Bis-ureidodeazapterin (Bis-DeAP) as a general route to supramolecular star polymers

Article abstract of DOI:10.1016/j.tet.2008.05.076

Supramolecular recognition unit Bis-DeAP, 1, containing two high affinity hydrogen-bonding acceptor-acceptor-donor-donor (AADD) arrays was designed to self-assemble into cyclic assemblies. It was prepared through a highly scalable synthesis and was further functionalized with 2-bromo-2-methylpropanoyl bromide and used to initiate the polymerization of methylmethacrylate (MMA). Bis-DeAP-PMMA polymers quantitatively self-assembled into star polymers in toluene. In DMF Bis-DeAP-PMMA forms a mixture of star polymers and unassembled polymers. Bis-DeAP was also functionalized with polyethylene glycol (PEG) polymers. The Bis-DeAP-PEG polymers formed star polymers in DMF; however, higher molecular weight polymeric assembles that varied with concentration were observed in water. Mixing studies in toluene indicated that the self-assembled star polymers are kinetically stable and resist mixing even at elevated temperatures. In DMF, kinetically controlled structures are initially observed, however, mixing occurs at a faster rate and assembled star polymers show a decrease in polydispersity index (PDI) over time. In addition, Bis-DeAP functionalized PS and PMMA were mixed in DMF to generate a star copolymer through self-assembly.

Full text of DOI:10.1016/j.tet.2008.05.076

Tetrahedron 64 (2008) 8558–8570
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Bis-ureidodeazapterin (Bis-DeAP) as a general route to supramolecular
star polymersq
*
Eric M. Todd, Steven C. Zimmerman
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Supramolecular recognition unit Bis-DeAP, 1, containing two high affinity hydrogen-bonding acceptor–
acceptor–donor–donor (AADD) arrays was designed to self-assemble into cyclic assemblies. It was
prepared through a highly scalable synthesis and was further functionalized with 2-bromo-2-methyl-
propanoyl bromide and used to initiate the polymerization of methylmethacrylate (MMA). Bis-DeAP–
PMMA polymers quantitatively self-assembled into star polymers in toluene. In DMF Bis-DeAP–PMMA
forms a mixture of star polymers and unassembled polymers. Bis-DeAP was also functionalized with
polyethylene glycol (PEG) polymers. The Bis-DeAP–PEG polymers formed star polymers in DMF; how-
ever, higher molecular weight polymeric assembles that varied with concentration were observed in
water. Mixing studies in toluene indicated that the self-assembled star polymers are kinetically stable
and resist mixing even at elevated temperatures. In DMF, kinetically controlled structures are initially
observed, however, mixing occurs at a faster rate and assembled star polymers show a decrease in
polydispersity index (PDI) over time. In addition, Bis-DeAP functionalized PS and PMMA were mixed in
DMF to generate a star copolymer through self-assembly.
Received 11 March 2008
Received in revised form 13 May 2008
Accepted 16 May 2008
Available online 21 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
units connected by flexible linkers (either discrete or polymeric).
Flexible linkers allow for a large amount of entropic freedom and
Significant effort has gone into the development of recognition
units for use in supramolecular polymers. Partly this is a result of
the unique properties noncovalent interactions can bestow upon
polymeric materials.1 These properties include stimuli responsive
and self-healing abilities, as well as, dramatic decreases in melt
viscosity, permitting facile processing. The directionality of hy-
drogen bonds and the ability to prepare modules containing
hydrogen-bonding arrays, thereby controlling the strength and
specificity of their interactions, has lead to hydrogen bonding
occupying a privileged place among the noncovalent forces utilized
in supramolecular polymer chemistry.2 Although numerous rec-
ognition units that use hydrogen bonding are available, and several
have been used in applications, the ureidopyrimidinone (UPy)
hydrogen-bonding module developed by Meijer and co-workers3
has seen the most widespread use and has maturated to the point
of commercialization.4 More recent advances involve newly de-
veloped hydrogen-bonding modules that form heterocomplexes
with high fidelity.5
typically lead to main-chain random-coil polymers when ditopic
modules are used and network polymers when tritopic, or higher,
modules are employed (Fig.1a). An alternative approach is to fix the
hydrogen-bonding arrays at a specific angle to each other, either
through constraining the faces in a common heterocyclic scaffold or
connecting the modules through a conformationally biased linker.
As a result of the fixed angle, constrained ditopic modules tend
to form discrete, cyclic structures that often show cooperative
behavior leading to assemblies with unique stability and responses
to stimuli.6–8 In addition, the angle between the recognition units
provides an additional level of molecular information storage by
determining the type of cyclic structure that is formed (Fig. 1b).
Using ditopic hydrogen-bonding modules that assembled den-
drimers,7b we investigated the supramolecular assembly of star
polymers.9 Herein, we describe the synthesis and characterization
of a general-purpose ditopic hydrogen-bonding module based on
the bis-ureidodeazapterin (Bis-DeAP) motif (Fig. 2).10 This general-
purpose module, 1, is an analog of a previously reported ditopic
module.7b It contains two di-tert-butyl benzyl groups providing
solubility in nonpolar organic solvents and an alcohol group as an
attachment point for polymerization initiators or direct function-
alization with telechelic polymers. Furthermore, we describe the
incorporation of 1 into conventional polymers and report the self-
assembly behavior of these materials.
The majority of hydrogen-bonding supramolecular polymers
previously investigated have been based on individual recognition
q
Taken in part from the Ph.D. thesis of Eric M. Todd, University of Illinois, 2007.
* Corresponding author.
E-mail address: sczimmer@uiuc.edu (S.C. Zimmerman).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.076

E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
8559
alkylated at the 4-postion. Alkylation of 2 proceeded in poor yield,
most likely a result of the oxidative instability of 4; however, this
yield was serviceable as the THP protected bromohydrin, 3, is easily
and cheaply prepared from 1,4-butanediol and methyl gallate is an
inexpensive, commercially available starting material. Alkylation of
4 with di-tert-butyl benzyl bromide, 5, proceeded in good yield
affording 6, which showed no sign of instability. Ester 6 was easily
reduced to benzyl alcohol 7 with DIBAL-H.
2.2. Preparation of ditopic hydrogen-bonding module
An improved preparation of 1 was developed that avoided the
Curtius rearrangement.7b Thus, Meijer and co-workers reported the
synthesis of ureidopyrimidinones by reacting amines with 1,10-
carbonyldiimidazole (CDI) activated isocytosines.11 This approach
was adapted to the synthesis of 1 as outlined in Scheme 2. Begin-
ning with dinitrophenol 8, the aryl-ether solubilizing group, 7, was
attached using a Mitsunobu reaction to yield 9. Quantitative re-
duction of the nitro-groups yielded the bis-amine 10 that was
coupled with the CDI activated deazapterin 13. Compound 13 was
difficult to characterize as a result of its low solubility. Because
the presence of unreacted starting material could not be ruled out,
6–8 equiv of 13 was used in coupling with bis-amine 10. Sub-
sequent removal of the THP group in acidic THF yielded the
general-purpose ditopic hydrogen-bonding module 1.
The synthetic approach in Scheme 2 offers multiple advantages
over the previously published route.7b The reactions generally
afford products in higher yields and require shorter reaction times
with less purification. Indeed, only one silica gel column was
required for the conversion of 8 to 1 (Scheme 2). As a result, the
synthesis was quite scalable and multiple grams of 1 could be
prepared within 2 weeks.
Figure 1. Schematic representations of ditopic hydrogen-bonding modules. (a) Flexi-
ble linkers lead to main-chain supramolecular polymers. (b) Modules connected by
a conformationally constrained linker favor discrete, cyclic structures. The size of the
cyclic assemblies is determined by the angle between the hydrogen-bonding modules.
2.3. Characterization of ditopic hydrogen-bonding modules
The MALDI spectrum and a representative SEC trace (toluene
eluent) for 11 are shown in Figure 3. The sodium, potassium, and
proton adducts of 11 are all clearly present, as is the proton adduct
of 1, which may result from the acid wash used in the workup of 11
or be formed during the MALDI ionization process. Using poly-
styrene (PS) standards the number average molecular weight (Mn)
determined for the aggregates by SEC is 6.6 kDa, which is close to
2. Synthesis and characterization
2.1. Preparation of aryl-ether solubilizing group
The synthesis of the aryl-ether solubilizing group (Scheme 1)
began with methyl gallate, 2, which can be regioselectively
Figure 2. Design and self-assembly of general-purpose bis-ureidodeazapterin (Bis-DeAP) module.

