Solid-phase synthesis and acidolytic degradation of sterically congested oligoether dendrons

Article abstract of DOI:10.1039/c2ob25691f

Up to third-generation sterically crowded polyether dendrons were prepared on a solid support, using a novel building block derived from dimethyl 5-hydroxyisophthalate via O-allylation/Claisen rearrangement key steps. These dendrons underwent smooth disas

Full text of DOI:10.1039/c2ob25691f

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PAPER
Solid-phase synthesis and acidolytic degradation of sterically congested
oligoether dendrons†
Jeny Karabline and Moshe Portnoy*
Received 23rd February 2012, Accepted 27th April 2012
DOI: 10.1039/c2ob25691f
Up to third-generation sterically crowded polyether dendrons were prepared on a solid support, using a
novel building block derived from dimethyl 5-hydroxyisophthalate via O-allylation/Claisen rearrangement
key steps. These dendrons underwent smooth disassembly to monomers, when subjected to acidic
solution. The reason for this decomposition was traced to the increased electron density of the aromatic
rings of the new monomers that destabilizes the bonds connecting the building blocks.
unit for polyether dendrons, the assembly of such dendrons on
polystyrene support and the unexpected decomposition of the
Introduction
In the past two decades an impressive variety of dendritic mol-
ecules were prepared and investigated for a broad range of appli-
cations.1 These molecules were mostly prepared in solution,
while only a relatively small portion of the dendritic compounds
were assembled on an insoluble matrix or post-synthetically
attached to solid supports.2,3 While, in general, the structure and
properties of monomeric units usually strongly affect the proper-
ties of the dendritic molecules assembled from these modules, in
the case of dendronized solid supports these features of the
branched monomers strongly affect not only the properties of the
dendritic fragment, but also those of the whole matrix–dendron
composite material. The strongest influence is that of the term-
inal units decorating the dendritic periphery, as we demonstrated
in the past for polyether dendrons on cross-linked polystyrene.4
However, the structure and properties of the inner parts of the
dendrons can also impart important features on the properties
and functioning of the entire construct. For instance, we
observed the influence of the coordinating heteroatoms in the
dendritic backbone of supported catalysts on the outcome of the
Heck reaction.5
new dendrons in acidic solution.
Results and discussion
So far the majority of dendritic motifs used in insoluble
support–dendron composites were the easily accessible “privi-
leged” structures, such as PAMAM, polylysine or polyurea
dendrons.6–8 While in a number of cases steric hindrance of the
dendrons was reported (usually as a factor obstructing their effec-
tive synthesis), it did not originate from the monomeric unit
structure, but rather emerged during the dendron assembly.9 Due
to the extensive experience in solid-phase synthesis of polyether
dendrons gathered in our group in the past decade,4,10 we
decided to design and prepare a sterically congested monomeric
unit that will enable assembly of dendrons based on this motif.
Though soluble polyether dendrons, mostly of the Fréchet-type,
are used frequently for a variety of applications,11 polyether-
dendronized supports are relatively scarce.4,10,12
A literature search concluded that incorporation of substituents
in the ortho-to-hydroxyl positions in 5-hydroxyisophthalates,
which we used previously as a monomer in the polyether
dendron synthesis,4,10c can be accomplished in an efficient and
selective manner only for allyl substituents via the Claisen
rearrangement reaction.13,14 The bis-allylated compound 1 was
obtained from dimethyl 5-hydroxyisophthalate by a stepwise
introduction of two allylic groups in the ortho-to-hydroxyl
positions of dimethyl 5-hydroxyisophthalate via the O-allylation/
While this was a purely electronic effect, steric effects in the
dendritic backbone of dendronized supports are also an intri-
guing possibility. In this regard, the questions that we asked our-
selves are whether it is possible to construct dendrons on solid
support from sterically congested monomers, what would be the
properties of such dendrons and how will such a dendritic
design affect the properties and functioning of the new support?
Herein we report the synthesis of a sterically crowded building
Claisen
rearrangement
sequence
performed
twice
(Scheme 1).14a–f The synthesis can be carried out in a highly
efficient and practical way. The O-allylation reactions afford allyl
ether intermediates in excellent yield and high purity, so that in
the next steps they could be used after a short workup without
further purification. Moreover, there is usually no need for exten-
sive purification after the first Claisen rearrangement, since
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact
Sciences, Tel Aviv University, Tel Aviv 69978, Israel. E-mail:
portnoy@post.tau.ac.il; Fax: +972 3640 9293; Tel: +972 3640 6517
†Electronic supplementary information (ESI) available: NMR spectra.
