Synthesis and recognition properties of polymers containing embedded binding sites

Article abstract of DOI:10.1021/ma0346355

We report the synthesis and guest affinities of polymers featuring a single recognition site in the middle of the polymer chain. These polymers were synthesized from difunctional initiators based on the 2,6-diacyldiaminopyridine moiety. Binding efficiencies were experimentally determined using a complementary fluorescent guest, N(10)-isopropyl flavin. The effect of polymer length on recognition was explored by the synthesis of 5 PMMA samples ranging from 4K to 25K. Over this range binding constants increased almost 2-fold, from 282 to 522 M^-1. Variable temperature fluorescence of bound samples shows a 15% difference in release between polymer samples and model compounds.

Full text of DOI:10.1021/ma0346355

310
Macromolecules 2004, 37, 310-314
Synthesis and Recognition Properties of Polymers Containing
Embedded Binding Sites
Ka n a d Da s,† Hir osh i Na k a d e,† J a cqu es P en elle,*,‡ a n d Vin cen t M. Rotello*,†
Department of Chemistry and Department of Polymer Science and Engineering, University of
Massachusetts, Amherst, Massachusetts 01003
Received May 14, 2003; Revised Manuscript Received November 4, 2003
ABSTRACT: We report the synthesis and guest affinities of polymers featuring a single recognition site
in the middle of the polymer chain. These polymers were synthesized from difunctional initiators based
on the 2,6-diacyldiaminopyridine moiety. Binding efficiencies were experimentally determined using a
complementary fluorescent guest, N(10)-isopropyl flavin. The effect of polymer length on recognition was
explored by the synthesis of 5 PMMA samples ranging from 4K to 25K. Over this range binding constants
increased almost 2-fold, from 282 to 522 M-1. Variable temperature fluorescence of bound samples shows
a 15% difference in release between polymer samples and model compounds.
In tr od u ction
Control of macromolecular structure and function
through specific noncovalent interactions is central to
a widevarietyofapplications in bio-and nanotechnology.1-12
Systems studied include soluble polymers,3,13-17 bulk
solids,18-23 and thin films.24,25 In recent studies, the
incorporation of specific recognition elements has been
used to generate a diverse array of architectures in
solution and the solid state.9,10,13,26 In these studies,
recognition elements have been employed to transform
common polymer backbones (acrylates, styrenics) into
drug delivery systems,27 liquid crystals,26,28,29 highly
ordered nanostructures,3,8,17,30-39 vesicles,40 and orga-
nogels.41
Embedding a recognition element within a polymer
chain can potentially provide biologically inspired cata-
lysts and delivery systems. This information is difficult
to assess with random copolymers due to the heteroge-
neity of binding sites, a feature that arises from the
synthetic methodologies typically employed. To examine
the effects of polymer chains on host-guest affinity, we
have designed polymers that have a single recognition
element at the center of the polymer chain. These
polymers were synthesized by living/controlled poly-
merizations. The effect of the binding site buried in the
middle of the three-dimensional polymeric globule can
then be quantified by the comparison of binding con-
stants (Ka) obtained from the polymers to that of
monomeric model compounds.
F igu r e 1. Structure of host-guest dyads used in this study,
2,6-diacyldiaminopyridine-based systems (1-3) and N(10)-
isopropyl flavin (4). 3 stands for polymers 7-13, polymer
blocks on both sides of the diaminopyridine moiety.
bromide (97%), anisole (99.7%), copper(I) bromide (99.999%),
4,4′-dinonyl-2,2′-bipyridyl (DNBP, 97%), N,N,N′,N′,N′′-pen-
tamethyldiethylenetriamine (PMDETA, 99%), 4-pentenoic acid
(97%), oxalyl chloride (99+%), 0.5 M solution of 9-borabicyclo-
[3.3.1]nonane (BBN) in tetrahydrofuran (THF), 4-(dimethy-
lamino)pyridine (99%), and DL-lactide were used as received.
Solvents were purchased from VWR. All reactions were carried
out under argon using oven-dried glassware. All polymeriza-
tions and water/air-sensitive manipulations were carried out
using standard Schlenk techniques in a dry argon atmosphere.
