of metal ions with the eventual goal of preparing
systems containing active site analogues of metalloenzymes
encapsulated inside a dendrimer. In the molecules we envisage,
the coordinated metal ion will not play a structural role in form-
ing the dendrimer but rather the dendrimer itself will provide a
unique environment for the metal ion.8 For example, coordin-
ation inside a dendrimer could prevent access by other ligands
and lead to weakly solvated “vacant” coordination sites that
would normally be occupied by other ligands. This is of par-
ticular interest in our development of enzyme models: nature
often modifies the properties and coordination numbers of
metal ions by burying them in a substrate binding pocket thus
enabling them to play a catalytic role. Dendrimer systems of
this type may thus be considered to provide a model for func-
tional metal ion sites in proteins; most metallodendrimers
containing metal ions in their interior reported to date mimic
the structural role played by protein-bound metal ions.
To investigate how we might prepare such systems we focused
on the incorporation of a tripodal N3-donor ligand, tri-2-
pyridylmethanol,9 although we envisage that the same tech-
niques may readily be adapted to permit incorporation of a
wide range of biomimetic sites. Tripodal N3-donor ligands are
of particular interest in the investigation of zinc enzymes such
as carbonic anhydrase which contain a tetrahedral zinc() ion
with three sites occupied by N-donor atoms from the protein
framework and a vacant or weakly solvated fourth site in a
pseudo-tetrahedral arrangement—a system that has proved
extremely difficult to replicate in free solution due to either the
coordination of a second ligand to give a hexadentate pseudo-
octahedral ZnL2 arrangement or the formation of hydroxy-
bridged LZn(OH)nZnL species.10
Results and discussion
Divergent strategy
Our initial synthetic studies centered around divergent strat-
egies: that is the growth of a dendrimer outwards from a central
core molecule. Tri-2-pyridylmethanol has a hydroxy functional-
ity which can act as a dendrimer growth point. Efficient syn-
thetic procedures for the divergent growth of ester-linked den-
drimers based upon an acid chloride or carbodiimide ester
coupling and benzyl protection strategy that ultimately leads to
hydroxy-terminated, water-soluble compounds have already
been established in our laboratories.11 However, the tertiary
alcohol of the core molecule was found to be rather
unreactive—tripyridylmethanol itself shows no reaction with
either acid chloride 1 or the corresponding acid in the presence
of dicyclohexylcarbodiimide (DCC) under a variety of reaction
conditions.
If the sodium salt of tripyridylmethanol is prepared by
treatment with sodium hydride in tetrahydrofuran, the reaction
with acid chloride 1 then proceeds smoothly in DMF to give
ester 2. However, attempts to remove the benzyl protecting
groups to give dihydroxy compound 3 were unsuccessful under
a variety of conditions (Scheme 1). Under all conditions, the
main product obtained was 3,5-dihydroxybenzoic acid, indicat-
ing cleavage of not only the protecting groups but also the ester
function. When the reaction was carried out using transfer
hydrogenation conditions,12 the only nitrogen containing com-
ponent found was tri-2-pyridylmethane13 and when con-
A wide variety of dendrimer systems has been described in
the literature. Given our biomimetic goals, we desired dendritic
systems that would best model the relatively rigid micro-
environment found in the interior of protein structures while
maintaining a small degree of flexibility. For this reason, we
discounted relatively flexible aliphatic dendrimers and very
rigid alkyne and alkyne-aryl dendrimers and chose instead to
focus on aryl dendrimers. Functionality placed on the exterior
of a dendrimer is important for determining its solubility;
clearly aqueous solubility is an important target in biomimetic
† Synthetic procedures for compounds 1 to 13 are available as sup-
plementary data. For direct electronic access see http://www.rsc.org/
suppdata/p1/b0/b002026p/
DOI: 10.1039/b002026p
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This journal is © The Royal Society of Chemistry 2000
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Scheme
1
Attempted synthesis using benzyl protecting groups.
Reagents, conditions and yields: (i) (2-Py)3COϪNaϩ, DMF, 18 h, RT
(80%); (ii) 10% Pd/C, chloroform–methanol, 30 psi H2, 18 h or 10%
Pd/C, cyclohexene, ethanol, reflux 18 h.
ventional hydrogenation techniques11 were used, to our surprise
di-2-pyridyl(2-piperidyl)methane was the major product.14
Since the tri-2-pyridylmethanol core was clearly not stable to
hydrogenation, we decided to investigate alternative protecting
groups. The choice of suitable groups is somewhat limited since
they must be removed in near quantitative yield under condi-
tions that will enable the resulting hydroxy-terminated den-
drimers to be readily purified despite their high polarity and
relative insolubility in organic solvents (particularly at higher
generations). We decided to investigate the methoxyethoxy-
methyl (MEM) group which can be removed in the presence of
acid or Lewis acid. Ester 415 was hydrolysed to acid 5 under
basic conditions (Scheme 2), but attempts to prepare the acid
chloride using thionyl chloride were unsuccessful presumably
due to the sensitivity of the MEM protecting groups to hydro-
gen chloride generated in the reaction. We therefore decided to
attach the core molecule via an ether link: ester 4 was reduced to
alcohol 6 with lithium aluminium hydride and brominated with
PPh3–CBr4 to give bromide 7. Treatment of 7 with the sodium
salt of tripyridylmethanol afforded ether-linked compound 8
which was readily deprotected with strong acid to give the core
molecule 9 as its hydrochloride salt. DCC coupling11 of 9 with
2 equivalents of acid 5 gave the second generation dendrimer 10
in good yield. However, attempts to deprotect 10 under similar
conditions were unsuccessful due to the sensitivity to acid of
the ester functions, so no larger dendrimers were prepared. A
divergent preparation of ether-linked dendrimers was not
pursued since the yields obtained in the ether synthesis are not
high enough to allow the preparation of larger dendrimers in
good yield and high purity.
Scheme
2
Divergent synthesis using MEM protecting groups.
Reagents, conditions and yields: (i) 40% KOH, ethanol, reflux 3 h (76%);
(ii) LiAlH4, Et2O, 4 h, RT (100%); (iii) PPh3, CBr4, THF, 0 ЊC to RT,
0.25 h (49%); (iv) (2-Py)3COϪNaϩ, DMF, 18 h, RT (85%); (v) 36% HCl,
MeOH, 3 h, RT (100%); (vi) acid 5, DCC, dimethylpyridinium toluene-
p-sulfonate, CH2Cl2, RT, 18 h (64%).
13 failed to give the corresponding bromide in a synthetically
useful yield. The lower bromination yields at higher gener-
ations presumably reflect the increased number of surface MEM
groups that are susceptible to acidic cleavage.