See DOI: 10.1039/c2ob25691f
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to the reported procedures. In this manner we succeeded in
building the first to third generation structures G1(dipropyl-X)–
G3(dipropyl-X) (X = CO2Me, CH2OH or CH2Cl).
Gel phase 13C NMR spectroscopy of the resins was used to
monitor the synthetic transformations, while the structure and
purity of the dendrimers were determined via the TFA-induced
cleavage, followed by 1H NMR and 13C NMR. 1H NMR
measurements of the dendrons of the first generation demon-
strated excellent conversion and purity of each of the steps,
based on the following characteristic changes. The reduction step
was accompanied by the disappearance of the carboxymethyl
signal at 4.00 ppm and the appearance of the CH2OCOCF3
signals (under the cleavage conditions the alcohols gradually
undergo trifluoroacetylation) at 5.44 ppm; the latter disappeared
upon chlorodehydroxylation, being replaced by the CH2Cl signal
at 4.62 ppm.
Scheme 1 Synthesis of the branched building blocks.
1
The H NMR measurements of the cleaved second and third
generation dendrons revealed that under acidic conditions these
molecules are being disassembled gradually to the monomeric
building blocks (e.g. Scheme 3, R = n-propyl). This was some-
what surprising, since similar dendrons built from dimethyl
5-hydroxyisophthalate (which lacks propyl substituents) are
stable under equivalent conditions.4,10c
The observed phenomenon does not represent a synthetic
problem, since we intend to use the intact matrix–dendron com-
posite support. However, it somewhat complicated the character-
ization. Accordingly, the analysis of each synthetic step followed
the complete disassembly of the dendron and was based on the
total loading of the monomeric units and the proportion between
their different variants. These measurements demonstrated excel-
lent conversion and purity of each of the synthetic steps forming
the second and third generation dendrons. The characteristic
changes in the aromatic region of the 1H NMR spectrum,
observed upon the decomposition described in Scheme 3,
are demonstrated in Fig. 1. Thus, the disassembly of intact
G2(dipropyl-CO2Me) was accompanied by the disappearance
of the aromatic signals at 8.17 and 7.64 ppm and the appearance
of the signal of 2 at 7.95 ppm and the signals of 3 at 8.17 and
7.33 ppm (Fig. 1a–b). The subsequent disassembly of 3 was
accompanied by the disappearance of its aromatic signals and
Scheme 2 Synthesis of dendrons on solid support.
partial solvent removal usually leads to spontaneous crystalliza-
tion of the pure product as a colorless solid.15 Chromatographic
purification must be carried out only after the second Claisen
rearrangement, yielding compound 1.
In order to avoid unwanted side reactions of the allylic substi-
tuents during the dendron-building procedures, we decided to
continue working with n-propyl substituted monomer 2, which
was obtained via hydrogenation of 1 in excellent yield and
purity after a simple workup (Scheme 1).14b,e
The synthetic route to the dendron preparation followed the
one reported in the past for the assembly of polyether dendrons
from the hydroxyisophthalate units without the propyl substitu-
ents (Scheme 2).10c It included immobilization of 2 via nucleo-
philic substitution, followed by the reduction with LiBH4 and,
then, activation of the hydroxybenzyl arms, used for the dendri-
mer growth, by the chlorodehydroxylation reaction with PPh3
and C2Cl6. The replacement of the LiH base by a more “user-
friendly” K2CO3 at the substitution step was the only alteration
Scheme 3 Post-cleavage acidolytic degradation of dendrons.
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Fig. 2 “Mixed” second generation dendrons.
Fig. 1 The aromatic part of the 1H NMR spectra of G2(dipropyl-
CO2Me) in the cleavage solution (TFA–CDCl3, 1 : 1) after (a) 0.5 h; (b)
2.5 h; (c) 5 h; (d) 7.5 h.
the appearance of the G1(dipropyl-CH2OCOCF3) signal at
7.12 ppm in addition to the increase in the intensity of the signal
of 2 at 7.95 ppm.
The introduction of the propyl substituents on the dendron-
forming modules could affect the dendron stability under acidic
conditions in a number of possible ways. The stabilization of the
benzyl cations in the respective ortho/para positions makes the
benzylic carbon–oxygen bond more labile and may facilitate its
cleavage. Alternatively, the increase in the electron density on
the propylated aromatic rings raises the basicity of phenol
oxygen, facilitates its protonation and thus may increase the rate
of the bond cleavage. Finally, the steric strain may destabilize
the dendritic structure.
Fig. 3 The aromatic part of the 1H NMR spectra of G2(dipropyl/
2H-CO2Me) in the cleavage solution (TFA–CDCl3, 1 : 1) after (a) 1 h;
(b) 2.5 h; (c) 7.5 h; (d) 24 h.