8560
E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
OTHP
Br
3
CO2Me
CO2Me
K2CO3, 18-Crown-6
Acetone
HO
OH
HO
OH
OH
O
20%
2
OTHP
4
R
O
Br
O
O
5
K2CO3, 18-Crown-6
Acetone
OTHP
R = CO2Me
R = CH2OH
6
DIBAL-H
THF
98%
74%
7
Scheme 1.
7
OH
THPO
PPh3, DIAD
THF
O2N
NO2
O
O
O
83%
8
O
R = NO2
9
Pd/C, H2
EtOH/CH2Cl2
quant.
R = NH2 10
R
R
RO
Figure 3. (a) Toluene SEC of Bis-DeAP–OTHP, 11; molecular weights determined from
RI signal using conventional calibration with polystyrene standards. (a) MALDI mass
spectrum of 11, using IAA as matrix.
O
O
O
O
13
CHCl3
85%
the calculated molecular of a hexamer (7.2 kDa). The narrow
polydispersity index (PDI) suggests that there is only one species
present and the calculated molecular weight of the peak does not
change significantly over a 10-fold change in concentration, sug-
gesting the formation of a discrete aggregate. The UV detector
detects the presence of the heterocyclic portion of the Bis-DeAP
module at a wavelength of 310 nm, where the modified dendron is
mostly transparent.
O
N
O
O
NH
O
HN
N
N
N
H
N
H
N
N
N
H
H
R = THP 11
25% HCl(aq)
THF
R = H
1
Proton NMR analysis of 11 is complicated by broadening of the
signals (Fig. 4). This broadening can be attributed to the formation
of polymeric aggregates, either main-chain supramolecular poly-
mers or polymeric stacks of the assembled, cyclic 11. However,
there was no evidence for large polymeric structures that could
lead to the observed broadening. Alternatively, the broadness of the
proton NMR spectrum may be the result of a large number of ste-
reoisomers. The ureidodeazapterin (DeAP) heterocycle exists in
several protomeric forms,12 which would also exist in 11 (Fig. 5).
These stereoisomers can be combined in thousands of ways13
leading to the observed broadness in the NMR spectrum.
58%
O
N
O
CDI
THF
O
HN
HN
H2N
N
N
H
N
N
N
N
69%
13
12
Scheme 2.

E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
8561
H
N
(a)
O
O
O
N
O
H
N
O
H
N
H
O
N
N
H
N
n-Bu
H
N
N
H
N
N
N
N
H
N
H
H
N
n-Bu
n-Bu
(b)
O
O
H
N
O
N
O
n-Bu
n-Bu
N
N
N
H
N
H
N
N
N
H
N
H
H
N
H
N
H
N
H
N
N
O
N
N
O
n-Bu
n-Bu
O
N
N
Figure 4. Proton NMR of Bis-DeAP–OTHP 11 in CDCl3 with an expansion of the hy-
drogen-bonding region.
O
N
N
H
H
13% (40%)
N
N
46% (43%)
Although compound 1 is only sparingly soluble in toluene, the
UV signal from the SEC indicates the formation of a discrete
assembly with a molecular weight close to what would be pre-
dicted for a hexamer. Unfortunately, compound 1 is not soluble
enough to get a reliable RI signal, which is needed to apply the PS
standard calibration curve (PS is not observable in toluene by UV).
The MALDI mass spectrum of 1 is shown in Figure 6, along with
a representative SEC trace (THF eluent). Compound 1 has better
solubility in THF and forms assemblies whose relative amounts vary
with concentration.
N
N
n-Bu
N
H
H
O
n-Bu
O
N
H
N
O
H
O
H
N
H
N
H
H
O
H
N
H
N
N
N
O
N
N
O
n-Bu
N
O
N
O
N
H
n-Bu
H
N
2% (6%)
39% (11%)
(c)
2.4. Molecular modeling and hexagonal close-packed
approximation
O
H
OR
O
OR
H
N
O
N
H
H
N
A computational investigation was undertaken to gain further
insight into the structure of the Bis-DeAP assemblies. Although
there are always difficulties in unequivocally determining the
structure of supramolecular assemblies, the above data is consis-
tent with a discrete hexamer, which agrees with previous work
involving the Bis-DeAP modules self-assembly of dendrimers.7b
Figure 7a shows the semi-empirical PM3 equilibrium geometry of
a hexameric Bis-DeAP core, substituting methyl groups where the
aryl-ether solubilizing groups would be attached. Viewed from
above, the assembly appears to be circular with a diameter of
approximately 33 Å and an approximately 12 Å void in the center.
When the assembly is viewed from the side it appears to have
a significant curvature. This curvature is most likely a result of
the heterocycles’ inability to form a planar dimer due to steric
interaction between the aryl C–H and the substituent attached to
the urea (Fig. 7b). Although similar tilting has been observed in the
crystal structures of related recognition units, a reported crystal
structure of the DeAP dimer indicates that the modules are nearly
planar. This discrepancy may be due to the PM3 method over-
estimating steric interactions or to crystal packing effects forcing
planar arrangements in the solid state. Regardless of these ambi-
guities, the structure in Figure 7 is still a useful first approximation
of the size and shape of the Bis-DeAP assembly.
N
N
N
H
N
H
N
N
N
N
N
H
N
H
N
N
H
N
H
O
H
O
H
N
N
O
N
N
O
N
OR
N
OR
H
H
N
O
N
O
H
H
O
N
N
H
N
H
N
O
N
N
H
N
H
N
H
N
H
O
H
N
O
H
N
N
N
N
N
O
O
N
Figure 5. Self-association of ureidodeazapterin (DeAP) regardless of tautomerism.
(a) Self-complementary protomeric forms of DeAP. Two non-complementary proto-
meric forms omitted. (b) Dimers of DeAP with percentage of each dimer in toluene-d6
(CDCl3) as measured by 1H NMR.12 (c) Four likely stereoisomers of Bis-DeAP after
considering the multiple tautomeric forms of DeAP.
To understand better the self-assembly behavior of 1, it is useful
to know the amount of space available to each substituent attached
to a Bis-DeAP unit before it begins to interact sterically with its
neighbors. To obtain an estimate of this parameter, the Bis-DeAP
module was assumed to form a perfect, circular hexamer with its
substituents arranged on a hexagonal close-packed lattice (Fig. 8).
Addition of the aryl-ether solubilizing groups to the Bis-DeAP core
increases the size of the assembly to a point were semi-empirical
calculations are no longer feasible, therefore, molecular mechanics
was employed to minimize the structure and obtain an estimate
of 55 Å for its diameter. In the approximation of hexagonal
close-packed spheres this implies that a substituent larger then
55 Å will be in physical contact with its nearest neighbors.
3. Atom transfer radical polymerization (ATRP) of
methylmethacrylate (MMA)
Controlled polymerization methods have recently received an
impressive amount of attention because their living character
produces polymers of low polydispersity, wide monomer scope,
and ability to generate a range of polymer architectures.14 With this

8562
E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
Figure 6. (a) THF SEC of Bis-DeAP–OH, 1, using an RI detector. Molecular weights
determined using conventional calibration with polystyrene standards. (b) MALDI
mass spectrum of 1 using IAA as matrix.
utility in mind, 1 was reacted with 2-bromo-2-methylpropanoyl
bromide to yield the atom transfer radical polymerization (ATRP)
initiator 14 (Scheme 3). We have previously reported the prepa-
ration of polystyrene star polymers using 14 as the initiator.9 To
further expand the utility of the Bis-DeAP module, 14 was used to
initiate the polymerization of methylmethacrylate at 70 ꢀC in ani-
sole with [14]¼[CuBr]¼[PMDETA]¼11 mM and [MMA]¼3.1 M
(Fig. 9). Model initiator 16 was also subjected to identical poly-
merization conditions to estimate the molecular weight of the
polymer in the absence of self-assembly. Analysis of the polymer by
SEC (DMF with 50 mM LiBr eluent, 50 ꢀC) results in two peaks that
do not significantly shift over a 10-fold concentration range in-
dicating the formation of discrete aggregates. The larger molecular
weight peak is assigned as assembled star polymer and the lower
molecular weight peak, which is very similar to the PMMA gener-
ated from model initiator 16, is assigned as unassembled polymer.
The lower molecular weight Bis-DeAP–PMMA could also be ana-
lyzed by SEC with toluene eluent resulting in a single, high
molecular weight peak, indicating that all the polymers contained
Figure 7. Semi-empirical/PM3 energy minimizations. (a) Bis-DeAP core with the aryl-
ether solubilizing groups replaced by methyl groups. (b) Single DeAP dimer illustrating
its inability to form a planar complex through PM3 minimization.
the Bis-DeAP module. In addition, reinvestigation of the Bis-DeAP–
PS star polymers by DMF SEC gave similar results with a high and
a low molecular weight peak.
Closer examination of the data in Figure 9 shows that the best-fit
lines for the assembled star polymer and unassembled PMMA
polymers have a lower R2 value then in the previously reported bulk
PS polymerization.9 This is a result of the PMMA polymerization

