Tandem Functionalization in a Highly Branched Polymer with Layered Structure

Article abstract of DOI:10.1002/chem.201800683

A hyperbranched polymer with multilayer structure was developed to demonstrate the possibility of highly efficient tandem functionalization reactions at different domains within one nanostructured platform. The polymer scaffold was constructed by chain-growth copper-catalyzed azide–alkyne cycloaddition polymerization of three functional monomers with sequential monomer addition in one pot. Subsequent reactions with different monomer units resulted in efficient functionalization of each segment with construction of a highly sophisticated polymer structure by a robust procedure. As a proof of concept, the ability of this polymer structure to quantitatively load six species of guest molecules through three different types of conjugation reactions was demonstrated.

Full text of DOI:10.1002/chem.201800683

A Journal of
Accepted Article
Title: Tandem Functionalization in One Highly Branched Polymer with
Layered Structure
Authors: Xiaosong Cao, Yi Shi, Weiping Gan, and Haifeng Gao
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To be cited as: Chem. Eur. J. 10.1002/chem.201800683
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Tandem Functionalization in One Highly Branched Polymer with
Layered Structure
Xiaosong Cao, Yi Shi, Weiping Gan, and Haifeng Gao*
Dedication ((optional))
Abstract: In this report, we developed a hyperbranched polymer
with multi-layer structure to demonstrate the possibility of highly
efficient tandem functionalization reactions at different domains
within one nanostructured platform. The polymer scaffold was
constructed using the chain-growth copper-catalyzed azide-alkyne
cycloaddition (CuAAC) polymerization of three functional monomers
with sequential monomer addition in one pot. Subsequent reactions
onto different monomer units exhibited efficient functionalization in
each segment, constructing a highly sophisticated polymer structure
via a robust procedure. As a proof of concept, we demonstrated the
ability of this polymer structure to quantitatively load six species of
guest molecules through three different types of conjugation
reactions.
m
polymerization of AB (m ≥ 2) monomers show difficulty in this
goal because of the poorly defined structure (both interior and
exterior) and the inability to incorporate reactive groups into
specific segments. As a matter of fact, a versatile chain-growth
polymerization of AB
2
monomers (where A represents an alkynyl
group and B represents a di-azido unit) using the efficient
2
copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction
has been recently developed in our group, producing
hyperbranched polytriazoles with low dispersity (M
and up to a million molecular weight.[10] More importantly, the
use of a tris-triazoleamine-based trifunctional B core during the
CuAAC polymerization accurately control the polymer’s degree
w n
/M ~1.05)
3
of polymerization (DP) following DP = [AB
allowing sequential addition of different AB
2
]
0
/[B
3
]
0
× conversion,
monomers in
2
multiple batches to produce segmented hyperbranched
copolymers.[ In this progress, we see the chance to introduce
multiple functional sites through sequential chemical
conjugations on the polytriazole skeleton, which can reach
never-reported sorphitication of hyperbranched structures
carrying an array of reactive groups.[12]
11]
Introduction
Incorporation of functional groups into polymers significantly
determines the properties and applications of polymeric
materials.[1] As the choices of functional monomer species are
Herein, three types of AB
2
-F functional monomers carrying diene,
often limited by their compatibility in the polymerization
techniques,[1d, 2] the strategy of post-polymerization modification
becomes attractive, which provides alterative options to
introduce functional groups into well-structured polymers,
especially by using several efficient click reactions.[1a, 1e, 3]
A
3
B core
AB -F Monomer