In order to distinguish between these mechanistic explanations
of the dendrimer degradation, we synthesized two additional
second-generation dendritic molecules (Fig. 2). One of the den-
drons was built starting with the dipropylated building block 2
as the first generation module, while the second generation was
assembled using dimethyl 5-hydroxyisophthalate (G2(dipropyl/
2H-CO2Me)). The use of these two building blocks in the con-
struction of the second dendron was in the opposite order
(G2(2H/dipropyl-CO2Me)). In this way each of the dendrons
expressed only one of the electronic factors, which might be
responsible for the Gn(dipropyl) dendrons’ disassembly. If the
stabilization of the benzylic cations by the ortho- and para-
positioned propyls is the main reason for the instability of the
Gn(dipropyl) (n > 1) dendrons in the TFA solution, then the
“mixed” dendron G2(dipropyl/2H-CO2Me) will be also decom-
posed in this solution. However, if the increase in the basicity of
the phenol oxygen induced by the propyl substituents contributes
to the instability of Gn(dipropyl) in the acidic solution, then we
may expect that the second “mixed” dendron (G2(2H/dipropyl-
CO2Me)) will be decomposed upon acidic treatment. The dis-
assembly of both “mixed” dendrons will proceed slower than
that of G2(dipropyl-CO2Me), if at all, in the case that the steric
strain is the main reason for the phenomenon. In the latter case,
one may expect that the more sterically congested dendron
G2(2H/dipropyl-CO2Me) will undergo the decomposition
faster than G2(dipropyl/2H-CO2Me).
Both dendrons were analyzed by a series of 1H NMR
measurements in the 1 : 1 TFA–CDCl3 cleavage solution, which
revealed that only the G2(dipropyl/2H-CO2Me) dendron was
decomposed under the acidolytic conditions (Scheme 3 (R =
H)), while G2(2H/dipropyl-CO2Me) remained as an intact
structure in this solution, even after 72 h. This behavior proves
that the major factor contributing to the sensitivity of the
Gn(dipropyl) (n > 1) dendrons to acid is the stabilization of the
benzylic cations by the ortho- and para-positioned propyl
substituents.
1
The characteristic changes in the aromatic region of the H
NMR spectrum, observed upon the degradation of G2(dipropyl/
2H-CO2Me), are demonstrated in Fig. 3. The disassembly of
intact G2(dipropyl/2H-CO2Me) was accompanied by the dis-
appearance of the aromatic signals at 8.36, 7.94 and 7.24 ppm
and the appearance of the dimethyl 5-hydroxyisophthalate
(G1(CO2Me)) signals at 8.35 and 7.87 ppm and the signals of
4 at 8.37, 7.95 and 7.17 ppm (Fig. 3a–b). The subsequent
decomposition of 4 was accompanied by the disappearance of its
aromatic signals and the appearance of the G1(dipropyl-
CH2OCOCF3) signal at 7.11 ppm, as well as the increase in the
intensity of the signals of G1(CO2Me) at 8.35 and 7.87 ppm.
Processing of the raw NMR monitoring data of the decompo-
sition of the second generation dendrons in the 1 : 1 TFA–CDCl3
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solution is summarized in the charts in Fig. 4a–b. Though it is
difficult to compare the rates of the conversion of the intact den-
drons G2(dipropyl-CO2Me) and G2(dipropyl/2H-CO2Me) into
the partially disassembled dendrons 3 and 4, respectively, due to
the partial overlap of the signals of the two-arm and one-arm
structures and the fast reaction rate, the subsequent decompo-
sition of the one-arm G2 structures is notably faster for com-
pound 3 (kobs 0.44 h−1 for 3 and 0.19 h−1 for 4).16 In order to
carefully monitor the first disassembly process, we performed a
1
series of H NMR measurements in the less acidic 1 : 9 TFA–
CDCl3 solvent mixture. The characteristic changes in the aro-
matic region of the 1H NMR spectrum, observed upon the degra-
dation of both dendrons in this solvent mixture, were similar to
those depicted in Fig. 1 and 3,17 but occurred at a slower rate.
Processing of these data (Fig. 4c–d) proved that G2(dipropyl-
CO2Me) undergoes decomposition significantly faster than G2-
(dipropyl/2H-CO2Me) (kobs values of 0.19 h−1 and 0.076 h−1
respectively).18 It is likely that these differences, as well as those
between the decomposition rates of 3 and 4, are caused by the
increased phenol–oxygen basicity induced by the propyl substi-
tuents and/or higher steric strain in the case of the G2(dipropyl-
CO2Me) dendron and compound 3, whereas these properties by
themselves are not sufficient to induce acidolytic degradation.