Convergent strategy
Further attempts to prepare hydroxy-terminated dendrimers
utilised the MEM-bromide 7 in a convergent strategy. MEM-
protected, benzyl ether-linked dendrimers were synthesised as
outlined in Scheme 3. Treatment of bromide 7 with 3,5-
dihydroxybenzyl alcohol, potassium carbonate and catalytic
18-crown-6 in a Fréchet-type synthesis2c gave the G2-OH den-
drimer 11 in good yield. However, bromination of 11 using
CBr4–PPh3 gave G2-Br 12 in a rather low yield (39%). Further
investigations revealed that this low yield was due to partial
cleavage of the MEM protecting groups presumably due to the
formation of acidic by-products during the course of the reac-
tion. A second coupling with dihydroxybenzyl alcohol gave
G3-OH dendrimer 13 in good yield but attempts to brominate
Rather than pursue other protecting group strategies, we
decided to investigate whether we could develop a convergent
synthesis using a non-removable surface group, but one which
would ensure solubility in as wide a range of solvents as pos-
sible including, most importantly, water and aqueous solvent
mixtures as well as organic solvents. This was prompted by
recent reports which suggest that the triethylene glycol mon-
omethyl ether group could afford the required solubility in ali-
phatic dendrimer systems16 so we developed a synthesis based
upon this terminal group as outlined in Scheme 4.17 Triethylene
glycol monomethyl ether was treated with toluene-p-sulfonyl
chloride in pyridine to give tosylate 1518 which was used to
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Scheme 3 Convergent synthesis using MEM protecting groups. Reagents, conditions and yields: (i) 3,5-dihydroxybenzyl alcohol, K2CO3, 18-crown-
6, acetone, reflux 18 h (100%); (ii) PPh3, CBr4, THF, 0 ЊC to RT, 0.5 h (39%); (iii) 3,5-dihydroxybenzyl alcohol, K2CO3, 18-crown-6, acetone, reflux
18 h (88%).
alkylate the disodium salt of methyl 3,5-dihydroxybenzoate
to give ester 16. Reduction with lithium aluminium hydride
followed by bromination with 1,2-bis(diphenylphosphino)-
ethane (DPPE) and tetrabromomethane gave bromide 18. The
use of triphenylphosphine (TPP) in the bromination step was
found to result in troublesome separation of the bromo den-
drimers and the triphenylphosphine oxide by-product.19 This
problem is overcome by the use of DPPE as reported in the
literature.20
Bromide 18 was elaborated to higher generation dendrimers
via successive applications of the Fréchet-type cycle2c based
upon alkylation of 3,5-dihydroxybenzyl alcohol and activation
via bromination of the terminal hydroxy group. G1-Br gave G2-
OH 19 in quantitative yield and bromination gave G2-Br 20
(79%). A second application of the cycle gave G3-OH 21 (93%)
followed by G3-Br 22 (81%). A final cycle gave G4-OH 23 (84%)
and G4-Br 24 (80%). Treatment of G1-Br 18, G2-Br 20, G3-Br 22
and G4-Br 24 with sodium tripyridylmethoxide in DMF gave
G1-OCPy3 25 (62%), G2-OCPy3 26 (60%), G3-OCPy3 27 (55%)
and G4-OCPy3 28 (60%) respectively as shown in Scheme 5. The
relatively low yield for the final step is consistent with the
difficulty of alkylation of the hindered tertiary alcohol of tri-2-
pyridylmethanol which we observed even in simple small
Fig. 1 300 MHz 1H NMR spectra of G2-OH dendrimer 19 in
molecule reactions.
To allow for the water solubility of all the compounds, the
Fréchet methodology2c was modified and an aqueous work up
procedure was avoided. The yields compare well with those
reported by Fréchet in the organic soluble benzyl-terminated
dendrimer series2c although purification was somewhat more
difficult: the non-crystalline nature of the compounds meant
that recrystallisations were not possible and purification was by
flash chromatography on silica gel.
(a) CDCl3 and (b) D2O. * Denotes residual solvent peaks.
Fig. 1. At higher generations, the water solubility is somewhat
reduced thus making CDCl3 a more practical choice for acqui-
sition of NMR data, but the water solubility is still more than
adequate for the types of biomimetic catalytic studies that we
ultimately envisage. The 1H NMR spectra are typically broader
in D2O than CDCl3.
The series of compounds obtained do indeed have excellent
solubility properties: this is well illustrated by our ability to use
CDCl3 and D2O virtually interchangeably as solvents when
recording NMR spectra of the dendrons and dendrimers, par-
ticularly for the lower generations. The H NMR spectrum of
G2-OH dendron 19 is illustrated in both CDCl3 and D2O in
The presence of the ethylene glycol units on the exterior also
affords another important property: unlike many other neutral
dendrimers, the compounds are readily characterised by electro-
spray mass spectrometry. Addition of a small amount of alkali
metal ions (Liϩ, Naϩ or Kϩ) results in the formation of adducts
with the dendrimers (presumably via binding to the triethylene
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Scheme 4 Convergent synthesis of triethylene glycol terminated dendrimers. Reagents, conditions and yields: (i) toluene-p-sulfonyl chloride, DMAP,
pyridine, 18 h, 0–5 ЊC (90%); (ii) methyl 3,5-dihydroxybenzoate (disodium salt), DMF, 55 ЊC, 18 h (76%); (iii) LiAlH4, Et2O, RT, 18 h (97%); (iv)
DPPE, CBr4, THF, 0 ЊC, 10 min (60%); (v) 3,5-dihydroxybenzyl alcohol, K2CO3, 18-crown-6, acetone, reflux, 18 h (100%); (vi) DPPE, CBr4, THF,
0 ЊC, 10 min (79%); (vii) 3,5-dihydroxybenzyl alcohol, K2CO3, 18-crown-6, acetone, reflux, 18 h (93%); (viii) DPPE, CBr4, THF, 0 ЊC, 10 min (81%);
(ix) 3,5-dihydroxybenzyl alcohol, K2CO3, 18-crown-6, acetone, reflux, 18 h (84%); (x) DPPE, CBr4, THF, 0 ЊC, 10 min (80%).
metal ions as illustrated for the G3-CPy3 dendrimer 27 in the
presence of Naϩ ions in Fig. 2. The formation of highly charged
species allows the characterisation of very high molecular
weight dendrimers on a mass spectrometer with a relatively
modest m/z range: for example, we have characterised den-
drimers with a molecular weight approaching 10 kDa on an
instrument where the m/z detection range is limited to 4000.