THF was distilled from sodium/benzophenone ketyl. Dichlo-
romethane was distilled from calcium hydride. Methyl meth-
acrylate (MMA, 99%) was vacuum-distilled from calcium
hydride prior to use. tert-Butyl acrylate (tBA, 98%) was
extracted three times with 5% aqueous solution of NaOH and
washed with distilled water. After stirring over calcium
chloride overnight, the monomer was vacuum-distilled prior
to use. All compounds were stored in the dark and under
refrigeration to avoid photodegradation or thermal degrada-
tion. NMR spectra were recorded using a Bruker 200 MHz
spectrometer. Elemental analyses were performed by the
Microanalytical Lab at the University of Massachusetts,
Amherst. Compounds 1, 2, and 4 were synthesized according
to literature procedures.44
For our studies, we used diacyl diaminopyridines
(DAP) 1 and 2 as hosts, with the complementary three-
point hydrogen-bonding partner, N(10)-isopropyl flavin
(4), as guest (Figure 1). The use of flavin 4 allows for
quantification of the Ka via fluorescence titrations.42,43
Here, we report the synthesis of well-defined polymers
containing a single recognition unit, and the corre-
sponding thermodynamic characterization of the host-
guest chemistry.
Exp er im en ta l Section
In st r u m en t a t ion . Absolute and/or relative molecular
weights of the polymers were determined by gel permeation
chromatography (GPC) with a Polymer Laboratories (PL) LC
1120 pump, a Waters R403 differential refractometer detector,
and three PL gel columns (particle size ) 50 µm, pore size )
mixed D and 50 Å) with THF as an eluent at 1 mL/min at
Gen er a l. All reagents were purchased from Aldrich. 2,6-
Diaminopyridine (98%), triethylamine (99.5%), bromopropionyl
† Department of Chemistry.
‡ Department of Polymer Science and Engineering.
10.1021/ma0346355 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/16/2003

Macromolecules, Vol. 37, No. 2, 2004
Polymers Containing Embedded Binding Sites 311
room temperature. The system was calibrated with poly-
(methyl methacrylate) (PMMA) and polystyrene (PS) stan-
dards. Fluorescence spectroscopy was performed on a Shimad-
zu RF-5301PC spectrofluorophotometer.
Sch em e 1. Syn th esis of Bis-In itia tor s for ATRP (5)
a n d La ctid e ROP (6) Con ta in in g a Cen tr a l Moiety
Ca p a ble of Molecu la r Recogn ition a
Syn th esis of 5. To a solution of 2,6-diaminopyridine (1.0
g, 9.2 mmol) and triethylamine (2.83 mL, 20.0 mmol, 2.2 equiv)
in dichloromethane (150 mL) was slowly added 2-bromopro-
pionyl bromide (1.92 mL, 20.0 mmol). The solution was stirred
for 12 h, the solvent removed in vacuo, and the resulting red
solid dissolved in ethyl acetate (100 mL) and successively
extracted with brine (100 mL), saturated sodium bicarbonate
(100 mL), and 0.1 M HCl (75 mL). The organic layer was
collected and dried using MgSO4, and the residue was purified
by flash column chromatography on silica (1:1 hexanes:ethyl
acetate). The resulting white solid was vacuum-dried over-
night. Yield 1.68 g, 83%; mp 128-129 °C. 1H NMR (CDCl3): δ
) 8.42 (s, NH, 2 H), 7.96 (d, 3,5-PyH, 2 H, 7.9 Hz), 7.76 (t,
4-PyH, 1 H, 8.0 Hz), 4.53 (q, Br-CH-, 2 H, 6.9 Hz), 1.93 (d,
-CH3, 6 H, 6.9 Hz). C11H13N3O2Br2 (379.05) Calcd: C, 34.86;
H, 3.46; N, 11.09. Found: C, 34.62; H, 3.46; N, 10.91.
a
(a) 2-Bromopropionyl bromide (2 equiv), NEt3 (2.2 equiv),
CH2Cl2; (b) 4-pentenoyl chloride (2 equiv), NEt3 (2.2 equiv),
CH2Cl2; (c) 9-BBN (4 equiv), THF; (d) NaOH, H2O2.