Experimental
General
All reactions were conducted under a nitrogen atmosphere in
oven-dried glassware with magnetic stirring. THF was dried
over, and distilled from, sodium metal with benzophenone as the
indicator. Dichloromethane was dried over, and distilled from,
CaH2.
Wang bromo polystyrene resin is 1% crosslinked divinyl-
benzene–styrene copolymer, 100–200 mesh, with loading
0.90 mmol g−1 and was purchased from Novabiochem.
1H NMR (400.13 MHz) and 13C NMR (100.62 MHz) spectra
were recorded on Bruker AVANCE-200 and AVANCE-400 spec-
trometers, in CDCl3 or CDCl3–TFA 1 : 1, with residual CHCl3
(1H, 7.26 ppm) or CDCl3 (13C, 77.0 ppm) as an internal stan-
dard. Gel-phase 13C NMR (100.62 MHz) spectra were recorded
in benzene-d6 on a Bruker AVANCE-400 instrument using the
solvent as an internal standard (13C, 126.0 ppm).
Column chromatography was performed using silica gel 60
(particle size 0.04–0.06 mm).
For solid-phase synthesis, yields were determined using the
1H NMR spectra of TFA–CDCl3 (1 : 1, v/v) cleavage solutions
with 11 mM C6H6 (7.36 ppm) as an internal standard. Alcohols
were fully converted to TFA esters under these conditions. For
MALDI measurements, dendrons were cleaved by TFA–CDCl3
(1 : 9, v/v) for 15 min and the solvents were evaporated immedi-
ately after filtration.
Synthesis in solution
Typical O-allylation procedure: synthesis of dimethyl 5-(allyl-
oxy)isophthalate.13 Allyl bromide (4.12 ml, 47.6 mmol, 2
equiv.) was slowly added to a stirred solution of dimethyl
5-hydroxyisophthalate (5.00 g, 23.8 mmol, 1 equiv.) and K2CO3
(4.93 g, 35.7 mmol, 1.5 equiv.) in dry DMF (44 ml). The slurry
was stirred at room temperature for 19 h and the progress of the
reaction was monitored by TLC. After completion of the
Fig. 4 Monitoring of the disassembly of (a) G2(dipropyl-CO2Me) in
TFA–CDCl3, 1 : 1; (b) G2(dipropyl/2H-CO2Me) in TFA–CDCl3, 1 : 1;
(c) G2(dipropyl-CO2Me) in TFA–CDCl3, 1 : 9; (d) G2(dipropyl/
2H-CO2Me) in TFA–CDCl3, 1 : 9.
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reaction, the mixture was diluted with H2O (100 ml) and
extracted with ether (3 × 200 ml). The combined extracts were
washed with H2O (6 × 150 ml), brine (2 × 150 ml) and dried
over Na2SO4. The solvent was removed under reduced pressure
to give dimethyl 5-(allyloxy)isophthalate (5.61 g, 95%) as a col-
orless solid used in the next step without further purification.
1H NMR (400 MHz, CDCl3): δ 8.27 (t, J = 1.4 Hz, 1H); 7.76
(d, J = 1.4 Hz, 2H); 6.10–6.00 (m, 1H); 5.44 (dq, J = 17.2 Hz,
J = 1.5 Hz, 1H); 5.32 (dq, J = 10.5 Hz, J = 1.3 Hz, 1H); 4.62
(dt, J = 5.2 Hz, J = 1.5 Hz, 2H); 3.93 (s, 6H). 13C NMR
(100.6 MHz): δ 166.1, 158.6, 132.4, 131.8, 123.1, 120.1, 118.2,
69.2, 52.4.
1 (2.20 g, 7.6 mmol, 1 equiv.) in MeOH, in a flask with an
attached valve-equipped hydrogen-filled balloon. The mixture
was stirred under hydrogen for 4 h at room temperature and the
progress of the reaction was monitored by TLC. After com-
pletion of the reaction, the catalyst was filtered and washed with
MeOH. The filtrate and washings were combined and the solvent
was evaporated to yield the pure product as a colorless solid
(2.10 g, 96%).
1H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H); 5.07 (s, 1H);
3.89 (s, 6H); 2.97–2.93 (m, 4H); 1.67–1.57 (m, 4H); 1.02 (t, J =
7.3 Hz, 6H). 13C NMR (100.6 MHz): δ 167.5, 152.8, 133.5,
128.3, 124.8, 52.1, 29.1, 23.0, 14.4.
MS (ESI): Calcd for C16H21O5 (M − H) 293.1, found 293.1.