E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
8563
Br
O
O
O
O
O
Br
Br
O
O
1
Et3N, Toluene
O
N
O
O
N
50%
NH
O
HN
N
N
N
H
N
H
N
N
H
H
14
O
Br
OH
O
Br
Br
O
Et3N, Toluene
BnO
OBn
BnO
OBn
51%
15
16
Scheme 3.
best-fit line has a slope 1/9 that of the assembled material and
considering each time point separately, the assembled material is
on average 8 times the molecular weight of the unassembled
material. Comparison of the assembled material with the PMMA
generated from the model initiator 16 gave similar results. That the
SEC molecular weight is independent of concentration indicates the
presence of cyclic aggregates. A hexamer model is favored by
analogy to the previously examined systems and the uncertainty in
these measurements. However, the presence of other similar sized
aggregates (pentamers, heptamers) cannot be ruled out with the
data reported here.
Figure 8. Estimating the amount of space available to substituents attached to a hex-
americ assembly of 1 using a hexagonal close-packed approximation. Compound 1 was
minimized using molecular mechanics employing the MMFF force field.
occurring in solution and the concentration of the monomer de-
creasing as the polymerization proceeds. This causes the rate of
polymerization to slow with conversion and the relationship
between molecular weight and time is no longer linear. To provide
a valid comparison using a linear approximation, the polymeriza-
tion was only carried out to approximately 10% conversion, result-
Figure 9. Mn of PMMA generated by ATRP of 14 and of model initiator 16 versus time.
Molecular weights determined from DMF SEC (50 mM LiBr, 50 ꢀC) using RI detection and
conventional calibration with polystyrene standards. Labels indicate the MW of
assembled and unassembled 17. Polymerization conditions: [Initiator]¼[CuBr]¼
[PMDETA]¼11 mM, [MMA]¼3.1 mM in anisole, 70 ꢀC.
ing in
a minimal change in the monomer concentration.
Comparison of the slopes indicates that the unassembled material’s

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E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
4. Size exclusion chromatography (SEC) studies of star
polymer mixing
Investigation of the mixing of different sized star polymers in
toluene by SEC indicated that they were very slow to mix, sug-
gesting that the star polymers are kinetically stable. Thermody-
namically, mixing should occur both for entropic reasons and also
to minimize steric interactions.7c Figure 10 shows the toluene SEC
chromatograms of a solution containing Bis-DeAP–PMMA 17 and
Bis-DeAP–PS 19 that was stirred at room temperature. The exper-
iment was set up so that there was significantly less of the smaller
polymeric component in hopes that this would decrease the time
needed for mixing to occur. However, even after 4 months, the
polymers do not appear to be completely mixed as indicated by the
discrepancy between the RI and UV signals. Both detector signals
should be identical when the polymers have mixed to a homoge-
nous composition. Similar results were obtained when the larger
and smaller polymers were identical (PMMA or PS).
To determine if annealing could facilitate mixing, a solution was
prepared containing Bis-DeAP–PMMA 17 and unfunctionalized Bis-
DeAP, 20 (Fig. 11). Compound 20 was prepared using the literature
method and is proposed to assemble into a dodecameric structure
in toluene.7b A solution was prepared with equal amounts by mass
Figure 11. Bis-DeAP–PMMA, 17, and Bis-DeAP, 20, mixed in toluene at 80 ꢀC. Aliquots
analyzed by toluene SEC at room temperature. Molecular weights determined from RI
signal using conventional calibration with polystyrene standards.
of 17 and 20. After 5 days of stirring at 80 ꢀC, there is clear evidence
for mixing, including a decrease in the RI signal for 20, and an
increase in the UV signal for the polymeric material. The molecular
weight of the star polymer peak also decreases as it incorporates
20. Mixing is still very slow in toluene, even at 80 ꢀC and un-
fortunately further heating led to decomposition, observed as
lower molecular weight peaks in the chromatogram.
The mixing of different sized star polymers occurs much faster
in DMF. Figure 12 illustrates the mixing of equal amounts by mass
of Bis-DeAP–PS 19 and Bis-DeAP–PMMA 17 in DMF at room tem-
perature. A significant amount of mixing is evident immediately
after the solution was prepared and the polymers appear to be
mostly mixed after 24 h. This mixing process represents an alter-
native synthesis of star copolymers where instead of utilizing
covalent chemistry the PMMA/PS copolymer is generated through
self-assembly.
5. Decreased polydispersity with increased molecular weight
Previously published results demonstrated how Bis-DeAP rec-
ognition units assemble low molecular weight polymers into high
molecular weight materials accompanied by a decrease in the
molecular weight distribution as measured by the PDI.9 Application
of quantitative statistical models to the assembly of the star poly-
mers indicated that even more dramatic decreases in the molecular
weight distribution should be achievable.15 Two possible explana-
tions for this larger than statistical molecular weight distribution
Figure 10. Bis-DeAP–PMMA, 17, and Bis-DeAP–PS, 19, mixed in toluene at room
temperature. Aliquots analyzed by toluene SEC. Molecular weights determined from RI
signal using conventional calibration with polystyrene standards.

E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
8565
Figure 12. Relatively fast mixing of Bis-DeAP–PMMA 17 and Bis-DeAP–PS 19 in DMF at
room temperature to generate a star copolymer through self-assembly. Molecular
weights determined from DMF SEC (50 mM LiBr, 50 ꢀC) using RI detection and
conventional calibration with polystyrene standards.
Figure 13. Schematic representation of possible explanations for larger then statistical
PDI. (a) Initially the smaller polymeric material assembles first followed by the larger
material leading to a kinetically controlled molecular weight distribution. Sterically the
polymer coils should want to alternate between large and small leading to a thermo-
dynamically controlled molecular weight distribution. (b) The original star polymer
distribution contains multiple discrete aggregates.
seem likely and are illustrated schematically in Figure 13. The as-
sembly of the polymers in toluene could be under kinetic control,
where small polymers assemble together before larger polymers.
Alternatively, there could be more then one discrete structure
present. It is also conceivable that both mechanisms are active.
The mixing studies reported above indicated that the assemblies
were more dynamic in DMF, although a kinetically controlled
structure is still initially observed. When monitored over time the
PDI of the assembled material slowly decreases and approaches
a presumably thermodynamic state as illustrated in Figure 14. In
Figure 14a the number (Mn), weight (Mw), and peak (Mp) molecular
weights of an assembled Bis-DeAP–PS star polymer are plotted.
There is little variation in Mn and Mp over time; however, Mw de-
creases dramatically from 287.7 kDa to almost 200 kDa in 24 h and
continues to decrease slightly over time. This drop in Mw corre-
sponds to a similar drop in PDI of the assembled material from 1.69
to 1.28, which further drops to a minimum value of 1.20 (Fig. 14b).
Both the molecular weight parameters and PDI appear to increase
near the end of the experiment, which is attributed to experimental
error. The molecular weight parameters and PDI of the
unassembled material do not significantly change over the course
of the experiment (Fig. 14c). Furthermore the fraction of assembled
polymer increases over time, as would be predicted for a state
closer to a thermodynamic minimum. Although it seems clear that
the initial assembly of the polymers is governed by kinetics, this
kinetic state could consist of both large and small discrete star
polymers that mix to form an alternating structure or a mixture of
different sized aggregates that eventually coalesce into a smaller
number of more stable aggregates.
6. Polyethylene glycol functionalized Bis-DeAP for assembly
in water
The assembly of hydrogen-bonding modules in water has re-
ceived considerable interest over the past several years.16,17 As
a result of the general-purpose design of 1, it is easy to functionalize