2
CuAAC
Small molecules
F
x
, x = 1, 2, 2’, 3
polymerization
S, S
x
Highly branched polymers that have a compact nanostructure
and multiple terminal groups are intriguing candidates as
unimolecular containers in diverse fields such as theranostic
reagents,[4] catalysts[5] and optoelectronic materials.[6] Further
functionalization of the backbones and the interior of these
highly branched polymers brings up opportunities to increase the
density and diversity of active guest species in these
unimolecular containers.[7] However, different from linear
polymers whose functionalization is less affected by the polymer
structure, functionalization of highly branched polymers,
especially sequential functionalization of the inside structure
HBP(Fx)
x
S -grafted, S-capped HBP
x x
HBP(F /S )-c-S
B
Chain-
extension
Fy
y = 1, 2, 2’, 3
x y
S, S , S
F
1
Segmented HBP(F
x
-b-F
y
)
Tri-functional segmented
HBP(F /S -b-F /S )-c-S
x
x
y
y
2 2
F (n = 1) F ' (n = 2)
becomes rare and challenging, mainly due to the steric
hindrance of polymer structures on the reaction efficiency.[6a, 8]
C
Reactive
group
Guest
molecule
Reaction
Product
CuAAC
We have an intention to develop an applicable highly branched
polymer platform that could efficiently, orthogonally, and
quantitatively load cargo molecules bearing different types of
functional groups in minimum synthetic effort.[1a, 9] The traditional
hyperbranched polymers synthesized from step-growth
TAD-diene
F
3
Alkoxyamine-
ketone
Thiol-epoxy
[
a]
X. Cao, Dr. Y. Shi, W. Gan, Prof. Dr. H. Gao
Department of Chemistry and Biochemistry
University of Notre Dame
B
3
3
05C McCourtney Hall, Notre Dame, Indiana, 46556, USA
Scheme 1. A) Schematic illustration of the synthesis of multifunctional
hyperbranched polytriazoles, B) structure of the AB monomers and B
E-mail: hgao@nd.edu
2
3
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
core, and C) summary of reactions used for backbone construction and
post-polymerization functionalization.
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ketone, and epoxy groups (denoted
as F
details
1
, F
2
, and F
in the
3
with synthesis
supporting
A
C
HBP(F1)
HBP(F )-c-Ph
1
information, Figures S1-S2) were
designed for use in the CuAAC
HBP(F /nBu)
1
HBP(F /nBu)-c-Ph
1
(
co)polymerization to construct
hyperbranched polymers with
layered structure and periphery
azido groups. Correspondingly,
three efficient metal-free click
2
0
21 22 23 24 25 26 27 28 29
Elution Volume (mL)
reactions, including triazolinedione
(
TAD)-diene
reaction,[3f,
13]
B
alkoxyamine-ketone
reaction,[14]
and thiol-epoxy reaction,[15] were
H2O DMSO
D
HBP(F /nBu)-c-Ph
1
a'
b'
b'
×
HBP(F /nBu)
-CH2N3
a'
carefully adopted for the post-
polymerization modification. The
highly efficient nature of these
reactions and their orthogonality
was demonstrated in details using
many transformation reactions
1
×
HBP(F )-c-Ph
1
b'
b'
×
×
a
-CH2N3
HBP(F1)
a
9
8
7
6
5
4
3
2
1
0
(
Scheme 1).

(ppm)
Results and Discussion
#
5
H2O DMSO
E
F
c'
G
a',c'
×
×
b'
b'
#
#
#
#4
#
1
2
3
Tg = 51.4
The chain-growth mechanism in
-CH2N3
#4
#3
a'
the CuAAC polymerization of AB
monomers was based on the rapid
complexation between in-situ
2
#5
-
CH2N3
Tg = 28.6
Tg = 28.2
5
b
a'
a'
×
HBP(F /nBu)
1
#
2
-CH2N3
-CH2N3
×
×
#4
formed triazole groups and the Cu
catalyst, which efficiently confines
the catalyst in the polytriazole
polymers[ and selectively favors
the polymer-monomer reaction
rather than monomer-monomer
reaction. To demonstrate the
compatibility of several highly
reactive groups, the CuAAC
polymerization of each functional
#1
T = 38.0
g
a
#2
2
1
22 23 24 25 26 27 28 29 30
Elution volume (mL)
9
8
7
6
5
4
3
2
1
0
20
40
60
80
16]
o
 (ppm)
Temperature ( C)
Figure 1. A) Rapid CuAAC polymerization of F
1
monomer and subsequent functionalization reactions,
.
o
conditions: 1. [F
1
]
0
:[B
3 0
]
:[CuSO
4
5H
2
O]
0
:[ascorbic acid]
0
= 300:1:10:10, [F
1
]
0
= 0.5 M in DMF, 45 C; 2.
phenylacetylene (1 equiv.), 45 oC; 3. nBuTAD (1.1 equiv.), DMF, r.t.; 4. phenylacetylene (1 equiv.),
.