Typical Claisen rearrangement procedure: synthesis of di-
methyl 4-allyl-5-hydroxyisophthalate.13 A solution of dimethyl
5-(allyloxy)isophthalate (2.50 g, 10.0 mmol, 1 equiv.) in
o-dichlorobenzene (13 ml) was refluxed under nitrogen for 44 h.
The progress of the reaction was followed by TLC analysis. Part
of the solvent was removed under high vacuum until precipi-
tation started. Following the crystallization the solid was filtered
and dried in vacuum to give dimethyl 4-allyl-5-hydroxyisophtha-
late (2.13 g, 84%) as a colorless solid used in the next step
without further purification.
Solid phase synthesis
Typical procedure for nucleophilic substitution: synthesis of
G1(dipropyl-CO2Me). K2CO3 (0.56 g, 4.1 mmol, 3 equiv.),
2 (1.99 g, 6.8 mmol, 5 equiv.), TBAI (0.75 g, 2.0 mmol, 1.5
equiv.) and 18-crown-6 ether (0.11 g, 0.4 mmol, 0.3 equiv.) were
added to a suspension of Wang bromo polystyrene resin (1.50 g,
1.4 mmol, 0.90 mmol g−1, 1 equiv.) in DMF (12 ml). The sus-
pension was heated to 60 °C for 3 days. The resin was washed
with DMF–water, DMF, THF–water, THF, CHCl3 and then dried
1H NMR (400 MHz, CDCl3): δ 8.11 (d, J = 1.7 Hz, 1H); 7.64
(d, J = 1.7 Hz, 1H); 6.07–5.97 (m, 1H); 5.47 (s, 1H); 5.14–5.07
(m, 2H); 3.92 (s, 3H); 3.91 (s, 3H); 3.82 (dt, J = 6.0 Hz, J = 1.6
Hz, 2H). 13C NMR (100.6 MHz): δ 167.4, 166.1, 155.0, 135.3,
132.1, 131.8, 129.2, 124.1, 119.7, 116.4, 52.4, 31.2.
under vacuum. Yield 100%, loading 0.76 mmol g−1
.
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 165.1,
156.5, 113.2, 74.0, 49.6, 28.0, 23.1, 12.8. Following TFA-
induced cleavage: 1H NMR (400 MHz, CDCl3–TFA 1 : 1):
δ 7.93 (s, 1H); 4.01 (s, 6H); 2.95–2.91 (m, 4H); 1.67–1.59 (m,
4H); 1.01 (t, J = 7.3 Hz, 6H). 13C NMR (100.6 MHz, CDCl3–
TFA 1 : 1): δ 170.9, 152.9, 134.8, 128.1, 125.4, 53.3, 29.4, 23.0,
13.9.
MS (ESI): Calcd for C13H13O5 (M − H) 249.1, found 249.1.
Synthesis
of
dimethyl
4-allyl-5-(allyloxy)isophthalate.
Dimethyl 4-allyl-5-(allyloxy)isophthalate was prepared from
dimethyl 4-allyl-5-hydroxyisophthalate (5 g, 20.0 mmol, 1
equiv.) under O-allylation reaction conditions, using allyl
bromide (3.46 ml, 40.0 mmol, 2 equiv.) and K2CO3 (4.14 g,
30.0 mmol, 1.5 equiv.) in dry DMF (44 ml). The product was
characterized and used without further purification (5.24 g,
90%).
Typical procedure for reduction: synthesis of G1(dipropyl-
CH2OH). LiBH4 (12.11 ml, 24.2 mmol, 20 equiv., 2 M solution
in THF) and B(OMe)3 (0.14 ml, 1.2 mmol, 1 equiv.) were added
to a suspension of the resin G1(dipropyl-CO2Me) (1.60 g,
1.2 mmol, 0.76 mmol g−1, 1 equiv.) in THF (5 ml). The mixture
was heated to 40 °C for 24 h. The resin was washed with an
aqueous solution of ammonium chloride–THF, ethanolamine–
THF, DMF, THF–water, THF, CHCl3 and then dried under
1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 1.5 Hz, 1H); 7.62
(d, J = 1.4 Hz, 1H); 6.09–5.90 (m, 2H); 5.43 (dq, J = 17.3 Hz,
J = 1.6 Hz, 1H); 5.29 (dq, J = 10.6 Hz, J = 1.4 Hz, 1H);
5.03–4.95 (m, 2H); 4.61 (dt, J = 5.0, J = 1.6, 2H); 3.91 (s, 3H);
3.89 (s, 3H); 3.81 (dt, J = 6.2 Hz, J = 1.5 Hz, 2H). 13C NMR
(100.6 MHz): δ 167.4, 166.2, 156.8, 135.8, 135.5, 132.5, 131.6,
128.7, 123.7, 117.6, 115.2, 69.4, 52.2, 30.8.
vacuum. Yield 83%, loading 0.65 mmol g−1
.