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E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
O
O
O
n
O
O
O
O
O
O
HO
nO
1
DCC, DMAP
CH2Cl2
O
N
O
O
N
H
H
N
O
O
N
N
N
H
N
H
N
H
N
H
N
98%
76%
21a (5 kDa PEG)
21b (20 kDa PEG)
OH
O
O
O
25% HCl (aq)
THF
9
O
77%
O2N
NO2
O
22
O
O
n
O
O
O
(20 kDa)
O
O
O
HO
nO
DCC, DMAP
CH2Cl2
O
86%
O2N
NO2
23
Scheme 4.
Figure 14. Kinetic investigation of Bis-DeAP–PS 19 in DMF at room temperature. (a)
Molecular weight parameters of assembled material in DMF over time. The molecular
weight of the unassembled material did not change appreciably over the course of the
experiment. (b) PDI of assembled and unassembled material over time. (c) Repre-
sentative chromatographs at beginning of experiment and after 40 days.
in the SEC chromatogram (Fig. 15a). The absolute molecular
weights determined by DMF SEC appear to be significantly over-
estimated. In particular, the 20 kDa unassembled material is cal-
culated as 62 kDa from the chromatogram. This is a result of the
molecular weight being derived from a polystyrene calibration
curve and analysis of the MPEG–20K-acid starting material yields
a molecular weight of approximately 60 kDa in DMF.
Analysis by water SEC using conventional calibration with PEG
standards provides a more accurate estimation of the molecular
weight. First looking at the control compound 23, peaks at 18 and
28 kDa are observed. The 18 kDa peak is assigned as the aryl-ether
functionalized PEG, which assumes a collapsed confirmation in
water to bury the hydrophobic aryl groups and therefore appears to
be a smaller molecular weight than the starting MPEG–acid.18 The
peak at 28 kDa is most likely unreacted MPEG–acid. There is also
a small, higher molecular weight shoulder that could arise from
either hydrophobic association of 23 or larger polymers generated
from impurities in the PEG starting material. The water SEC chro-
matogram of Bis-DeAP–20K-PEG 21b contains lower molecular
it with polyethylene glycol (PEG) polymers and investigate its as-
sembly in water. Initially, 1 was functionalized with a 5 kDa PEG
with a single acid end group (MPEG–5K-acid) through a DCC/DMAP
esterification. Unfortunately, the Bis-DeAP–5K-PEG 21a was not
soluble in water, although it did appear to form hexameric struc-
tures in DMF along with unassembled material. Bis-DeAP–OH 1 was
then reacted under the same conditions with MPEG–20K-acid. End
group analysis by proton NMR indicated approximately 80% func-
tionalization and this material was water-soluble. In addition
compound 23 was prepared as a control compound, maintaining
the majority of the design of 1 but lacking the DeAP heterocycles
capable of forming hydrogen-bonded assemblies (Scheme 4).
Bis-DeAP–20K-PEG, 21b, appears to form hexameric assemblies
in DMF as evidenced by a value of 6.2 for the ratio of the peak
molecular weights (Mp) of the assembled to unassembled material

E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
8567
this peak is much larger then the presumably unassembled mate-
rial (approximately 35 times larger in the chromatogram shown)
and shifts as the concentration is varied. The higher molecular
weight peak is assigned as either a random-chain supramolecular
polymer or an assembly of stacked, cyclic structures. The lack of
high molecular weight components in the chromatogram of the
control polymer suggests that the hydrogen-bonding modules are
necessary for the assembly process in water. Interestingly, if these
assignments are correct, these data suggest that the Bis-DeAP core
absorbs at 310 nm only when engaged in hydrogen bonding.
7. Conclusion
We presented the synthesis and characterization of a general-
purpose ditopic hydrogen-bonding module, 1, which is programed
to self-assemble into cyclic aggregates stabilized by hydrogen
bonding. This module can be prepared on a gram scale in 2 weeks,
a significant improvement over previous synthetic routes to
analogous compounds. Bis-DeAP–OH 1 was functionalized with
2-bromo-2-methylpropanoyl bromide to yield atom transfer
radical polymerization (ATRP) initiator 14, which was used to
polymerize methylmethacrylate. The resultant polymers self-
assembled into higher molecular weight structures with narrowed
molecular weight distributions. Although large and small Bis-DeAP
star polymers are very slow to mix in toluene, much faster mixing
kinetics are observed in DMF and mixing of a larger Bis-DeAP–
PMMA 17 and a smaller Bis-DeAP–PS 19 in DMF yielded a PMMA/PS
star copolymer through self-assembly. The general-purpose nature
of 1 was further demonstrated by its facile functionalization with
MPEG acids to generate water-soluble self-assembled structures
that appear to depend both on hydrogen-bonding and hydrophobic
interactions. The general-purpose nature of this module and its
unique self-assembly behavior in both aqueous and organic sol-
vents makes Bis-DeAP–OH, 1, a valuable addition to the rapidly
developing ‘supramolecular toolbox’ available to chemists and
material scientists for the generation of ordered nanoscale
materials.
8. Experimental
8.1. General methods
All reactions were carried out under a dry nitrogen atmosphere
and reported reaction temperatures are the temperatures of the
heating medium. Tetrahydrofuran (THF) was freshly distilled from
sodium benzophenone ketyl prior to use. Toluene, chloroform
(CHCl3), methylene chloride (CH2Cl2), DMF, and DMSO were dried
over 4 Å molecular sieves and stored under nitrogen. Monomers
where purified by passage through a basic alumina plug to remove
inhibitors and then oxygen was displaced by bubbling N2(g) through
the liquids for 1 h. All other solvents and reagents were of reagent
grade quality and used without further purification.
Analytical thin-layer chromatography (TLC) was performed on
0.25 mm silica gel coated glass plates (Merck) with F254 indicator.
Flash chromatography was performed on Merck 40–63 mm silica
gel and ratios of solvents for flash chromatography are reported as
volume percentages. Preparative size exclusion chromatography
(SEC) was performed on polystyrene Bio-BeadsÒ S-X (Bio-Rad:
400–14,000) in toluene. Melting points were determined on
a Thomas–Hoover melting point apparatus without calibration.
Brine refers to a saturated aqueous solution of NaCl. Light petro-
leum ether is abbreviated as PE and ethyl acetate as EtOAc.
Figure 15. (a) SEC analysis of Bis-DeAP–20K-PEG 21b in DMF. (b) SEC analysis of
Bis-DeAP–20K-PEG 21b and control polymer 23 in water. SEC samples prepared at
approximately 7 mg/mL.
All NMR spectra were acquired in the VOICE NMR laboratory at
the University of Illinois at Urbana-Champaign. 1H and 13C spectra
were acquired on a Varian Unity 500 MHz spectrometer (13C,
125 MHz) in CDCl3 unless otherwise noted. 1H coupling constants
weight peaks that are very similar to the chromatogram obtained
for the control polymer, in addition to, a high molecular weight
peak with a strong absorbance at 310 nm. The molecular weight of