(0.03 equiv.), ascorbic acid (0.03 equiv.), 45 oC; B) one-pot sequential synthesis of tri-
CuSO
4
5H
2
O
functionalized
[F :[B
:[CuSO .
. [F :[CuSO
.5H
phenyl acetylene (1 equiv.), CuSO
segmented
5H O] :[ascorbic acid]
O]
hyperbranched
polymer
using
F
1
monomer,
conditions:
1.
o
1
]
0
3
]
0
4
2
0
0
= 100:1:10:10, [F
= 200:10:10, [F
1
]
0
= 0.5 M in DMF, 45 C; 2. PhTAD (1 equiv.), r.t.;
= 0.5 M in DMF, 45 C; 4. nBuTAD (1 equiv.), r.t.; 5.
o
3
]
1 0
4
2
0
:[ascorbic acid]
0
1
]
0
monomer in the presence of the B
core was conducted at molar ratios
of
3
.5H
O (0.03 equiv.), ascorbic acid (0.03 equiv.), 45 C; C) DMF SEC traces
o
4
2
(
crude products, RI signal) and D) 1H NMR spectra (purified products, DMSO-d
6
) of the precursor HBP(F
1
) and
its functionalized derivatives; E) DMF SEC traces (crude products, RI signal) and F) 1H NMR spectra (purified
[
F
x
]
0
:[B
acid]
monomer concentration [F
mol L-1 in DMF solution at 45 oC,
where the B molecule functions as
3
]
0
:[CuSO .
= m:1:10:10 with constant
= 0.5
4
5H
2
O]
0
:[ascorbic
products, DMSO-d of individual product in the sequential synthesis of tri-functionalized segmented
hyperbranched polymer; G) Differential scanning calorimetry (DSC) curves of purified HBP(F /nBu),
HBP(F /Ph), HBP(F /Ph-b-F /nBu) and HBP(F /Ph-b-F /nBu)-c-Ph.
6
)
1
0
1
1
1
1
1
x 0
]
3
(
Figure S7), representing a highly arborescent and dense
an initiator to define the DP of polymers in proportion to
monomer conversion.[10b] For instance, when m = 300, all
polymerizations reached nearly complete conversion (conv. >
polymer structure.
Tandem functionalization of hyperbranched polymers on
periphery and at interior was first demonstrated using HBP(F
m = 300) as an example (Table 1, Figure 1A). By the end of the
polymerization, adding 1 equiv. of phenylacetylene in situ
quantitatively reacted all peripheral azido groups on HBP(F ) in
min (Route I, Figure 1A), evidenced by complete
1
)
9
5%) in 4~6 min, producing hyperbranched polymers with very
low dispersity M /M ~ 1.04. More importantly, the absolute
molecular weight of these highly branched polymers, Mn,MALLS
(
w
n
,
1
determined by size exclusion chromatography (SEC) in THF
equipped with a multi-angle laser light scattering (MALLS)
5
disappearance of the methylene proton signal adjacent to azido
units (δ = 3.43 ppm) in H NMR spectroscopy (Figure 1D) and
the azido signal at 2100 cm-1 in IR spectroscopy (Figure S11A).