Gen er a l P r oced u r e of th e Atom -Tr a n sfer Ra d ica l
P olym er iza tion (ATRP ) of P MMA In itia ted by 5. A heat-
dried, nitrogen-purged 10 mL Schlenk tube was charged with
freshly distilled MMA, anisole (50 wt %), copper(I) bromide,
and 9,9′-dinonyl-2,2′-bipyridine. The dark red solution was
degassed by a freeze-pump-thaw technique three times,
backfilled with argon, and then sealed via a Teflon stopcock.
It was then heated with stirring at 90 °C. The resulting green
solution was then dissolved in THF (15 mL) and precipitated
into hexanes (100 mL), filtered, and dried in vacuo. The green
solid was then dissolved in ethyl acetate (100 mL) and washed
with aqueous ammonia (10 wt %) (2 × 50 mL) and brine (1 ×
50 mL). The organic layer was collected and dried over MgSO4,
and the solvent was removed by rotary evaporation.
P olym er iza tion of DL-La ctid e w ith ROP (P olym er 12).
N,N′-(Dimethylamino)pyridine (DMAP, 0.28 g, 23 mmol), 6 (18
mg, 0.58 mmol), DL-lactide (0.50 g, 35 mmol), and dry dichlo-
romethane (2.5 mL) were added to a dry tube equipped with
a Teflon stopcock. The mixture was degassed via a repeated
freeze-pump-thaw cycle (3×). The polymerization tube was
placed in the oil bath at 35 °C. The mixture was added to cold
methanol (50 mL) to quench the polymerization. The precipi-
tate was filtered and dried in vacuo to give a white polymer
(0.42 g, 82%). Mn ) 7.5 × 103, Mn/Mw ) 1.34 (PS standards).
Resu lts a n d Discu ssion
P olym er iza tion of tBu A w ith ATRP (P olym er 13). A
heat-dried, nitrogen-purged 10 mL Schlenk tube was charged
with freshly distilled tBuA (3.5 mL, 24 mmol), 5 (64 mg, 0.17
mmol), CuBr (24 mg, 0.17 mmol), and PMDETA (36 µL, 0.17
mmol). The green solution was degassed by a freeze-pump-
thaw procedure three times, backfilled with argon, and then
sealed via a Teflon stopcock and placed in a 60 °C oil bath for
3 h. The solution was then dissolved in THF (10 mL) and
precipitated into a mixed solvent (H2O:MeOH 1:1 v:v, 50 mL),
filtered, and dried in vacuo to give a white polymer (0.56 g,
16%). Mn ) 4.7 × 103, Mn/Mw ) 1.27 (PMMA standards).
N,N′-(5-Hyd r oxylp en ta n oyl)-2,6-d ia m in op yr id in e (6).
Initiator 6 was synthesized through a three-step reaction
sequence from 2,6-diaminopyridine. To a solution of 4-pen-
tenoic acid (2.0 g, 20 mmol) and oxalyl chloride (2.0 mL, 2.2
mmol) in dry CH2Cl2 (150 mL) was added one drop of DMF.