8568
E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
are given in hertz. 1H NMR chemical shifts were referenced to the
residual protio solvent peak at 7.26 ppm in CDCl3. 13C NMR chem-
ical shifts were referenced to the solvent peak at 77.0 ppm in CDCl3.
Mass spectra (MS) were obtained on a Micromass ZAB-SE (FAB)
mass spectrometer, a Micromass Q-Tof Ultima (ESI) spectrometer
or a PerSeptive Biosystems Voyager-DE-STR (MALDI-TOF) at the
University of Illinois Mass Spectrometry Laboratory. Elemental
analyses were preformed at the University of Illinois School of
Chemical Sciences Microanalysis Laboratory.
8.3.2. Polymerization kinetic measurements
Aliquots were removed from the polymerizations by opening
the sealed tube to a high positive pressure of N2(g) and then with-
drawing a portion of the reaction mixture (typically 0.3–0.7 mL)
with a N2(g) flushed syringe. The aliquot was then purified as
described above.
8.4. Synthetic methods
Compounds 3,19 8,20 and 1221 were prepared using methods that
have already been published in the literature.
8.2. General polymerization methods
8.4.1. N-(4-Oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-1H-
imidazole-1-carboxamide (13)
8.2.1. Preparation of polymethylmethacrylate (PMMA)
The polymerization was conducted with [Initiator]¼[CuBr]¼
[PMDETA]¼11 mM, [MMA]¼3.1 mM in anisole at 70 ꢀC. A typical
procedure follows: an oven dried schlenk tube was charged with
100 mg (0.08 mmol) of 14 and 11.5 mg (0.08 mmol) of CuBr. The
schlenk tube was placed under vacuum for 45 min, occasionally
venting to N2(g). The tube was then placed under a high positive
pressure of N2(g) and 5 mL of anisole and 2.5 mL of methyl-
methacrylate were added by a N2(g) flushed syringe. After adding
A heterogeneous solution of 4.14 g (25.5 mmol, 1 equiv) of 12,
5.35 g (33 mmol, 1.3 equiv) of CDI, and 135 mL of THF was heated
for 14 h at 60 ꢀC. The solution was then allowed to cool to room
temperature and 4.53 g (69.4%) of the desired product was col-
lected by vacuum filtration, rinsing with dry acetone, as a white
powder. Characterization was complicated by the insolubility of
product. It was assumed to be pure for the yield calculation and it
was used in excess in next reaction.
16.7 mL (13.9 mg, 0.08 mmol) of PMDETA, the tube was sealed and
heated at 70 ꢀC.
8.4.2. 3,5-Dihydroxy-4-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-
benzoic acid methyl ester (4)
8.2.2. Preparation of polystyrene (PS)
A mixture of 10.13 g (55 mmol, 1.3 equiv) of methyl 3,4,5-tri-
hydroxybenzoate, 2.05 g (7.8 mmol, 0.2 equiv) of 18-crown-6,
550 mL of acetone (dried over 4 Å sieves), and 5.83 g (42.2 mmol,
1 equiv) of K2CO3 was cooled in an ice bath. A solution of 10 g
(42.2 mmol, 1 equiv) of 3 in 200 mL of acetone was then added
dropwise. The reaction mixture was refluxed for 19 h. The mixture
was concentrated under reduced pressure and the residue was
partitioned between 300 mL of CH2Cl2 and 300 mL of H2O. The
organic phase was separated and the aqueous phase was extracted
twice with 300 mL of CH2Cl2. The combined organic phases were
washed with 600 mL of brine, dried with Na2SO4, and concentrated
under reduced pressure. The crude material was purified by column
chromatography on silica gel (9:1 CHCl3–acetone, Rf¼0.26) to give
2.92 g (20%) of the desired product as a colorless oil. 1H NMR
The polymerization was conducted with [Initiator]¼[CuBr]¼
[PMDETA]¼21 mM in styrene at 90 ꢀC. A typical procedure follows:
an oven dried schlenk tube was charged with 40 mg (0.032 mmol)
of 14 and 4.6 mg (0.032 mmol) of CuBr. The schlenk tube was place
under vacuum for 45 min, occasionally venting to N2(g). The tube
was then placed under a high positive pressure of N2(g) and 1.5 mL
of styrene was added by a N2(g) flushed syringe. After adding 6.6 mL
(5.5 mg, 0.032 mmol) of PMDETA, the tube was sealed and heated
at 90 ꢀC.
8.2.3. Purification of polymers
Both PS and PMMA were purified by diluting in CHCl3 (30 mL)
and washing with an aqueous Na2EDTA solution (30 mM in 5%
NaHCO3, 15 mL). The organic layer was then reduced to approxi-
mately 2–5 mL and precipitated into cold MeOH (PS) or cold
heptane (PMMA).
(CDCl3)
3.90–3.83 (m, 2H), 3.86 (s, 3H), 3.52 (m, 2H), 1.91–1.68 (m, 6H),
1.64–1.48 (m, 4H); 13C NMR (CDCl3)
167.2, 149.3, 138.1, 125.6,
d
7.20 (s, 2H), 6.58 (s, 2H), 4.61 (t, J¼2.9), 4.17 (t, J¼6.3),
d
109.8, 99.4, 73.4, 67.6, 62.8, 52.4, 30.7, 27.5, 26.1, 25.4, 19.7. HRMS
(ESI): Calcd for C17H25O7 (MHþ): 341.1600. Found: 341.1594. Calcd
for C17H24O7Na: 363.1420. Found: 363.1412.
8.3. Analytical methods
8.3.1. Size exclusion chromatography (SEC)
Analytical SEC molecular weights were determined using
conventional calibration with polystyrene (THF, DMF, and toluene
eluents) or PEG/PEO (water eluent) standards. THF SEC was per-
formed using Waters Styragel columns (2ꢁHR3, 1ꢁHR4E) with a
flow rate of 1.0 mL/min at ambient temperature. Detection of peaks
was achieved using a Viscotek TDA 300 refractive index detector.
Toluene SEC was performed using Waters Styragel columns
(1ꢁHR3, 1ꢁHR4E, 1ꢁHR5E) with a flow rate of 1.0 mL/min at
ambient temperature. Detection of peaks was achieved using a
Viscotek VE3580 refractive index detector and a Hitachi L-4000H
UV detector. Water (100 mM of NaNO3) SEC was performed using
Waters Ultrahydrogel columns (1ꢁ250, 1ꢁ120) and Polymer Lab-
8.4.3. 3,5-Bis-(3,5-di-tert-butylbenzyloxy)-4-[4-(tetrahydro-pyran-
2-yloxy)-butoxy]-benzoic acid methyl ester (6)
A mixture of 1.84 g (5.4 mmol, 1 equiv) of 4, 70 mL of acetone
(dried over 4 Å sieves), 291 mg (1.1 mmol, 0.2 equiv) of 18-crown-6,
and 2.24 g (16.2 mmol, 3 equiv) of K2CO3 was cooled in an ice bath.
A solution of 3.36 g (11.88 mmol, 2.2 equiv) of 5 in 50 mL acetone
was then added. The reaction mixture was refluxed for 7 h. The
mixture was concentrated under reduced pressure and the residue
was partitioned between 50 mL of CH2Cl2 and 50 mL of H2O. The
organic phase was separated and the aqueous phase was extracted
twice with 50 mL of CH2Cl2. The combined organic phases were
washed with 150 mL of brine, dried with Na2SO4, and concentrated
under reduced pressure. The crude material was purified by column
chromatography on silica gel (9:1 to 1:1 PE–Et2O, Rf¼0.07, 0.58) to
give 3.02 g (74.0%) of the desired product as a white solid: mp 113–
oratories columns (2ꢁPL-aquagel-OH Mixed 8
mM) in series with
a flow rate of 0.5 mL/min at ambient temperature. Detection of
peaks was achieved using a Viscotek VE3580 refractive index de-
tector and a Hitachi L-4000H UV detector. DMF (50 mM of LiBr) SEC
was performed using Viscotek columns (2ꢁI-MBLMW-3078,
1ꢁMBHMW-3078) with a flow rate of 1 mL/min at 50 ꢀC. Detection
of peaks was achieved using a Viscotek TDA 300 refractive index
detector.
114 ꢀC. 1H NMR (CDCl3)
d
7.42 (s, 2H), 7.39 (t, J¼1.9, 2H), 7.32 (d,
J¼2.1, 4H), 5.13 (s, 4H), 4.51 (br t, J¼3.5, 1H), 4.15 (t, J¼6.5, 2H), 3.90
(s, 3H), 3.79(m, 1H), 3.66 (m, 1H), 3.43 (m, 1H), 3.30 (m, 1H), 1.90–
1.43 (m, 10H), 1.34 (s, 36H); 13C NMR (CDCl3)
d
166.9, 152.8, 151.1,
143.0, 136.0, 124.9, 122.1, 122.0, 109.3, 98.7, 73.4, 72.0, 67.2, 62.1,