The produced HBP(F
periphery showed smooth shift of SEC trace (Figure 1C) with
n,app = 54.1k and remained low dispersity M /M = 1.03 as
compared to HBP(F ): Mn,app = 49.1k and M /M = 1.03,
determined by DMF SEC based on linear poly(methyl
detector, were all very close to the theoretical values, Mn,theo
FWB3 + m×FWFx×conv. (FWB3 and FWFx standing for the formula
weights of B core and F monomer, respecitvely), confirming
=
1
3
x
1
)-c-Ph with phenyl (Ph) groups capped at
the controlled chain-growth polymerization during the processes
1
(
Table S1, Figures S3-S5). H NMR spectroscopy of the purified
M
w
n
HBPs (Figure S6) confirmed the quantitative preservation of
dangling reactive groups during the polymerization. The degree
of branching (DB) of polymers was calculated as DB ~ 0.8
1
w
n
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methacrylate) (PMMA) standards. Meanwhile, the absolute
polymerization with another batch of F
HBP(F /Ph-b-F ) before a subsequent step of decoration with
nBuTAD to get HBP(F /Ph-b-F /nBu). In the chain-extension
step, it was noticed that additional Cu catalyst should be added
1
(m = 200) to produce
molecular weight increased from the Mn,MALLS = 112.6k of
1
1
HBP(F
SEC-MALLS, in which the latter value was very close to the
theoretical value of m×FW of
1
) to Mn,MALLS = 139.1k of HBP(F
1
)-c-Ph, as recorded by
1
1
Mn,MALLS of HBP(F
1
)
+
since the acidic urazole groups (pK
previous reaction could complex Cu catalysts.
a
~ 5) generated in the
I
[18]
phenylacetylene = 112.6k + 300×102 = 143.2k. If we purified the
The “living”
I
polymer HBP(F
1
)-c-Ph by removing the Cu catalyst and excess
chain-growth feature was retained in this step as confirmed by
linear increase of apparent molecular weights over conversions
(Figure S10). Finally, the copolymer was end-capped with
ascorbic acid, the second TAD-diene reaction[3f, 17] inside the
polymer could be complete in 15 seconds by reacting with 1
equiv.
of
4-n-butyl-1,2,4-triazole-3,5-dione
(nBuTAD),
phenylacetylene to obtain well-defined final polymer HBP(F
1
/Ph-
quantitatively producing HBP(F
1
/nBu)-c-Ph polymer with grafted
b-F /nBu)-c-Ph with Mn,app = 57.3k, and M /M = 1.04 (Figure 1E).
1
w
n
nBu groups at interior. The 2nd step TAD-diene reaction could
During these sequential chain-extension and functionalizations,
the crude and purified polymers after each step were carefully
characterized using 1H NMR spectroscopy (Figure 1F),
demonstrating more than 95% monomer conversion in each
polymerization, as well as 94%, 91%, and 100% incorporation of
PhTAD, nBuTAD and phenylacetylene units in each layer from
inside to outside, respectively. As a further proof, the absolute
molecular weight for the four precursors and the final product
were also measured, with gradually increased Mn,MALLS = 37.2k,
54.7k, 124.9k, 152.8k and 175.3k, respectively. Thermal
also be accomplished in tandem without any purification of
HBP(F )-c-Ph when using 1.1 equiv. of nBuTAD since some of
1
the TAD groups was reduced to urazole by the ascorbic acid
I
and Cu present in the solution (Figure S8). The reaction could
be carried out in many aprotic solvents, e.g., dichloromethane,
chloroform, THF, DMSO, and the final product HBP(F
Ph showed a monomodal SEC trace with Mn,app = 56.9k, Mn,MALLS
179.8k and M /M = 1.03. The sequence of these tandem
reactions could be reversed without any influence on the
functionalization efficiency (Route II in Figure 1A, and Figure S9). properties of the polymers HBP(F
1
/nBu)-c-
=
w
n
1
/Ph), HBP(F
1 1
/Ph-b-F /nBu),
With the interest of using one single monomer to construct a
sophisticated core-shell polymer structure, the synthesis of a
hyperbranched polymer tri-functionalized at different layers was
HBP(F /Ph-b-F /nBu)-c-Ph were strongly influenced by the
1 1
attached peripheral functional moieties, with an up-and-down
o
change of the glass transition temperature (T
g
) from 38.0 C to
o
o
demonstrated merely using F
The crude HBP(F with m = 100 was synthesized and
subsequently modified with 1 equiv. of 4-phenyl-1,2,4-triazole-
,5-dione (PhTAD) to produce HBP(F /Ph). This polymer without
1
monomer (Table 1, Figure 1B).