After stirring for 2 h, the mixture was added dropwise to a
solution of 2,6-diaminopyridine (1.1 g, 10 mmol) and triethy-
lamine (3.1 mL, 22 mmol) in dry CH2Cl2 (100 mL) under an
argon atmosphere. After stirring overnight at room tempera-
ture, the mixture was washed with brine (100 mL), the organic
fractions were collected and dried with MgSO4, and the solvent
was removed by rotary evaporation. The crude product was
purified by flash column chromatography on silica gel with
hexane/EtOAc (1:1 v:v) to give a white solid (1.1 g, 40%). This
product was sufficiently pure for the subsequent reaction and
was used without further purification. A 0.5 mol L-1 solution
of 9-BBN in THF (16 mL) was added dropwise to a solution of
dipentenoyl-2,6-diaminopyridine (0.54 g, 2.0 mmol) in dry THF
(4 mL) at room temperature. After stirring for 1 h at room
temperature H2O (5 mL) was added dropwise, followed by 3
M NaOH (10 mL). 30% H2O2 solution (10 mL) was added
carefully to maintain the reaction temperature stay between
30 and 50 °C. The precipitate was filtered, and the filtrate was
evaporated and purified with flash chromatography on silica
gel with CH2Cl2/MeOH (95:5 v:v) to give a white solid (2, 0.27
Syn th esis. We used initiators 5 and 6 (Scheme 1)
capable of initiating living/controlled polymerizations to
provide polymers with a single recognition element
embedded within the backbone. Soluble polymers con-
taining one recognition unit were synthesized from
bifunctionalized DAP-based initiators (5 and 6) using
well-defined living/controlled polymerization methodolo-
gies, either atom-transfer radical polymerization (ATRP)
(using 5) or (N,N-dimethylamino)pyridine-catalyzed liv-
ing ring-opening polymerization (ROP) (using 6) (Scheme
2).45 The use of controlled polymerization methodologies
allowed for control over molecular weight and provided
polymer samples with low polydispersities. Polymers
initiated by 5 and 6 were readily prepared according to
Scheme 2. Poly(methyl methacrylate) (PMMA) and poly-
(tert-butyl acrylate) (PtBA) were polymerized using a
CuBr-controlled ATRP methodology and resulted in
polymers of predictable molecular weight and expected
polydispersities (1.23-1.27) for a secondary initiator.46
Poly(DL-lactide) was synthesized at 35 °C in methylene
chloride using a procedure adapted from a recently
reported DMAP-catalyzed living ring-opening polymer-
ization methodology.45
Th er m od yn a m ic Ch a r a cter iza tion of P olym er -
F la vin Com p lexes. The affinity of the polymeric hosts
for flavin 4 was experimentally quantified via fluores-
cence titration in chloroform. Flavin 4 has characteristic
emission peak at 515 nm in chloroform that is strongly
quenched upon binding to diaminopyridine derivatives,
allowing the quantification of host-guest binding.42,43,47
As expected, addition of all of the polymers (except
PtBuA) to flavin solutions strongly quenched flavin
fluorescence. To eliminate the possibility that the
polymer chains were responsible for this quenching,
PMMA samples without the DAP moiety were added
to a chloroform solution containing flavin 4. As expected,
no change in fluorescence was observed, showing that
1
g, 43%); mp 125-6 °C. H NMR (d-DMSO): δ ) 10.0 (s, NH,
2H), 7.72 (s, PyH, 3H), 4.44 (s, OH, 2H), 3.42 (m, -CH2-OH,
4H), 2.41 (t, -CO-CH2-, 4H, 7.2 Hz), 1.70-1.35 (m, -CH2-,
8 H). C15H23N3O4 (309.36) Calcd: C, 58.24; H, 7.49; N, 13.58%.
Found: C, 58.26; H, 7.42; N, 13.38%.

312 Das et al.
Macromolecules, Vol. 37, No. 2, 2004
Ta ble 1. P olym er iza tion Con d ition s for th e Syn th esis of P olym er s 7-11
a
a
polymer
5 (mmol)
MMA (mmol)
anisole (mL)
CuBr (mmol)
DNDP (mmol)
time (h)
Mn
Mw/Mn
7
8
9
10
11
0.29
0.15
0.15
0.16
0.16
13.2
13.2
26.4
34.5
41.4
1.24
1.24
2.48
3.24
3.88
0.15
0.07
0.07
0.08
0.08
0.29
0.15
0.15
0.16
0.16
6
12
23
30
36
4 000
8 100
15 000
20 000
25 000
1.23
1.23
1.26
1.28
1.25
a
Detemined by GPC calibrated with PMMA standards.
Sch em e 2. Syn th esis of P olym er s Ba sed on 5 a n d 6
F igu r e 2. Fluorescence emission changes for flavin (4) upon
addition of 7-11 and 13 at room temperature. Excitation )
465 nm, emission ) 511 nm. Concentration of 4 ) 1 × 10-4
M, equivalents guest refers to the diaminopyridine recognition
element.