This is not dissimilar to the mass spectrometric characterisation
of large, multiply charged protein molecules.21 A great advan-
tage of the electrospray technique is the mild nature of the
ionisation method. Because of the low cone voltages used in the
ionisation process, we can assume that we see no significant
fragmentation of the molecule. We can therefore assign any
signals corresponding to partial dendrimer units as being
due to the presence of impurities rather than fragmentation in
the spectrometer and thus indicative that further purification is
required. Because the electrospray technique is very sensitive as
Fig. 2 Positive electrospray mass spectrum of G3-OCPy3 dendrimer 27
in the presence of NaCl.
glycol groups). These adducts give extremely intense signals in
the positive electrospray mass spectrum. Several signals are
observed corresponding to the binding of different numbers of
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Scheme 5 Preparation of tri-2-pyridylmethanol dendrimers. Reagents, conditions and yields: (2-Py)3COϪNaϩ, DMF, RT, 18 h (62% for 25, 60% for
26, 55% for 27, 60% for 28).
well as very mild, it will detect the presence of extremely small
amounts of impurity that may not be detected by other
techniques—for example, 1H NMR spectroscopy—particularly
at higher generations. Electrospray compatibility is also
an especially important feature for our future biomimetic
studies since metal–ligand coordination complexes are rarely
compatible with the harsher MALDI technique traditionally
favoured by dendrimer chemists.
Although the best spectra are obtained in the presence of
Naϩ ions, similar results can also be achieved using Liϩ or Kϩ
ions. The relative binding affinities have been investigated in a
qualitative manner by the addition of equimolar amounts of
lithium, sodium and potassium chlorides to G4-OH dendron 23
and acquisition of the electrospray spectrum illustrated in
Fig. 3. By considering the signals corresponding to the 2ϩ ions,
2ϩ
the MNa2 signal is most intense (although this signal is pre-
2ϩ
sumably a superimposition of MNa2 and the much weaker
2ϩ
MLiK2ϩ which have the same m/z value) followed by MLi2
2ϩ
and MK2 which are of approximately equal intensity. This
suggests a binding affinity thus: Naϩ > Liϩ ~ Kϩ.
Conclusions
Fig. 3 Positive electrospray mass spectrum of G4-OH dendrimer 23 in
the presence of equimolar amounts of LiCl, NaCl and KCl.
In conclusion, we have utilised a Fréchet-type methodology to
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prepare, in high yield, a series of water-soluble aryl ether den-
drimers containing a potentially biomimetic metal ion binding
site at their core. This convergent strategy is far more versatile
and straightforward than similar divergent approaches and
allows the rapid preparation of relatively large amounts of
dendrimers. The triethylene glycol functionality reproduces in
our aryl dendrimers the excellent solubility properties reported
by other workers in aliphatic dendrimer systems.16 Binding of
alkali metal ions by the triethylene glycol groups affords an
excellent means of characterisation and purity determination
via electrospray mass spectrometry. Preliminary studies confirm
that the tripyridyl containing dendrimers bind a range of metal
ions including zinc(). The preparation and investigation of
these complexes are currently underway in our laboratories and
will be reported elsewhere.
2-Ar); δC(75.5 MHz; CDCl3) 52.3, 59.1, 67.9, 69.7, 70.7, 70.8,
70.9, 72.1, 106.9, 108.1, 132.1, 160.0, 166.7; m/z (EIϩ) 460 (8%,
Mϩ), 238 (10), 103 (25), 91 (37), 59 (100), 45 (45).
3,5-Bis(methoxyethoxyethoxyethoxy)benzyl alcohol 17
To a mechanically stirred, ice-cooled suspension of lithium
aluminium hydride (3.29 g, 86.7 mmol) in dry ether (40 cm3)
was added a solution of ester 16 (20.0 g, 46.2 mmol) in dry ether
(200 cm3) dropwise over 1 hour. The resulting mixture was
stirred at room temperature for 2 hours and then gently refluxed
for 3 hours. After cooling, the reaction was quenched by the
sequential addition of water (3.3 cm3), 15% aqueous sodium
hydroxide (3.3 cm3) and water (10 cm3). The precipitate formed
was removed by filtration and washed well with tetrahydro-
furan. The combined filtrate and tetrahydrofuran washings
were dried over sodium sulfate, filtered and the solvent removed
under reduced pressure to give alcohol 17 (18.2 g, 97%) as a
pale oil (Found: C, 58.3; H, 8.5. C21H36O9 requires C, 58.3;
H, 8.4%); νmax (CH2Cl2 solution)/cmϪ1 3600w, 3461br, 3060s,
2881vs, 1955w, 1597vs, 1450vs, 1351vs, 1275vs and 1104vs;
δH(300 MHz; CDCl3) 2.04 (1H, t, J 5.8, OH), 3.35 (6H, s, OMe),
3.50–3.75 (16H, m, CH2), 3.81 (4H, t, J 4.9, CH2), 4.08 (4H, t,
J 4.8, CH2), 6.39 (1H, t, J 2.3, 4-Ar), 6.51 (2H, d, J 2.3, 2-Ar);
δC(75.5 MHz; CDCl3) 59.2, 64.9, 67.7, 70.0, 70.7, 70.9, 71.0,
72.1, 100.8, 105.5, 144.3, 160.2; m/z (EIϩ) 432 (100%, Mϩ), 286
(45), 183 (72), 140 (72), 103 (66), 59 (100).
Experimental
General
1H NMR and 13C NMR spectra were recorded on Bruker
ACF250 or AMX 300 spectrometers operated in Fourier
transform mode. Chemical shifts were referenced to TMS
as an internal standard or to residual solvent peaks (CHCl3 at
7.25 ppm in d-chloroform and CD3S(O)CHD2 at 2.52 ppm in
d6-DMSO). Positive electrospray spectra were recorded on a
Micromass Quattro II triple quadrupole mass spectrometer at
the EPSRC National Mass Spectrometry Centre, Swansea.
Samples were injected as a solution in methanol and typical
cone voltages were in the range 30–50 V. Samples containing
additional Naϩ were prepared by treatment of the sample with
a small volume of a saturated methanolic solution of sodium
chloride. Other mass spectra were recorded on a Kratos MS80
instrument. FABϩ spectra were recorded using a matrix of m-
nitrobenzyl alcohol (NOBA). Microanalyses were performed
on a Leeman Labs Inc. CE440 Elemental Analyser. Analytical
TLC was performed on aluminium plates precoated with
Merck silica gel 60 (F254). Flash chromatography was carried
out using Merck 9385 Kieselgel 60 silica (0.040–0.063 mm,
230–400 mesh).
Thionyl chloride was redistilled before use. Tetrahydrofuran,
diethyl ether and dimethylformamide used in reactions were the
best available commercial anhydrous grades. Other solvents
and reagents were standard grades available from commercial
suppliers and were used without any further purification.
Tripyridylmethanol9 and tosylate 1518 were prepared as
reported in the literature. Synthetic procedures for compounds
1 through to 13 are available in the electronic supplementary
information.
3,5-Bis(methoxyethoxyethoxyethoxy)benzyl bromide 18
To an ice-cooled solution of alcohol 17 (2.68 g, 6.20 mmol) and
tetrabromomethane (3.08 g, 9.30 mmol) in dry tetrahydrofuran
(6 cm3) was added a solution of 1,2-bis(diphenylphosphino)-
ethane (1.85 g, 4.65 mmol) in dry tetrahydrofuran (6 cm3)
dropwise over 10 minutes. The resulting mixture was stirred in
ice for 10 minutes and at room temperature for 10 minutes
before quenching by the addition of water (0.25 cm3). The
solvent was removed under reduced pressure and the product
purified by flash chromatography on silica gel (2 × 20 cm) using
2–3% methanol in dichloromethane as eluant to give bromide
18 (1.85 g, 60%) as a colourless oil (Found: C, 50.7; H, 7.1.