28.2 C and 51.4 C, respectively (Figure 1G). Intriguingly, the
1
)
bilayered HBP(F
the mono-functionalized HBP(F
1
/Ph-b-F
1
/nBu) showed nearly identical T
g
as
o
1
/nBu) (T
g
= 28.6 C), confirming
3
1
the segmented structure of the polymers and the dominant effect
of outermost layer on the polymer’s thermal property.[11]
any purification could serve as the inner core for chain-extension
in creasedfunct io na lit ie s
AA
B
HBP(F -b-F )-c-Ph
1
3
HBP(F /tBu-b-F /nBu)-c-Ph
1
3
Route I
Route II
2
0
21 22 23 24 25 26 27 28 29
Elution volume (mL)
C
H2O DMSO
a'
HBP(F /tBu-b-F /nBu)-c-Ph
1
3
b'
b'
c'
c'
×
HBP(F -b-F /nBu)-c-Ph
1
3
c'
c'
×
a
HBP(F /tBu-b-F )-c-Ph
a'
1
3
b
b
c'
c'
×
HBP(F -b-F )-c-Ph
1
3
c'
c'
×
a
9
8
7
6
5
4
3
2
1
0

(ppm)
Figure 2. A) A list of segmented hyperbranched polymers synthesized from chain-extension polymerization of two
different monomers with subsequent chemo-selective functionalization; B) DMF SEC traces (crude products, RI
1
signal) and C) H NMR spectra (purified products, DMSO-d
6
) of the precursor HBP(F
1 3
-b-F ) and its functionalized
derivatives.
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In a parallel effort, the
two-step
functionalization
tandem
of
Table 1. Summary of products from functionalization of hyperbranched homopolymers
HBP(F
demonstrated
complete and efficient
by reacting azido
groups with 1 equiv. of
phenylacetylene and
reacting ketone units
with 1.2 equiv. of
hydroxylamine
2
)
was
Conv. Mn,app
Precursor
Reaction Type
Time
Mw/Mn
f
[
%]e [ 10-3]f
>99
HBP(F1)-c-Ph
HBP(F1)a
CuAAC
TAD-diene
4 min
15 s
54.1
53.2
56.9
57.1
30.1
48.1
51.6
57.3
52.7
48.3
54.6
54.2
40.6
55.4
54.8
52.9
57.3
56.3
52.9
56.7
60.2
60.4
63.6
1.03
1.03
1.03
1.03
1.03
1.03
1.04
1.04
1.03
1.03
1.02
1.04
1.03
1.03
1.03
1.04
1.04
1.03
1.06
1.05
1.07
1.07
1.08
HBP(F1/nBu)
HBP(F1)a
>99
>99
>99
>99
94
HBP(F1/nBu)-c-Ph
HBP(F1/nBu)-c-Ph
HBP(F1)-c-Pha
HBP(F1/nBu)a
TAD-diene
15 s
CuAAC
1 hr
HBP(F /Ph)
HBP(F )a,c
TAD-diene
1 min
2.25 hr
15 s
1
1
compounds at room
temperature,
regardless of the order
HBP(F1/Ph -b-F1)
HBP(F1/Ph)a,c
CuAAC
HBP(F1/Ph-b-F1/nBu)
HBP(F1/Ph-b-F1/nBu)-c-Ph
HBP(F1/Ph-b-F1)a,d
TAD-diene
95
(
Scheme S5, Figure
HBP(F1/Ph-b-F1/nBu)a,d
CuAAC
2 hr
91
S12).[
19]
Several
interesting features are
worth of mentioning
during these tandem
reactions. First, the
HBP(F )-c-Ph
HBP(F )a
CuAAC
6 min
8 hr
>99
>99
>99
>99
>99
>99
>99
>99
>99
95
2
2
HBP(F2/nBu)
HBP(F2)b
alkoxyamine-ketone
alkoxyamine-ketone
CuAAC
HBP(F2/nBu)-c-Ph
HBP(F2)-c-Phb
8 hr
HBP(F
2
) polymer with
as
HBP(F /nBu)-c-Ph
HBP(F /nBu)b
30 min
8 hr
2
2
2-butanone
HBP(Facid)-c-Ph
HBP(Facid/nBu)-c-Ph
HBP(F2’)-c-Ph
HBP(F2)-c-Phb
HBP(Facid)-c-Phb
HBP(F2’)a
β-elimination
amidation
dangling group could
serve as the precursor
of polyacids, which
underwent complete β-