Ta ble 2. Bin d in g Con sta n ts Deter m in ed by F lu or escen ce
Titr a tion
compound/
polymer
Mn × 103
Mw/Mn
Ka (M-1
)
∆G (kcal/mol)
1
2
540c
-3.68
-3.07
190c
7 (PMMA)
8 (PMMA)
9 (PMMA)
10 (PMMA)
11 (PMMA)
12 (PLA)
4.0a
8.1a
1.23
1.23
1.23
1.28
1.25
1.39
1.27
282 ( 8
311 ( 9
365 ( 7
411 ( 7
522 ( 20
352 ( 20
56 ( 26
-3.30 ( 0.02
-3.36 ( 0.03
-3.45 ( 0.01
-3.52 ( 0.01
-3.66 ( 0.02
-3.47 ( 0.03
-2.3 ( 0.4
15.0a
20.0a
25.5a
7.5b
13 (PtBuA)
4.7b
the quenching we observed resulted directly from the
DAP-flavin 4 recognition process.
a
b
GPC (PMMA standards). GPC (PS standards). c Reference
44.
Efficient binding of 4 was obtained using both the
PLA and the PMMA polymers (Figure 2 and Table 2).
PtBuA has a lower affinity for flavin 4, presumably
arising from the steric hindrance of the bulky side
chains; a similar trend is observed in the comparison
of Kas between the model compounds 1 and 2 and
previously reported results.44 These results indicate that
the efficiency of this noncovalent interaction was de-
pendent on the polymer chain covalently attached to the
recognition unit and that the polymer chains surpris-
ingly have a favorable effect on the recognition process.
Preliminary insight into the temperature dependence
of host-guest interactions was obtained through vari-
able temperature release experiments. For these stud-
ies, 99%-bound solutions of 1:4 (model compound of low
molecular weight), 7:4 (PMMA), and 12:4 (PLA) in
chloroform were prepared, and fluorescence was mea-
sured as a function of temperature. As the temperature
was increased, the observed fluorescence intensity
increased, indicating a decrease in the concentration of
bound species (Figure 3). More binding efficiency for 1:4
is lost with increasing temperature than for any of the
polymer samples. These results are also consistent with
previous results reported by Rotello using random
copolymers.48
Molecular weight effects on the affinity of polymer
hosts with flavin 4 were examined using PMMA poly-
mers 7-11 systems using samples of molecular weight
4K, 8K, 15K, 20K, and 25K.49,51 The Kas could then be
compared with reference monomers 1 and the R-branched
monomer 2 that is sterically similar to the polymeric
hosts.44 The results demonstrate a monotonic increase
in the binding constant with increased molecular weight
(Table 2). For the shortest polymer chain (74K), the
obtained binding constant is slightly higher than that
of the 2:4 complex (280 M-1 vs 190 M-1). As the
molecular weight of the sample increased the Ka deter-
mined for each sample increased, ultimately reaching
a value more than twice that of the model compound 2
and close to the value of the less hindered host 1. It is
known that in a solvent such as ethyl acetate, a good
hydrogen-bond acceptor, the values for the binding
constant would be extremely low, below, or near the
lower limits that can be measured by our fluorescence

Macromolecules, Vol. 37, No. 2, 2004
Polymers Containing Embedded Binding Sites 313
Con clu sion s
We have designed, synthesized, and characterized
polymers containing a single recognition element em-
bedded in the middle of the polymer backbone. An
enhancement of binding affinity was observed for PMMA
and PLA polymer backbones, indicating the polymer
chains covalently attached to the recognition unit cause
a change in the local binding environment. Binding
affinity of 7-11 was ranged between those of 1 and 2.
The molecular weight dependence of binding affinity of
7-11 arises from the difference of the average solvent
concentration inside the volume enclosed by the polymer
chain. Further studies focused on determining the
origins of this enhancement as well as applications of
these systems in catalysis and delivery applications are
currently underway.
F igu r e 3. Percent release data for 99% bound (at 5 °C)
complexes of polymers (7 and 12) and monomer 1 with flavin
guest 4 as a function of temperature in CHCl3.
Ack n ow led gm en t. This work was supported by the
NSF-funded University of Massachusetts Materials
Research Science & Engineering Center (DMR-9809365
and DMR-0213695) and CHE-0213354 (VR). The au-
thors thank Prof. E. Voigtman and J avid Rzayev for
helpful discussions.
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