C21H35O8Br requires C, 50.9; H, 7.1%); νmax (CH2Cl2 solution)/
cmϪ1 3060s, 2882vs, 2827s, 1955w, 1596vs, 1450vs, 1351vs,
1296vs and 1104vs; δH(300 MHz; CDCl3) 3.37 (6H, s, OMe),
3.53 (4H, m, –CH2–), 3.65–3.70 (12H, m, 3 × –CH2–), 3.82 (4H,
t, J 4.7, –CH2–), 4.09 (4H, t, J 4.7, –CH2–), 4.38 (2H, s,
-CH2Br), 6.41 (1H, t, J 2.2, 4-ArH), 6.53 (2H, d, J 2.2, 2-ArH);
δC(75.5 MHz; CDCl3) 33.9 (CH2Br), 59.4 (OMe), 67.9, 70.0,
70.9, 71.0, 71.4, 72.2 (6 × CH2), 102.0 (4-Ar), 108.2 (2-Ar),
140.0 (C1), 160.3 (C3); m/z (EIϩ) 494/496 (100%, Mϩ), 416 (80),
383 (55), 295 (80).
Methyl 3,5-bis(methoxyethoxyethoxyethoxy)benzoate 16
To an ice-cooled suspension of sodium hydride (60% suspen-
sion in oil, 1.31 g, 32.7 mmol) in dry dimethylformamide
(3 cm3) was added methyl 3,5-dihydroxybenzoate (2.50 g,
14.9 mmol) in dimethylformamide (8 cm3) with stirring over 5
minutes. The mixture was heated at 60 ЊC for 2 hours before
cooling in ice. A solution of tosylate 15 (11.83 g, 37.2 mmol) in
dimethylformamide (8 cm3) was added dropwise over 10 min-
utes and the resulting mixture then heated at 55 ЊC for 18 hours.
After cooling, ethyl acetate (150 cm3) and water (25 cm3) were
added to the product to give a clear 2-phase solution. The ethyl
acetate layer was separated and washed with further water
(2 × 25 cm3), dried over sodium sulfate, filtered and the solvent
removed under reduced pressure. The crude product was puri-
fied by flash chromatography on silica gel (4 × 20 cm) using 4%
methanol in dichloromethane as eluant to give ester 16 (5.20 g,
76%) as a colourless oil (Found C, 57.0; H, 7.3. C22H36O10
requires C, 57.4; H, 7.9%); δH(250 MHz; CDCl3) 3.35 (6H, s,
OMe), 3.50–3.75 (16H, m, CH2), 3.84 (4H, t, J 4.8, CH2), 4.12
(4H, t, J 4.7, CH2), 6.67 (1H, t, J 2.3, 4-Ar), 7.16 (2H, d, J 2.3,
General procedure for the preparation of dendritic benzyl
alcohols
A mixture of the required benzyl bromide (2.05 equivalents),
3,5-dihydroxybenzyl alcohol (1.0 equivalents), dry potassium
carbonate (2.5 equivalents) and 18-crown-6 (0.2 equivalents)
were heated at reflux under nitrogen in dry acetone for 18 hours.
The product was diluted with dichloromethane, filtered and the
solvent removed under reduced pressure to yield the crude
product which was purified by flash chromatography on silica
gel.
General procedure for the preparation of dendritic benzyl
bromides
To an ice-cooled solution of the required benzylic alcohol
dendrimer (1.0 equivalents) and tetrabromomethane (1.5
equivalents) in dry tetrahydrofuran was added a solution of
1,2-bis(diphenylphosphino)ethane (0.75 equivalents) in dry
tetrahydrofuran over several minutes. The resulting mixture was
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stirred at 0 ЊC for 10 minutes and then allowed to warm to room
temperature over 20 minutes. The reaction was quenched by the
addition of water (0.25 cm3) and the solvent removed under
reduced pressure to yield the crude product which was purified
by flash chromatography on silica gel.
G3-Br Dendrimer 22
Dendrimer 22 was prepared from 21 (1.19 g, 0.583 mmol),
tetrabromomethane (0.290 g, 0.874 mmol) and 1,2-bis(diphenyl-
phosphino)ethane (0.174 g, 0.437 mmol) in dry tetrahydrofuran
(1.6 cm3 ϩ 0.7 cm3). Flash chromatography using 2–3% meth-
anol in dichloromethane as eluant gave bromide 22 (1.00 g,
81%) as a pale oil (Found: C, 59.8; H, 7.4. C105H155O38Br
requires C, 59.9; H, 7.4%); νmax (CH2Cl2 solution)/cmϪ1 3060w,
2881s, 1596vs, 1450vs, 1372s, 1273s, 1173vs, 1104vs, 1070s;
δH(300 MHz; CDCl3) 3.35 (24H, s, OMe), 3.53 (16H, m, –CH2–
), 3.60–3.75 (48H, m, 3 × –CH2–), 3.81 (16H, t, J 4.9, –CH2–),
4.09 (16H, t, J 4.9, –CH2–), 4.40 (2H, s, CH2Br), 4.93 (12H, s,
CH2Ј and CH2Љ), 6.42 (4H, t, J 2.3, 4-ArЉ), 6.52 (3H, m, 4-Ar
and 4-ArЈ), 6.57 (8H, d, J 2.1, 2-ArЉ), 6.61 (2H, d, J 2.1,
2-Ar), 6.64 (4H, d, J 2.1, 2-ArЈ); δC(300 MHz; CDCl3) 59.2
(OMe), 67.7 (OCH2CH2O), 69.9 (CH2Љ), 70.2 (CH2Ј), 70.8,
70.9, 71.1 (OCH2CH2O), 101.3 (C4Љ), 101.9 (C4Ј), 102.3 (C4),
106.2 (C2Љ), 106.7 (C2Ј), 108.5 (C2), 139.4 (C1 and C1Љ),
140.2 (C1Ј), 160.2, 160.3 and 160.4 (C3, C3Ј and C3Љ); m/z
(ESϩ with added Kϩ) 2144 (2%, MKϩ), 1091 (100%, MK22ϩ),
741 (35%, MK33ϩ).