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 113.2,
74.5, 60.6, 27.4, 22.9, 13.1. Following TFA-induced cleavage:
1H NMR (400 MHz, CDCl3–TFA 1 : 1): δ 7.11 (s, 1H); 5.44 (s,
4H); 2.72–2.68 (m, 4H); 1.67–1.57 (m, 4H); 1.05 (t, J = 7.3 Hz,
6H). 13C NMR (100.6 MHz, CDCl3–TFA 1 : 1): δ 152.3, 131.1,
130.2, 126.0, 68.6, 29.0, 23.2, 13.9.
Synthesis of dimethyl 4,6-diallyl-5-hydroxyisophthalate (1).
The product 1 was prepared from dimethyl 4-allyl-5-(allyloxy)
isophthalate (5 g, 17.2 mmol, 1 equiv.) under Claisen rearrange-
ment reaction conditions, but the reaction was completed in
17 h. The crude material was purified by column chromato-
graphy on a silica gel (5 : 95 EtOAc–hexanes) to give the pure
product (4.9 g, 97%) as a yellow oil.
Typical procedure for chlorodehydroxylation: synthesis of
G1(dipropyl-CH2Cl). Hexachloroethane (2.32 g, 9.8 mmol, 10
equiv.) and triphenylphosphine (2.57 g, 9.8 mmol, 10 equiv.)
were added to a suspension of the resin G1(dipropyl-CH2OH)
(1.51 g, 0.98 mmol, 0.65 mmol g−1, 1 equiv.) in THF (12 ml).
The suspension was mixed at room temperature overnight. The
resin was washed with THF–H2O, THF, CHCl3 and then dried
1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H); 6.06–5.96
(m, 2H); 5.52 (s, 1H); 5.14–5.07 (m, 4H); 3.89 (s, 6H); 3.83 (dt,
J = 6.0 Hz, J = 1.6 Hz, 4H). 13C NMR (100.6 MHz): δ 167.3,
154.3, 135.5, 131.0, 129.2, 124.9, 116.3, 52.2, 31.5.
under vacuum. Yield 80%, loading 0.50 mmol g−1
.
Synthesis of dimethyl 5-hydroxy-4,6-dipropylisophthalate (2).
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 113.2,
Pd/C (5%) was carefully added to the stirred solution of phenol
74.0, 42.3, 27.6, 22.7, 12.8. Following TFA-induced cleavage:
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1H NMR (400 MHz, CDCl3–TFA 1 : 1): δ 7.07 (s, 1H); 4.62
(s, 4H); 2.76–2.72 (m, 4H); 1.69–1.59 (m, 4H); 1.06 (t, J = 7.3
Hz, 6H). 13C NMR (100.6 MHz, CDCl3–TFA 1 : 1): δ 151.8,
134.9, 129.7, 126.0, 44.3, 28.8, 23.4, 14.0.
Synthesis of G2(2H/dipropyl-CO2Me)
K2CO3 (0.03 g, 0.2 mmol, 5 equiv.), 2 (0.10 g, 0.3 mmol, 8
equiv.), TBAI (0.04 g, 0.1 mmol, 2.5 equiv.) and 18-crown-6
ether (6.73 mg, 0.03 mmol, 0.6 equiv.) were added to a suspen-
sion of G1(CH2Cl) resin10c (0.15 g, 0.04 mmol, 0.28 mmol g−1
,
1 equiv.) in DMF (1.5 ml). The suspension was heated to 60 °C
for 3 days. The resin was washed with DMF–water, DMF, THF–
water, THF, CHCl3 and then dried under vacuum. Yield 100%,
Synthesis of G2(dipropyl-CO2Me)
We proceeded as for the synthesis of G1(dipropyl-CO2Me) but
used the following quantities: K2CO3 (0.35 g, 2.5 mmol, 5
equiv.), 2 (1.17 g, 4.0 mmol, 8 equiv.), TBAI (0.46 g, 1.3 mmol,
2.5 equiv.) and 18-crown-6 ether (79.24 mg, 0.3 mmol, 0.6
equiv.), and G1(dipropyl-CH2Cl) (1.00 g, 0.5 mmol,
0.50 mmol g−1, 1 equiv.) in DMF (10 ml). Yield 100%, loading
loading 0.25 mmol g−1
.