E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
8569
52.3, 35.0, 31.6, 30.8, 27.4, 26.3, 25.6, 19.6. HRMS (ESI): Calcd for
47H68O7Na: 767.4863. Found: 767.4886. Anal. Calcd for C47H68O7:
73.4, 72.1, 70.2, 67.3, 62.1, 35.0, 31.64, 31.61, 30.8, 27.4, 26.4, 25.6,
19.6.
C
C, 75.77; H, 9.20. Found: C, 75.88; H, 9.28.
8.4.7. 1,10-(5-(3,5-Bis(3,5-di-tert-butylbenzyloxy)-4-(4-
8.4.4. 3,5-Bis-(3,5-di-tert-butylbenzyloxy)-4-[4-(tetrahydro-pyran-
2-yloxy)-butoxy]-benzyl alcohol (7)
(tetrahydro-2H-pyran-2-loxy)butoxy) benzyloxy)-1,3-
phenylene)bis(3-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-
yl)urea). Bis-DeAP–OTHP (11)
A solution of 3.59 g (4.8 mmol, 1 equiv) of 6 and 30 mL of THF
was cooled in an ice bath before adding 16.8 mL (16.8 mmol,
3.5 equiv) of 1 M DIBAL-H in hexanes with a syringe pump (0.5 mL/
min). The solution stirred at room temperature for 16 h and then
was cooled in an ice bath before adding 2 mL of H2O dropwise. The
gray solid that formed was removed by vacuum filtration and
washed with EtOAc. The filtrate was concentrated under reduced
pressure to yield 3.40 g (97.9%) of the desired product as a colorless
A solution of 1.85 g (2.23 mmol,1 equiv) of 10, 4.53 g (17.7 mmol,
8 equiv) of 13, and 83 mL of CHCL3 was sealed in a round bottom
flash with a septum and heated in an oil bath at 60 ꢀC for 12 h. The
solution was then filtered through Celite to remove excess hetero-
cycle and diluted with 50 mL CHCl3. The organic layer was then
washed with 50 mL of 10% HCl(aq), 50 mL of satd NaHCO3(aq),100 mL
of brine, and solvent was removed under reduced pressure. The
crude material was dissolved in a minimal amount of toluene,
precipitated into cold MeOH, and 2.28 g (84.5%) of the desired
product was collected by vacuum filtration as a brown powder.
Further purification could be achieved by preparative SEC (toluene
eluent), although was not typically necessary. 1H NMR (CDCl3)
viscous oil that solidified to a white oily solid. 1H NMR (CDCl3)
d 7.42
(t, J¼1.7, 2H), 7.42 (d, J¼1.6, 4H), 6.74 (s, 2H), 5.12 (s, 4H), 4.62 (s,
2H), 4.55 (br t, J¼3.5, 1H), 4.12 (t, J¼6.5, 2H), 3.83 (m, 1H), 3.71 (m,
1H), 3.46 (m, 1H), 3.34 (m, 1H), 2.16 (br s, 1H), 1.95–1.46 (m, 10H),
1.38 (s, 36H); 13C NMR (CDCl3)
d 153.2, 150.9, 138.0, 136.5, 136.3,
121.9, 121.8, 106.5, 98.6, 73.3, 71.9, 67.2, 65.4, 62.0, 34.9, 31.6, 30.7,
27.3, 26.3, 25.5, 19.5. HRMS (ESI): Calcd for C46H68O6Na: 739.4914.
Found: 739.4905. Anal. Calcd for C46H68O6: C, 77.05; H, 9.56. Found:
C, 77.18; H, 9.54.
d 14.40–10.20 (br m, 3H), 9.40–6.00 (br m, 17H), 5.70–5.75 (br m,
11H), 2.10–0.80 (br m, 40H). MALDI-MS (IAA) m/z (rel int.) 1238.6
(30, MKþ), 1223.0 (70, MNaþ), 1199.6 (70, MHþ), 1115.5 (100,
MHþꢂTHP), 1060.8 (30), 1038.4 (30). Anal. Calcd for C68H82N10O10
:
C, 68.09; H, 6.89; N, 11.68. Found: C, 67.82; H, 7.03; N, 11.72.
8.4.5. 2-(4-(2,6-Bis(3,5-di-tert-butylbenzyloxy)-4-((3,5-dinitro-
phenoxy)methyl)phenoxy) butoxy) tetrahydro-2H-pyran (9)
8.4.8. 1,10-(5-(3,5-Bis(3,5-di-tert-butylbenzyloxy)-4-(4-
hydroxybutoxy)benzyloxy)-1,3-phenylene)bis(3-(4-oxo-3,4-
dihydropyrido[2,3-d]pyrimidin-2-yl)urea). Bis-DeAP–OH (1)
A solution of 4.52 g (6.3 mmol, 1 equiv) of 7, 1.28 g (7.0 mmol,
1.1 equiv) of 8, 2.49 g (9.5 mmol, 1.5 equiv) of PPh3, and 150 mL of
THF was cooled in an ice bath. A separate solution of 1.87 mL
(9.5 mmol, 1.5 equiv) of DIAD and 150 mL of THF was added to the
first dropwise with an addition funnel. The combined solutions
were stirred for 18 h while they slowly warmed to room temper-
ature and then solvent was removed under reduced pressure. The
residual was partitioned between 150 mL each of H2O and Et2O and
the aqueous layer was extracted twice with 150 mL of Et2O. The
combined organic fractions were washed twice with 400 mL of 5%
KOH(aq), once with 400 mL of H2O, once with 400 mL of brine, dried
with Na2SO4, and solvent was reduced under reduced pressure to
yield a yellow heterogeneous mixture. The crude material was
purified by column chromatography using silica gel (7:3 PE/Et2O,
Rf¼0.37) to yield 4.63 g (82.5%) of desired product as a yellow
A homogenous solution of 286.1 mg (0.24 mmol, 1 equiv) of 11,
25 mL of THF, and 4 mL of 25% HCl(aq) was heated in an oil bath at
45C for 12 h. The solution was added to 40 mL of H2O and the
precipitate that formed was collected by vacuum filtration, rinsing
with a large amount of H2O. The dry crude material was then dis-
solved in THF, precipitated into cold MeOH, and 153.5 mg (58.3%) of
desired product was collected by vacuum filtration as a brown
powder. 1H NMR (CDCl3)
d 14.20–10.10 (br m, 3H), 9.00–6.10 (br m,
14H), 5.5–3.0 (br m, 10H), 2.10–0.70 (br m, 40H). HRMS (ESI): Calcd
for C63H75N10O9 (MHþ): 1115.5718. Found: 1115.5662. MALDI-MS
(IAA) m/z (rel int.) 1172.1 (10) 1155.1 (10, MKþ), 1139.0 (45, MNaþ),
1115.6 (100, MHþ), 1074.6 (10). Anal. Calcd for C63H74N10O9: C,
67.84; H, 6.69; N, 12.56. Found: C, 67.43; H, 6.45; N, 11.67.
powder. 1H NMR (CDCl3)
7.39 (t, J¼1.8, 2H), 7.30 (d, J¼1.8, 4H), 6.78 (s, 2H), 5.13 (s, 2H), 5.10
(s, 4H), 4.50 (m, 1H), 4.10 (t, J¼6.6, 2H), 3.78 (m, 1H), 3.66 (m, 1H),
3.43 (m, 1H), 3.29 (m, 1H), 1.90–1.42 (m, 10H), 1.33 (s, 36H); 13C
d
8.66 (t, J¼2.0, 1H), 8.14 (d, J¼2.0, 2H),
8.4.9. 4-(4-((3,5-Bis(3-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-
2-yl)ureido)phenoxy) methyl)-2,6-bis(3,5-di-tert-butylben-
zyloxy)phenoxy)butyl-2-bromo-2-methylpropanoate. Bis-DeAP–
ATRP (14)
NMR (CDCl3)
d 159.9, 153.6, 151.1, 149.3, 139.3, 136.0, 129.5, 122.1,
121.9, 115.7, 111.2, 107.7, 98.7, 73.4, 72.2, 72.0, 67.2, 62.2, 35.0, 31.6,
30.8, 27.4, 26.3, 25.6, 19.6. HRMS (ESI): Calcd for C52H70N2O10Na:
905.4928. Found: 905.4919. Anal. Calcd for C52H70N2O10: C, 70.72;
H, 7.99; N, 3.17. Found: C, 70.63; H, 7.98; N, 3.29.
A heterogeneous solution of 400 mg (0.36 mmol, 1 equiv) of 1,
6.5 mL of toluene, 0.09 mL of Et3N, and 0.09 mL of (0.72 mmol,
2 equiv) 2-bromo-2-methylpropanoyl bromide was stirred at
room temperature overnight. The solution was added to 30 mL of
CHCl3 and washed with 15 mL of 10% HCl(aq), 15 mL of saturated
NaHCO3(aq), 30 mL of brine, dried with Na2SO4, and solvent was
removed under reduced pressure. The crude material was dissolved
in a minimal amount of toluene and precipitated into cold MeOH
and 233.4 mg (50.0%) of the desired product was isolated by
vacuum filtration. Further purification could be achieved by pre-
parative SEC (toluene eluent), although was not typically necessary.
8.4.6. 5-(3,5-Bis(3,5-di-tert-butylbenzyloxy)-4-(4-(tetrahydro-2H-
pyran-2-yloxy)butoxy) benzyloxy) benzene-1,3-diamine (10)
Pd/C (143 mg, 10%) was added to a solution of 2.0 g (2.26 mmol,
1 equiv) of 9, 45 mL of CH2CH2, and 45 mL of EtOH. H2(g) was
bubbled through the solution for 1 h using a balloon and needle
after which the solution was stirred for 4 h at room temperature
under a static H2(g) atmosphere (balloon). The solution was then
filtered through a pad of Celite to remove Pd/C and solvent was
removed from the filtrate under reduced pressure to yield 1.85 g
1H NMR (CDCl3)
d 14.20–10.10 (br m, 3H,), 9.00–6.10 (br m, 14H),
5.7–3.2 (br m, 10H), 2.10–0.70 (br m, 46H). MALDI-MS (IAA) m/z
(rel int.) 1317.1 (30) 1301.3 (100, MKþ), 1284.4 (40, MNaþ), 1262.3
(60, MHþ).
(quant) of desired product as a brown glass. 1H NMR (CDCl3)
d 7.38
(t, J¼1.8, 2H), 7.30 (d, J¼1.8, 4H), 6.76 (s, 2H), 5.79 (d, J¼1.8, 2H), 5.69
(t, J¼1.9, 1H), 5.08 (s, 4H), 4.87 (s, 2H), 4.50 (m, 1H), 4.08 (t, J¼6.7,
2H), 3.79 (m, 1H), 3.65 (m, 1H), 3.58 (br s, 4H), 3.43 (m, 1H), 3.29 (m,
8.4.10. 3,5-Bis(benzyloxy)benzyl 2-bromo-2-methyl-
propanoate (16)
A solution of 5.0 g (15.6 mmol, 1 equiv) of 15, 100 mL of CH2Cl2,
and 2.6 mL of Et3N was cooled in an ice bath before adding
1H), 1.89–1.45 (m, 10H), 1.33 (s, 36H); 13C NMR (CDCl3)
d
161.2,
153.3, 151.0, 148.6, 138.5, 136.4, 132.6, 121.9, 107.4, 98.7, 95.4, 93.1,