G2-OH Dendrimer 19
Dendrimer 19 was prepared from bromide 18 (1.85 g, 3.73
mmol), 3,5-dihydroxybenzyl alcohol (0.249 g, 1.776 mmol),
18-crown-6 (94 mg, 0.355 mmol) and dry potassium carbonate
(0.613 g, 4.44 mmol) in dry acetone (20 cm3). The crude product
was purified by flash chromatography using 3–4% methanol in
dichloromethane as eluant to give dendrimer 19 (1.73 g, 100%)
as a colourless oil (Found: C, 59.8; H, 7.7. C49H76O19ؒH2O
requires C, 59.6; H, 8.0%); νmax (CH2Cl2 solution)/cmϪ1 3600w,
3463br, 3060s, 2881vs, 1956w, 1712w, 1597vs, 1450vs, 1350vs,
1296vs and 1105vs; δH(300 MHz; CDCl3) 3.35 (12H, s, OMe),
3.53 (8H, m, –CH2–), 3.60–3.75 (24H, m, 3 × –CH2–), 3.82 (8H,
t, J 4.8, –CH2–), 4.09 (8H, t, J 4.8, –CH2–), 4.59 (2H, d, J 5.5,
-CH2OH), 4.94 (4H, s, CH2Ј), 6.42 (2H, t, J 2.3, 4-ArЈ), 6.48
(1H, t, J 2.3, 4-Ar), 6.57 (6H, m, 2-Ar and 2-ArЈ); δC(300 MHz;
CDCl3) 59.2 (OMe), 64.8 (CH2), 67.7 (CH2Ј), 69.9, 70.0, 70.8,
70.9, 71.0 and 72.1 (3 × OCH2CH2O), 101.2 (C4 and C4Ј),
105.7 (C2), 106.2 (C2Ј), 139.6 (C1Ј), 144.6 (C1), 160.0 and
160.3 (C3 and C3Ј); m/z (ESϩ with added Naϩ) 991 (52%,
MNaϩ), 507 (100%, MNa22ϩ).
G4-OH Dendrimer 23
Dendrimer 23 was prepared from 22 (0.780 g, 0.371 mmol), 3,5-
dihydroxybenzyl alcohol (0.026 g, 0.185 mmol), 18-crown-6 (9.8
mg, 0.037 mmol) and potassium carbonate (0.064 g, 0.463
mmol) in dry acetone (3 cm3). Flash chromatography using
2–5% methanol in dichloromethane as eluant gave dendrimer
26 (0.650 g, 84%) as a colourless oil (Found: C, 61.2; H, 7.5.
C217H316O79ؒ4H2O requires C, 61.2; H, 7.7%); νmax (CH2Cl2
solution)/cmϪ1 3502w, 3060s, 2881vs, 1955w, 1596vs, 1450vs,
1372s, 1296s, 1245w, 1145vs and 1070vs; δH(300 MHz; CDCl3)
2.58 (1H, t, J 5.2, OH), 3.33 (48H, s, OMe), 3.51 (32H, m,
–CH2–), 3.60–3.75 (96H, m, 3 × –CH2–), 3.80 (32H, t, J 4.7,
–CH2–), 4.07 (32H, t, J 4.7, –CH2–), 4.57 (2H, d, J 5.2,
-CH2OH), 4.92 and 4.95 (28H, 2s, CH2Ј, CH2Љ and CH3ٞ), 6.41
(8H, t, J 2.1, 4-Arٞ), 6.51 (7H, m, 4-Ar, 4-ArЈ and 4-ArЉ), 6.56
(16H, d, J 2.1, 2-Arٞ), 6.60 (2H, d, J 2.1, 2-Ar), 6.64 (8H, d,
J 2.1, 2-ArЉ), 6.66 (4H, d, J 2.1, 2-ArЈ); δC(75.5 MHz; CDCl3)
59.3 (OMe), 64.8, 67.8, 69.9, 70.2, 70.8, 70.9, 71.1, 72.2 (CH2),
101.4 and 101.8 (C4, 4Ј, 4Љ, 4ٞ), 105.9, 106.43 and 106.7 (C2,
C2Ј, C2Љ, C2ٞ), 139.4 (C1ٞ), 139.6 (C1Љ), 139.8 (C1Ј), 144.8
(C1), 160.2, 160.3 and 160.4 (C3, C3Ј, C3Љ, C3ٞ); m/z (ESϩ with
added Naϩ) 2118 (5%, MNa22ϩ), 1420 (82%, MNa33ϩ), 1070
(100%, MNa44ϩ).
G2-Br Dendrimer 20
Dendrimer 20 was prepared from 19 (1.70 g, 1.75 mmol), tetra-
bromomethane (0.873 g, 2.63 mmol) and 1,2-bis(diphenyl-
phosphino)ethane (0.526 g, 1.32 mmol) in dry tetrahydrofuran
(2 cm3 ϩ 2 cm3). Flash chromatography using 2–3% methanol
in dichloromethane as eluant gave dendrimer 20 (1.42 g, 79%)
as a pale oil (Found: C, 56.8; H, 7.3. C49H75O18Br requires C,
57.0; H, 7.3%); νmax (CH2Cl2 solution)/cmϪ1 3060w, 2882vs,
1964w, 1736w, 1596vs, 1450vs, 1322s and 1105vs; δH(300 MHz;
CDCl3) 3.36 (12H, s, OMe), 3.53 (8H, m, –CH2–), 3.60–3.75
(24H, m, 3 × –CH2–), 3.83 (8H, t, J 4.9, –CH2–), 4.09 (8H, t,
J 4.9, –CH2–), 4.39 (2H, s, -CH2Br), 4.93 (4H, s, CH2Ј), 6.43
(2H, t, J 2.1, 4-ArЈ), 6.50 (1H, t, J 2.1, 4-Ar), 6.56 (4H, d, J 2.1,
2-ArЈ), 6.59 (2H, d, J 2.1, 2-Ar); δC(75.5 MHz; CDCl3) 34.0
(CH2Br), 59.3 (OMe), 67.6, 70.0 (2 × CH2), 70.3 (OCH2Ar),
70.9, 71.0, 71.1, 72.2 (4 × CH2), 101.4 (C4Ј), 102.5 (C4), 106.3
(C2Ј), 108.5 (C2), 139.3 (C1Ј), 140.1 (C1), 160.3 (C3), 160.4
(C3Ј); m/z (ESϩ with added Naϩ) 1056 (90%, MNaϩ), 539
(100%, MNa22ϩ).
G3-OH Dendrimer 21
G4-Br Dendrimer 24
Dendrimer 21 was prepared from 20 (1.42 g, 1.38 mmol), 3,5-
dihydroxybenzyl alcohol (0.0964 g, 0.688 mmol), 18-crown-6
(0.036 g, 0.138 mmol) and potassium carbonate (0.238 g, 1.72
mmol) in dry acetone (10 cm3). Flash chromatography using
2–4% methanol in dichloromethane as eluant gave dendrimer 21
(1.31 g, 93%) as a colourless oil (Found: C, 60.0; H, 7.4.