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 165.1,
156.4, 140.7, 111.2, 113.1, 73.9, 68.1, 49.7, 28.0, 23.2, 12.8.
1
Following TFA-induced cleavage: H NMR (400 MHz, CDCl3–
TFA 1 : 1): δ 8.18 (s, 2H); 7.33 (s, 1H); 7.12 (s, 2H); 4.93
(s, 4H); 4.04 (s, 12H); 3.06–3.02 (m, 8H); 1.66–1.56 (m, 8H);
0.97 (t, J = 7.3 Hz, 12H). 13C NMR (100.6 MHz, CDCl3–TFA
1 : 1): δ 171.5, 156.9, 154.6, 143.8, 139.7, 130.1, 128.9, 120.0,
114.5, 76.2, 53.7, 30.2, 25.0, 14.0.
0.40 mmol g−1
.
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 165.0,
155.7, 140.9, 113.1, 73.7, 72.5, 49.7, 28.0, 23.3, 12.8. Following
1
TFA-induced cleavage: H NMR (400 MHz, CDCl3–TFA 1 : 1):
δ 7.95 (s, 2H); 7.12 (s, 1H); 5.45 (s, 4H); 4.03 (s, 12H);
2.97–2.93 (m, 8H); 2.72–2.68 (m, 4H); 1.68–1.57 (m, 12H);
1.07–1.00 (m, 18H). 13C NMR (100.6 MHz, CDCl3–TFA 1 : 1):
δ 171.3, 153.0, 152.3, 135.1, 131.0, 130.1, 128.2, 125.8, 125.6,
68.5, 53.4, 29.5, 29.0, 23.1, 13.9, 13.8.
MS (MALDI): Calcd for C46H62O11Na (M + Na) 813.4,
found 813.4; calcd for C46H62O11K (M + K) 829.4, found
829.4.
Synthesis of G2(dipropyl/2H-CO2Me)
LiH (3.18 mg, 0.4 mmol, 10 equiv.), dimethyl 5-hydroxy-
isophthalate (0.17 g, 0.8 mmol, 20 equiv.) and TBAI (0.09 g,
0.2 mmol, 6 equiv.) were added to a suspension of G1(dipropyl-
CH2Cl) resin (0.10 g, 0.04 mmol, 0.40 mmol g−1, 1 equiv.) in
DMF (1 ml). The suspension was heated to 60 °C for 2 days.
The resin was washed with DMF–water, DMF, THF–water, THF,
CHCl3 and then dried under vacuum. Yield 100%, loading
Synthesis of G2(dipropyl-CH2OH)
0.35 mmol g−1
.
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 163.8,
157.2, 130.5, 121.5, 118.2, 113.2, 73.8, 66.8, 50.0, 27.6, 22.6,
12.8. Following TFA-induced cleavage: 1H NMR (400 MHz,
CDCl3–TFA 1 : 1): δ 8.35 (t, J = 1.4, 2H); 7.87 (d, J = 1.5, 4H);
7.12 (s, 1H); 5.45 (s, 4H); 4.06 (s, 12H); 2.72–2.68 (m, 4H);
1.67–1.57 (m, 4H); 1.05 (t, J = 7.3 Hz, 6H). 13C NMR
(100.6 MHz, CDCl3–TFA 1 : 1): δ 166.3, 156.3, 152.2, 137.0,
131.8, 126.4, 122.8, 120.8, 63.3, 52.5, 28.2, 23.2, 14.4.
MS (MALDI): Calcd for C34H38O11Na (M + Na) 645.2,
found 645.2; calcd for C34H38O11K (M + K) 661.2, found
661.2.
We proceeded as for the synthesis of G1(dipropyl-CH2OH) but
for 48 h, using the following quantities: LiBH4 (8.19 ml,
16.4 mmol, 40 equiv., 2 M solution in THF), B(OMe)3
(93.01 μl, 0.8 mmol, 2 equiv.) and the resin G2(dipropyl-
CO2Me) (1.05 g, 0.4 mmol, 0.39 mmol g−1, 1 equiv.) in THF
(5 ml). Yield 88%, loading 0.35 mmol g−1
.
Partial gel-phase 13C NMR (100.8 MHz, C6D6): δ 75.7, 61.1,
28.2, 24.0, 13.0. Following TFA-induced cleavage: 1H NMR
(400 MHz, CDCl3–TFA 1 : 1): δ 7.12 (s, 3H); 5.45 (s, 12H);
2.72–2.68 (m, 12H); 1.67–1.57 (m, 12H); 1.05 (t, J = 7.2 Hz,
18H). 13C NMR (100.8 MHz, CDCl3–TFA 1 : 1): δ 152.3,
131.0, 130.1, 125.9, 68.6, 28.9, 23.2, 13.9.