8570
E.M. Todd, S.C. Zimmerman / Tetrahedron 64 (2008) 8558–8570
a separate solution of 2.3 mL (18.7 mmol, 1.2 equiv) of 2-bromo-2-
methylpropanoyl bromide in 5 mL of CH2Cl2. Combined solution
was left stirring in ice bath to slowly warm to room temperature
over 18 h and then washed with 100 mL of H2O, 100 mL of brine,
dried with Na2SO4, and solvent was removed under reduced
pressure. The crude material was purified by column chromato-
graphy on silica gel (8:2 PE/Et2O, Rf¼0.41) to yield 4.19 g (57.1%) of
References and notes
1. For a general review of supramolecular polymers, see: Lehn, J.-M. Makromol.
Chem., Macromol. Symp. 1993, 69, 1–17; (b) Zeng, F.; Zimmerman, S. C. Chem.
Rev. 1997, 97, 1681–1712; (c) Zimmerman, N.; Moore, J. S.; Zimmerman, S. C.
Chem. Ind. 1998, 604–610; (d) Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.;
Sijbesma, R. P. Chem. Rev. 2001, 101, 4071–4097; (e) Supramolecular Polymers,
2nd ed.; Ciferri, A., Ed.; CRC: Boca Raton, FL, 2005; (f) ten Cate, A. T.; Sijbesma,
R. P. Macromol. Rapid Commun. 2002, 23, 1094–1112.
2. Selected reviews: (a) Lehn, J.-M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304–
1319; (b) Fredericks, J.; Yang, J.; Geib, S. J.; Hamilton, A. D. Proc. Indian Acad.
Sci., Chem. Sci. 1994, 106, 923–935; (c) Whitesides, G. M.; Simanek, E. E.;
Mathias, J. P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Acc. Chem.
Res. 1995, 28, 37–44; (d) Lawrence, D. S.; Jiang, T.; Levett, M. Chem. Rev. 1995,
95, 2229–2260; (e) Conn, M. M.; Rebek, J., Jr. Chem. Rev. 1997, 97, 1647–1668;
(f) Zimmerman, S. C.; Corbin, P. S. Struct. Bonding 2000, 96, 63–94; (g) Prins,
L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem., Int. Ed. 2001, 40,
2382–2426; (h) Archer, E. A.; Gong, H.; Krische, M. J. Tetrahedron 2001, 57,
1139–1159; (i) Jeffery, T. D. Angew. Chem., Int. Ed. 2004, 43, 668–698.
3. Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.; Spek, A. L.; Meijer, E. W. J. Am. Chem.
Soc. 1998, 120, 6761–6769; (b) Sontjens, S. H. M.; Sijbesma, R. P.; van Genderen,
M. H. P.; Meijer, E. W. J. Am. Chem. Soc. 2000, 122, 7487–7493.
desired product as a white powder. 1H NMR (CDCl3)
d
7.43–7.37 (m,
8H, H-2), 7.33 (t, J¼7.0, 2H), 6.62 (d, J¼2.1, 2H), 6.59 (t, J¼1.8, 1H),
5.14 (s, 2H), 5.04 (s, 4H), 1.94 (s, 6H); 13C NMR (CDCl3)
171.5, 160.2,
137.9, 136.8, 128.7, 128.2, 127.6, 106.7, 102.0, 70.2, 67.4, 55.9, 30.9.
HRMS (ESI): Calcd for
25H26O4Br (MHþ): 469.1014. Found:
d
C
469.1016. Anal. Calcd for C25H25O4Br: C, 63.97; H, 5.37. Found: C,
63.95; H, 5.35.
8.4.11. Bis-DeAP–PEG (21b)
A
solution of 11.2 mg (0.01 mmol, 1 equiv) of 1, 200 mg
4. Bosman, A. W.; Sijbesma, R. P.; Meijer, E. W. Mater. Today 2004, 7, 34–39.
5. (a) Park, T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 14236–14237; (b) Park,
T.; Zimmerman, S. C. J. Am. Chem. Soc. 2006, 128, 11582–11590; (c) Ong, H. C.;
Zimmerman, S. C. Org. Lett. 2006, 8, 1589–1592; (d) Park, T.; Todd, E. M.; Naka-
shima, S.; Zimmerman, S. C. J. Am. Chem. Soc. 2005, 127,18133–18142; (e) Park, T.;
Zimmerman, S. C.; Nakashima, S. J. Am. Chem. Soc. 2005,127, 6520–6521; (f) Todd,
E. M.; Quinn, J. R.; Park, T.; Zimmerman, S. C. Isr. J. Chem. 2005, 45, 381–389.
6. Selected examples of heterocycles that form cyclic assemblies: (a) Zerkowski,
J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1992, 114, 5473–5475; (b)
Vreekamp, R. H.; van Duynhoven, J. P. M.; Hubert, M.; Verboom, W.; Reinhoudt,
D. N. Angew. Chem., Int. Ed. 1996, 35, 1215–1218; (c) Marsh, A.; Silvestri, M.;
Lehn, J.-M. Chem. Commun. 1996, 1527–1528; (d) Mascal, M.; Hext, N. M.;
Warmuth, R.; Moore, M. H.; Turkenburg, J. P. Angew. Chem., Int. Ed. 1996, 35,
2204–2206; (e) Fenniri, H.; Mathivanan, P.; Vidale, K. L.; Sherman, D. M.;
Hallenga, K.; Wood, K. V.; Stowell, J. G. J. Am. Chem. Soc. 2001, 123, 3854–3855;
(f) Keizer, H. M.; Gonzalez, J. J.; Segura, M.; Prados, P.; Sijbesma, R. P.; Meijer, E.
W.; de Mendoza, J. Chem.dEur. J. 2005, 11, 4602–4608; (g) Zimmerman, S. C.;
Duerr, B. F. J. Org. Chem. 1992, 57, 2215–2217; (h) Boucher, E.; Simard, M.;
Wuest, J. D. J. Org. Chem. 1995, 60, 1408–1412; (i) Yang, J.; Fan, E.; Geib, S. J.;
Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 5314–5315; (j) Tirumala, S.; Davis, J.
T. J. Am. Chem. Soc. 1997, 119, 2769–2776; (k) Shi, X.; Fettinger, J. C.; Cai, M.;
Davis, J. T. Angew. Chem., Int. Ed. 2000, 39, 3124–3127.
7. Cyclic, hydrogen-bonded self-assembled dendrimers: (a) Zimmerman, S. C.;
Zeng, F.; Reichert, D. E. C.; Kolotuchin, S. V. Science 1996, 271, 1095–1098; (b)
Corbin, P. S.; Lawless, L. J.; Li, Z. T.; Ma, Y. G.; Witmer, M. J.; Zimmerman, S. C.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 5099–5104; (c) Ma, Y.; Kolotuchin, S. V.;
Zimmerman, S. C. J. Am. Chem. Soc. 2002, 124, 13757–13769; (d) Zeng, F.; Zim-
merman, S. C.; Kolotuchin, S. V.; Reichert, D. E. C.; Ma, Y. Tetrahedron 2002, 58,
825–843; Noncyclic self-assembled dendrimers: (e) Wang, Y.; Zeng, F.; Zim-
merman, S. C. Tetrahedron Lett. 1997, 38, 5459–5462; (f) Partridge, K. S.; Smith,