C105H156O39ؒCH2Cl2 requires C, 59.9; H, 7.5%); νmax (CH2Cl2
solution)/cmϪ1 3600w, 3463br, 3060s, 2881vs, 1955w, 1596vs,
1450vs, 1350vs, 1296vs and 1130vs; δH(300 MHz; CDCl3) 2.37
(1H, t, J 5.5, OH), 3.34 (24H, s, OMe), 3.52 (16H, m, –CH2–),
3.60–3.75 (48H, m, 3 × –CH2–), 3.81 (16H, t, J 4.8, –CH2–),
4.08 (16H, t, J 4.8, –CH2–), 4.58 (2H, d, J 5.5, -CH2OH), 4.93
and 4.95 (12H, 2s, CH2Ј and CH2Љ), 6.42 (4H, t, J 2.3, 4-ArЉ),
6.49 (3H, m, 4-Ar and 4-ArЈ), 6.56 (10H, m, 2-Ar and 2-ArЉ),
6.62 (4H, d, J 2.1, 2-ArЈ); δC(300 MHz; CDCl3) 59.2 (OMe),
64.7 (G1 CH2), 67.7 (OCH2CH2O), 69.9 (G3 CH2), 70.1 (G2
CH2), 70.7, 70.8, 71.0, 72.1 (OCH2CH2O), 101.0 (C4), 101.3
(C4Љ), 101.7 (C4Ј), 105.7 (C2), 106.2 (C2Љ), 106.5 (C2Ј), 139.5
(C1Љ), 139.8 (C1Ј), 144.8 (C1), 160.1, 160.2 and 160.3 (C3, C3Ј
and C3Љ); m/z (ESϩ with added Naϩ) 2065 (0.5%, MNaϩ), 1044
(100%, MNa22ϩ), 704 (100%, MNa33ϩ).
Dendrimer 24 was prepared from 23 (0.590 g, 0.141 mmol),
tetrabromomethane (0.233 g, 0.705 mmol) and 1,2-bis(diphenyl-
phosphino)ethane (0.140 g, 0.353 mmol) in dry tetrahydrofuran
(1.0 cm3 ϩ 0.5 cm3). Flash chromatography using 2–4% meth-
anol in dichloromethane as eluant gave dendrimer 24 (0.480 g,
80%) as a colourless oil (Found: C, 59.6; H, 7.2. C217H315O-
78Brؒ6H2O requires C, 59.8; H, 7.5%); νmax (CH2Cl2 solution)/
cmϪ1 3060w, 2881vs, 1596vs, 1450vs, 1371s, 1297s, 1245w,
1173vs, 1146vs and 1070s; δH(300 MHz; CDCl3) 3.31 (48H, s,
OMe), 3.50 (32H, m, –CH2–), 3.58–3.75 (96H, m, 3 × –CH2–),
3.81 (32H, t, J 4.7, –CH2–), 4.07 (32H, t, J 4.7, –CH2–), 4.35
(2H, s, –CH2Br), 4.91 and 4.95 (28H, 2s, CH2Ј, CH2Љ and
CH3ٞ), 6.38 (8H, t, J 2.1, 4-Arٞ), 6.48 (6H, m, 4-ArЈ and 4-ArЉ),
6.53 (18H, m, 2-Arٞ and 4-Ar), 6.58 (2H, d, J 2.1, 2-Ar), 6.62
(8H, d, J 2.1, 2-ArЉ), 6.64 (4H, d, J 2.1, 2-ArЈ); δC(75.5 MHz;
CDCl3) 34.0 (CH2Br), 59.2 (OMe), 67.8, 70.0, 70.3, 70.9, 71.0,
71.1, 72.0, 72.3 (CH2), 100.9 (C4ٞ), 101.4 (C4Љ and C4Ј), 101.9
(C4), 105.9 (C2ٞ), 106.4 (C2Љ and C2Ј), 108.6 (C2), 139.4 and
139.5 (C1ٞ, C1Љ and C1Ј), 140.2 (C1), 160.3 and 160.4 (C3ٞ,
C3Љ, C3Ј, C3); m/z (ESϩ with added Kϩ) 2164 (15%, MK22ϩ),
1456 (12%, MK33ϩ), 1101 (5%, MK44ϩ).
J. Chem. Soc., Perkin Trans. 1, 2000, 1881–1889
1887

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G1-OCPy3 Dendrimer 25
(C3), 160.4 (C3Љ) and 161.9 (C3Ј); m/z (ESϩ with added Naϩ)
2310 (1%, MNaϩ), 1167 (100%, MNa22ϩ), 785 (80%, MNa33ϩ),
595 (10%, MNa44ϩ).
Sodium tripyridylmethoxide (1.060 g, 3.72 mmol) and bromo
dendrimer 18 (1.84 g, 3.72 mmol) in anhydrous dimethyl-
formamide (7 cm3) were stirred at room temperature for 18
hours before the solvent was removed under reduced pressure.
Flash chromatography on silica gel (2 × 20 cm) using 2%
methanol in dichloromethane as eluant gave dendrimer 25 (1.56
g, 62%) as a colourless oil (Found: C, 64.0; H, 6.9; N, 6.1.
C37H47N3O9ؒH2O requires C, 63.9; H, 7.0; N, 6.0%); νmax
(CH2Cl2 solution)/cmϪ1 3049w, 2881vs, 1594vs, 1465s, 1432s,
1295w, 1173s, 1107vs and 1070s; δH(300 MHz; CDCl3) 3.35
(6H, s, OMe), 3.53 (4H, m, –CH2–), 3.60–3.75 (12H, m, 3 ×
–CH2–), 3.81 (4H, t, J 4.7, –CH2–), 4.06 (4H, t, J 4.7, –CH2–),
4.41 (2H, s, –CH2OCPy3), 6.35 (1H, t, J 2.4, 4-Ar), 6.51 (2H, d,
J 2.4, 2-Ar), 7.13 (3H, ddd, J 7.4, 4.8, 1.2, 5-PyH), 7.64 (3H,
ddd, J 8.2, 7.4, 1.8, 4-pyH), 7.71 (3H, d, J 8.2, 3-PyH), 8.56
(3H, d, J 4.8, 6-PyH); δC(75.5 MHz; CDCl3) 59.4 (OMe), 67.3
(CH2Ar), 67.8, 70.1, 70.9, 71.0, 71.2, 72.3 (CH2), 88.8 (CPy3),
100.8 (C4), 106.4 (C2), 122.5 (5-Py), 124.1 (3-Py), 136.5 (4-Py),
141.7 (C1), 148.9 (6-Py), 160.1 and 161.9 (2-Py and C3);
m/z (CIϩ) 678 (100%, MHϩ).
G4-OCPy3 Dendrimer 28
Sodium tripyridylmethoxide (0.038 g, 0.133 mmol) and bromo
dendrimer 24 (0.370 g, 0.087 mmol) in anhydrous dimethyl-
formamide (0.75 cm3) were stirred at room temperature for 18
hours before the solvent was removed under reduced pressure.