Synthesis of G3(dipropyl-CO2Me)
Synthesis of G2(dipropyl-CH2Cl)
We proceeded as for the synthesis of G1(dipropyl-CO2Me)
but used the following quantities: K2CO3 (0.23 g, 1.6 mmol,
8 equiv.), 2 (0.84 g, 2.9 mmol, 14 equiv.), TBAI (0.34 g,
0.9 mmol, 4.5 equiv.) and 18-crown-6 ether (46.02 mg,
0.2 mmol, 0.85 equiv.), and G2(dipropyl-CH2Cl) (0.50 g,
0.20 mmol, 0.40 mmol g−1, 1 equiv.) in DMF (4 ml). Yield
We proceeded as for the synthesis of G1(dipropyl-CH2Cl) but
for 48 h, using the following quantities: hexachloroethane
(1.62 g, 6.9 mmol, 20 equiv.), triphenylphosphine (1.80 g,
6.9 mmol, 20 equiv.) and the resin G2(dipropyl-CH2OH)
(0.98 g, 0.3 mmol, 0.35 mmol g−1, 1 equiv.) in THF (8 ml).
Yield 100%, loading 0.34 mmol g−1
.
100%, loading 0.29 mmol g−1
.
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 155.4,
Partial gel-phase 13C NMR (100.6 MHz, C6D6): δ 165.1,
155.7, 140.9, 132.4, 113.3, 72.5, 49.7, 28.1, 23.3, 12.8. Follow-
ing TFA-induced cleavage: 1H NMR (400 MHz, CDCl3–TFA
1 : 1): δ 7.92 (s, 4H); 7.07 (s, 3H); 5.41 (s, 12H); 4.00 (s, 24H);
2.94–2.90 (m, 16H); 2.69–2.65 (m, 12H); 1.66–1.55 (m, 28H);
1.05–0.99 (m, 42H). 13C NMR (100.6 MHz, CDCl3–TFA 1 : 1):
δ 171.4, 153.0, 152.3, 135.1, 130.9, 130.1, 128.5, 125.8, 125.7,
68.5, 53.5, 29.6, 28.9, 23.1, 13.9, 13.8.
134.5, 133.4, 113.0, 73.7, 72.0, 42.1, 27.5, 22.9, 13.1. Following
1
TFA-induced cleavage: H NMR (400 MHz, CDCl3–TFA 1 : 1):
δ 7.12 (s, 1H); 7.08 (s, 2H); 5.45 (s, 4H); 4.62 (s, 8H);
2.92–2.62 (m, 12H); 1.82–1.59 (m, 12H); 1.19–1.02 (m, 18H).
13C NMR (100.6 MHz, CDCl3): δ 152.3, 151.9, 135.1, 131.4,
130.4, 129.9, 126.4, 126.3, 68.8, 44.4, 29.1, 28.9, 23.5, 23.4,
14.1, 13.9.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4788–4794 | 4793

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MS (MALDI): Calcd for C106H142O23Na (M + Na) 1807.0,
found 1807.0; calcd for C106H142O23K (M + K) 1823.0, found
1823.0.
Conclusion
In conclusion, we developed new sterically congested building
blocks for the synthesis of polyether dendritic molecules and
demonstrated the solid-phase assembly of up to third-generation
dendrons, incorporating these branched modules. The increased
electron density of the aromatic rings of the new monomers
destabilizes the bonds, connecting them in the dendritic frame-
work. Accordingly, these dendrons exhibit clean acidolytic dis-
assembly into monomeric units. Although the dendrons reported
in this paper require relatively high acidity of the medium in
order to undergo complete degradation, the study of the prin-
ciples of such acidolytic decomposition may be of importance in
the future for design of functional dendritic constructs, for
instance in the field of drug delivery.19
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Acknowledgements
This research was supported by Grant No. 955/10 from the Israel
Science Foundation and Grant No. 2008193 from the United
States–Israel Binational Science Foundation (BSF).
15 Another way to purify the crude material is the recrystallization from
toluene and hexane.
16 kobs are pseudo-first-order decomposition constants calculated for 3 and 4
from the data in Fig. 4a–b after disappearance of the parent dendrons
(after 2 h in cleavage solution).
17 Slight changes in the chemical shifts were observed due to the change in
the solvent composition.
18 kobs are pseudo-first-order decomposition constants calculated for the
second generation dendrons from the data in Fig. 4c–d.
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4794 | Org. Biomol. Chem., 2012, 10, 4788–4794
This journal is © The Royal Society of Chemistry 2012