D. K.; Dykes, G. M.; McGrail, P. T. Chem. Commun. 2001, 319–320.
(0.01 mmol, 1 equiv) of MPEG–20K-acid, 6.1 mg (0.05 mmol,
5 equiv) of DMAP, 2.5 mL of CH2Cl2, and 31.0 mg (0.15 mmol,
15 equiv) of DCC was stirred at room temperature. After 12 h,
6.1 mg (0.05 mmol, 5 equiv) of DMAP and 31.0 mg (0.15 mmol,
15 equiv) of DCC were again added and the solution was stirred for
an additional 12 h. The solution was filtered to remove DHU, sol-
vent was reduced, and 151 mg (76%) of polymer was isolated as
a white solid after precipitation into cold Et2O.
8.4.12. Bis-DeAP–PEG (21a)
Prepared in analogous manner to 27b.
8.4.13. 4-(2,6-Bis(3,5-di-tert-butylbenzyloxy)-4-((3,5-
dinitrophenoxy)methyl)phenoxy) butan-1-ol (22)
A homogenous solution of 150 mg (0.17 mmol, 1 equiv) of 9,
18 mL of THF, and 3 mL of 25% HCl(aq) was heated in an oil bath at
45 ꢀC for 5 h. The solution was diluted with 50 mL of CHCl3 and
washed twice with 40 mL of saturated NaHCO3(aq), once with
40 mL of brine, dried with Na2SO4 and solvent was removed under
reduced pressure. The crude material was purified by column
chromatography on silica gel (1:1 PE/Et2O, Rf¼0.31) to yield
102.6 mg (76.5%) of desired product as a light yellow solid. 1H NMR
(CDCl3)
d
8.66 (t, J¼2.0, 1H, H-1), 8.14 (d, J¼2.0, 2H, H-2), 7.40 (t,
J¼1.8, 2H, H-7), 7.30 (d, J¼1.8, 4H, H-6), 6.79 (s, 2H, H-4), 5.14 (s,
8. Mulder, A.; Huskens, J.; Reinhoudt, D. N. Org. Biomol. Chem. 2004, 2, 3409–3424.
9. Initial results were reported in a communication: Todd, E. M.; Zimmerman, S. C.
J. Am. Chem. Soc. 2007, 129, 14534–14535.
2H, H-3), 5.09 (s, 2H, H-5), 4.09 (t, J¼6.1, 2H, H-9), 3.50 (q, J¼6.2, 2H,
H-12), 1.79 (m, 2H, H-10), 1.65 (m, 2H, H-11), 1.33 (s, 36H, H-8); 13
C
10. A recently reported recognition unit by Mascal and coworkers allows for the at-
tachmentofadditionalfunctionality, however, thismodulewasnotfunctionalized:
Mascal, M.; Farmer, S. C.; Arnall-Culliford, J. R. J. Org. Chem. 2006, 71, 8146–8150.
11. Keizer, H. M.; Sijbesma, R. P.; Meijer, E. W. Eur. J. Org. Chem. 2004, 2553–2555.
12. Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1998, 120, 9710–9711.
13. Total possible combinations calculated as 46¼4096, however, the total number
of distinguishable isomers is less than this amount.
NMR (CDCl3)
d 159.8, 153.6, 151.2, 149.4, 139.1, 135.9, 129.7, 122.2,
122.0, 115.7, 111.2, 107.5, 73.4, 72.2, 72.1, 62.7, 35.0, 31.6, 29.7, 27.0.
HRMS (ESI): Calcd for C47H63N2O9 (MHþ): 799.4534. Found:
799.4534. Anal. Calcd for C47H62N2O9: C, 70.65; H, 7.82; N, 3.51.
Found: C, 70.78; H, 7.95; N, 3.61.
14. Selected reviews: (a) Bielawski, C. W.; Grubbs, R. H. Prog. Polym. Sci. 2007, 32,
1–29; (b) Hawker, C. J.; Bosman, A. W.; Harth, E. Chem. Rev. 2001, 101, 3661–3688;
(c) Matyjaszewski, K.; Xia, J. H. Chem. Rev. 2001, 101, 2921–2990.
15. (a) Shiau, L.-D. Macromol. Theory Simul. 2004, 13, 783–789; (b) Zhu, S.; Li, D.; Yu,
Q.; Hunkeler, D. J. Macromol. Sci., Pure Appl. Chem. 1998, 35, 33–56.
16. (a) Nowick, J. S.; Chen, J. S. J. Am. Chem. Soc. 1992, 114, 1107–1108; (b) Fan, E.;
Van Arman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 369–
370; (c) Torneiro, M.; Still, W. C. J. Am. Chem. Soc. 1995, 117, 5887–5888; (d) Kato,
Y.; Conn, M. M.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 1208–1212; (e)
Hirschberg, J. H. K. K.; Brunsveld, L.; Ramzi, A.; Vekemans, J. A. J. M.; Sijbesma,
R. P.; Meijer, E. W. Nature 2000, 407, 167–170; (f) Brunsveld, L.; Vekemans, J. A.
J. M.; Hirschberg, J. H. K. K.; Sijbesma, R. P.; Meijer, E. W. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 4977–4982; (g) Zeng, H.; Yang, X.; Flowers, R. A.; Gong, B. J. Am. Chem.
Soc. 2002, 124, 2903–2910; (h) Li, M.; Yamato, K.; Ferguson, J. S.; Gong, B. J. Am.
Chem. Soc. 2006, 128, 12628–12629.
8.4.14. Control polymer for Bis-DeAP–PEG (23)
A solution of 5.8 mg (0.007 mmol, 1.2 equiv) of 22, 125 mg
(0.006 mmol, 1 equiv) of MPEG–20K-acid, 3.7 mg (0.03 mmol,
5 equiv) of DMAP, 2 mL of CH2Cl2, and 18.6 mg (0.09 mmol,
15 equiv) of DCC was stirred at room temperature. After 12 h,
3.7 mg (0.03 mmol, 5 equiv) of DMAP and 18.6 mg (0.09 mmol,
15 equiv) of DCC were again added and the solution was stirred
for an additional 12 h. The solution was filtered to remove DHU,
solvent was reduced, and 103.6 mg (86%) of polymer was isolated
after precipitation into cold Et2O.
17. Selected reviews: (a) Paleos, C. M.; Tsiourvas, D. Adv. Mater. 1997, 9, 695–710; (b)
Ariga, K.; Kunitake, T. Acc. Chem. Res. 1998, 31, 371–378.
Acknowledgements
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19. Kang, S. K.; Kim, W. S.; Moon, B. H. Synthesis 1985, 1161–1162.
20. (a) Organic Syntheses; John Wiley & Sons: New York, NY, 1941; Coll. Vol. 1, p 219;
Organic Syntheses; John Wiley & Sons: New York, NY, 1927; Coll. Vol. 7, p 28; (b)
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Funding of this work by the NSF (CHE-0212772) and by ICI
National Starch and Chemical Company (SRF 2209 R2AB3287) is
gratefully acknowledged.