Flash chromatography on silica gel (2 × 20 cm) using 2.5%
methanol in dichloromethane as eluant gave dendrimer 28
(0.231 g, 60%) as a colourless oil (Found: C, 56.2; H, 6.9; N, 0.6.
C233H327N3O79ؒ9CH2Cl2 requires C, 55.9; H, 6.7; N, 0.8%); νmax
(CH2Cl2 solution)/cmϪ1 3060w, 2881s, 1596vs, 1450vs, 1372s,
1297s, 1245w, 1244vs, 1105vs and 1070s; δH(300 MHz; CDCl3)
3.32 (48H, s, OMe), 3.51 (32H, m, –CH2–), 3.55–3.75 (96H, m,
3 × –CH2–), 3.83 (32H, t, J 4.6, –CH2–), 4.05 (32H, t, J 4.6,
–CH2–), 4.43 (2H, s, –CH2OCPy3), 4.90–4.94 (28H, m, CH2Ј,
CH2Љ and CH3ٞ), 6.42 (8H, t, J 2.1, 4-Arٞ), 6.51 (6H, m, 4-ArЈ
and 4-ArЉ), 6.55 (18H, m, 2-Arٞ and 4-Ar), 6.61 (2H, d, J 2.1,
2-Ar), 6.64 (8H, d, J 2.1, 2-ArЉ), 6.68 (4H, d, J 2.1, 2-ArЈ), 7.09
(3H, br, 5-PyH), 7.57–7.69 (6H, br, 3-PyH and 4-PyH), 8.54
(3H, br, 6-PyH); δC(75.5 MHz; CDCl3) 59.4 (OMe), 67.3, 67.9,
70.0, 70.4, 70.9, 71.0, 71.2 and 72.3 (CH2), 88.8 (CPy3), 101.5,
101.7 and 101.9 (C4, C4Ј, C4Љ, C4ٞ), 106.5 and 106.9 (C2, C2Ј,
C2Љ, C2ٞ), 122.5 (5-Py), 124.2 (3-Py), 136.5 (4-Py), 139.4 (C1Ј,
C1Љ and C1ٞ), 139.9 (C1), 148.9 (6-Py), 160.1 (C3), 160.4 (C3Ј,
C3Љ and C3ٞ) and 161.9 (2-Py); m/z (ESϩ with added Naϩ) 2240
(3%, MNa22ϩ), 1501 (50%, MNa33ϩ), 1131 (80%, MNa44ϩ), 909
(20%, MNa55ϩ).
G2-OCPy3 Dendrimer 26
Sodium tripyridylmethoxide (0.567 g, 2.00 mmol) and bromo
dendrimer 20 (2.06 g, 2.00 mmol) in anhydrous dimethyl-
formamide (4 cm3) were stirred at room temperature for 18
hours before the solvent was removed under reduced pressure.
Flash chromatography on silica gel (2 × 20 cm) using 2%
methanol in dichloromethane as eluant gave dendrimer 26
(1.45 g, 60%) as a pale oil. νmax (CH2Cl2 solution)/cmϪ1 3049w,
2881vs, 1596vs, 1450vs, 1351w, 1274w, 1174s, 1106vs and 1070s;
δH(300 MHz; CDCl3) 3.34 (12H, s, OMe), 3.52 (8H, m, –CH2–),
3.60–3.75 (24H, m, 3 × –CH2–), 3.80 (8H, t, J 4.6, –CH2–), 4.06
(8H, t, J 4.6, –CH2–), 4.42 (2H, s, –CH2OCPy3), 4.93 (4H, s,
CH2Ј), 6.42 (2H, t, J 2.4, 4Ј-Ar), 6.48 (1H, t, J 2.4, 4-Ar), 6.57
(6H, m, 2-Ar and 2Ј-Ar), 7.13 (3H, ddd, J 7.4, 4.8, 1.2, 5-PyH),
7.63 (3H, ddd, J 8.2, 7.4, 1.8, 4-PyH), 7.70 (3H, d, J 8.2,
3-PyH), 8.57 (3H, d, J 4.8, 6-PyH); δC(75.5 MHz; CDCl3) 59.4
(OMe), 67.3, 67.8, 70.0, 70.3, 70.9, 71.0, 71.2 and 72.3 (CH2),
88.8 (CPy3), 101.3 and 101.4 (C4 and C4Ј), 106.4 and 106.6 (C2
and C2Ј), 122.5 (5-Py), 124.2 and 136.5 (3,4-Py), 139.5 (C1Ј),
141.9 (C1), 148.9 (6-Py), 160.1, 160.4 and 161.9 (C3, C3Ј and
2-Py); m/z (ESϩ with added Naϩ) 1236.5853 (20%, MNaϩ.
C65H87N3O19Naϩ requires 1236.5831), 630 (100%, MNa22ϩ),
619 (25%, MNaH2ϩ).
Acknowledgements
We thank the Leverhulme trust for financial support of the
work and the EPSRC national mass spectrometry service
centre, Swansea for recording the electrospray mass spectra.
Notes and references
1 G. R. Newkome, C. N. Moorefield and F. Vögtle, Dendritic
Molecules: Concepts, Syntheses, Perspectives, VCH, Weinheim, 1996
and references therein.
2 (a) D. A. Tomalia, H. Baker, J. R. Dewald, M. Hall, G. Kallos,
S. Martin, J. Roeck, J. Ryder and P. A. Smith, Polym. J. (Tokyo),
1985, 17, 117; (b) G. R. Newkome, Z. Yao, G. R. Baker and
V. K. Gupta, J. Org. Chem., 1985, 50, 2003; (c) C. J. Hawker and
J. M. J. Fréchet, J. Am. Chem. Soc., 1990, 112, 7638; (d) T. M. Miller
and T. X. Neenan, Chem. Mater., 1990, 2, 346.
G3-OCPy3 Dendrimer 27
3 H. F. Chow, T. K. K. Mong, M. F. Nongrum and C. W. Wan,
Tetrahedron, 1998, 54, 8543.
Sodium tripyridylmethoxide (0.203 g, 0.713 mmol) and bromo
dendrimer 22 (1.50 g, 0.713 mmol) in anhydrous dimethyl-
formamide (2.0 cm3) were stirred at room temperature for 18
hours before the solvent was removed under reduced pressure.
Flash chromatography on silica gel (2 × 20 cm) using 2–3%
methanol in dichloromethane as eluant gave dendrimer 27
(0.060 g, 55%) as a pale oil (Found: C, 62.5; H, 7.3; N, 1.6.
C121H167N3O39ؒ2H2O requires C, 62.5; H, 7.4; N, 1.8%); νmax
(CH2Cl2 solution)/cmϪ1 3049w, 2881s, 1596vs, 1450vs, 1372s,
1274s, 1173vs, 1105vs and 1070s; δH(300 MHz; CDCl3) 3.35
(24H, s, OMe), 3.53 (16H, m, –CH2–), 3.60–3.75 (48H, m, 3 ×
–CH2–), 3.81 (16H, t, J 4.7, –CH2–), 4.09 (16H, t, J 4.7, –CH2–),
4.44 (2H, s, –CH2OCPy3), 4.91 (8H, s, CH2Љ), 4.93 (4H, s,
CH2Ј), 6.42 (4H, t, J 2.3, 4-ArЉ), 6.52 (3H, m, 4-Ar and 4-ArЈ),
6.56 (8H, d, J 2.1, 2-ArЉ), 6.60 (2H, d, J 2.1, 2-Ar), 6.65 (4H, d,
J 2.1, 2-ArЈ), 7.17 (3H, m, 5-PyH), 7.66 (6H, m, 3-PyH and
4-PyH), 8.61 (3H, d, J 4.7, 6-PyH); δC(75.5 MHz; CDCl3) 59.9
(OMe), 67.3, 67.8, 70.0, 70.3, 70.9, 71.0, 71.2 and 72.3 (CH2),
88.8 (CPy3), 101.3 (C4), 101.5 (C4Љ), 101.8 (C4Ј), 106.0, 106.5
and 106.7 (C2, C2Ј and C2Љ), 122.5 (5-Py), 124.1 (3-Py), 136.5
(4-Py), 139.4 (C1Љ), 139.8 (C1Ј), 141.9 (C1), 148.9 (6-Py), 160.1
4 G. R. Newkome, E. He and C. N. Moorefield, Chem. Rev., 1999, 99,
1689.
5 For example, see (a) R. A. Gossage, L. A. de Kuil and G. van Koten,
Acc. Chem. Res., 1998, 31, 423; (b) I. Cuadrado, M. Morán, C. M.
Casado, B. Alonso, F. Lobete, B. Garcia, M. Ibisate and J. Losada,
Organometallics, 1996, 15, 5278; (c) M. Bardaji, M. Kustos,
A.-M. Caminade, J.-P. Majoral and B. Chaudret, Organometallics,
1997, 16, 403. For a comprehensive review, see ref. 4.
6 For example, see (a) S. Campagna, G. Denti, S. Serroni, A. Juris,
M. Venturi, V. Ricevuto and V. Balzani, Chem. Eur. J., 1995, 1, 211;
(b) V. Huc, P. Boussaguet and P. Mazerolles, J. Organomet. Chem.,
1996, 521, 253; (c) G. R. Newkome, R. Güther, C. N. Moorefield,
F. Cardullo, L. Echegoyen, E. Pérez-Cordero and H. Luftmann,
Angew. Chem., Int. Ed. Engl., 1995, 36, 609; (d) W. T. S. Huck,
F. C. J. M. van Veggel, B. L. Kropman, D. H. A. Blank, E. G. Keim,
M. M. A. Smithers and D. N. Reinhoudt, J. Am. Chem. Soc., 1995,
117, 8293; (e) E. C. Constable, Chem. Commun., 1997, 1073. See
also ref. 4.
7 For example, see (a) R.-H. Jin, T. Aida and S. Inoue, J. Chem. Soc.,
Chem. Commun., 1993, 1260; (b) M. Kawa and J. M. J. Fréchet,
Chem. Mater., 1998, 10, 286; (c) H.-F. Chow, I. Y. K. Chan,
D. T. Chan and R. W. Kwok, Chem. Eur. J., 1996, 2, 1085.
8 There have been a number of reports of the modification of
electronic and redox properties of dendrimer-encapsulated metal
1888
J. Chem. Soc., Perkin Trans. 1, 2000, 1881–1889

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ions: for example, see (a) P. J. Dandliker, F. Diederich, M. Gross,
C. B. Knobler, A. Louati and E. M. Sanford, Angew. Chem., Int. Ed.
Engl., 1994, 33, 1739; (b) C. M. Cardona and A. E. Kaifer, J. Am.
Chem. Soc., 1998, 120, 4023; (c) P. Bhyrappa, J. K. Young,
J. S. Moore and K. S. Suslick, J. Am. Chem. Soc., 1996, 118, 5708.
9 (a) D. L. White and J. W. Faller, Inorg. Chem., 1982, 21, 3119;
(b) M. J. Hannon, P. C. Mayers and P. C. Taylor, Tetrahedron Lett.,
1998, 39, 8509.
10 For a discussion of the problems associated with formation of
inactive dimeric species, see (a) N. Narasimha Murthy and K. D.
Karlin, J. Chem. Soc., Chem. Commun., 1993, 1236; (b) A. Looney,
R. Han, K. McNeill and G. Parkin, J. Am. Chem. Soc., 1993, 115,
4690; (c) B. Greener, M. H. Moore and P. H. Walton, Chem.
Commun., 1996, 27.
11 D. M. Haddleton, H. S. Sahota, P. C. Taylor and S. G. Yeates,
J. Chem. Soc., Perkin Trans. 1, 1996, 649 and references therein.
12 For example, using cyclohexene or cyclohexa-1,4-diene as hydrogen
source: A. M. Felix, E. P. Heimer, T. J. Lambros, C. Tzougraki and
J. Meienhofer, J. Org. Chem., 1978, 43, 4194.
13 The preparation of this ligand has been reported in high yield:
J. W. Faller and Y. Ma, J. Am. Chem. Soc., 1991, 113, 1579.
14 To the best of our knowledge this is the first report of this ligand.
15 Prepared by an analogous procedure to that reported for the
MOM-protected compound: T. Nagata, Bull. Chem. Soc. Jpn., 1992,
65, 385.
16 D. K. Smith and F. Diederich, Chem. Commun., 1998, 2501.
Methoxytriethylene glycol terminated dendrimers have also recently
been reported by Moore: D. J. Pesak, J. S. Moore and T. E. Wheat,
Macromolecules, 1997, 30, 6467.
17 Monomer unit 18 and generation 2 dendrimer 19 were reported
by another worker during the preparation of this manuscript:
D. K. Smith, J. Chem. Soc., Perkin Trans. 2, 1999, 1563.
18 M. Ouchi, Y. Inoue, Y. Liu, S. Nagamune, S. Nakamura, K. Wada
and T. Hakushi, Bull. Chem. Soc. Jpn., 1990, 63, 1260.
19 If triphenylphosphine is used in place of DPPE, the resulting
impure bromo-dendrimer can be used in the subsequent coupling
step with no reduction in yield. The triphenylphosphine oxide
impurity is then readily removed during purification of the hydroxy-
dendrimer obtained. This was found to be preferable in very large
scale syntheses due to TPP being considerably less expensive than
DPPE.
20 I. A. O’Neil, S. Thompson, C. L. Murray and S. B. Kalindjian,
Tetrahedron Lett., 1998, 7787.
21 For
a general discussion of the application of electrospray
techniques to proteins and other biomolecules, see S. J. Gaskell,
J. Mass Spectrom., 1997, 32, 677.
J. Chem. Soc., Perkin Trans. 1, 2000, 1881–1889
1889