elimination reaction in
the presence of a mild
12 hr
9 min
8 hr
CuAAC
HBP(F2’/nBu)
HBP(F2’)b
alkoxyamine-ketone
alkoxyamine-ketone
ligand-exchange
CuAAC
HBP(F2’/nBu)-c-Ph
HBP(F2’)-c-Phb
8 hr
base
triethylamine (Et
e.g.,
N),[
20]
HBP(F ’/Ph)-c-Ph
HBP(F ’/nBu)-c-Phb
24 hr
4 min
12 hr
36 hr
36 hr
30 min
2
2
3
as
confirmed
by
HBP(F3)a
HBP(F3)-c-Ph
>99
>99
>99
>99
>99
successful amidation
of the polymer with n-
butylamine (Scheme
HBP(F /nBu)-c-Ph
HBP(F )-c-Phb
thiol-epoxy
esterification
azidation
3
3
HBP(F3/nBu/ene)-c-Ph
HBP(Fazide)-c-Ph
HBP(F3/nBu)-c-Phb
HBP(F3)-c-Phb
S6,
However,
with 2-pentanone as
dangling group
Figure
S14).
HBP(F ’)
2
HBP(Fazide/nBu)-c-Ph
HBP(Fazide)-c-Phb
CuAAC
a Precursor that was directly post-functionalized via sequential addition of reactants in one pot without any purification
remained stable under
the basic condition,
indicating that adding
one more methylene
unit blocked the β-
process from the previous step. b Precursor that was purified prior to use. c Precursor from CuAAC polymerization with m =
nd
1
100. d Precursor from CuAAC chain-extension with m = 200 for the 2 batch of F monomer. e Conversion of functionalizable
groups in the purified product, or conversion of the second batch monomer for CuAAC chain-extention of HBP(F
1
/Ph), as
1
determined by H NMR spectroscopy. f Apparent number-average molecular weight and dispersity measured by DMF SEC
with RI detector, calibrated with linear PMMA standards. Unless noted otherwise, initial homopolymers were prepared from
CuAAC polymerization with m = 300.
elimination
Fig. S13,
pathway
S14C).
Figure S17).[22] The ring-open epoxides by reacting with thiols
(
Second, the dynamic covalent character of the oxime bond was
demonstrated by exchange reaction between polymer
also generated a pendant secondary hydroxyl unit that
could undergo further esterification or isocyanate-hydroxyl
reaction. Similarly, epoxide ring-opening reaction using sodium
azide in the presence of ammonium chloride was also efficient to
introduce azido groups for subsequent CuAAC reaction
(Scheme S9, Figure S19).[6a]
HBP(F
yielding HBP(F
incorporated (Scheme S7, Figure S15).[21] The two-step tandem
functionalization of HBP(F ) was carried out using thiol-epoxy
reaction and phenylacetylene coupling reactions (Scheme S8,
2
’/nBu)-c-Ph and large excess of O-benzyl hydroxylamine,
2
’/Ph)-c-Ph with more than 95% benzyl groups
3
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Chemistry - A European Journal
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FULL PAPER
Table 2. Sequential functionalization of hyperbranched copolymers with segmented structure
Conv.
%]c
Mn,app
Precursor
Reaction Type
Time
Mw/Mnd
[
[ 10-3]d
a
HBP(F -b-F )-c-Ph
HBP(F -b-F )
CuAAC
TAD-diene
thiol-epoxy
thiol-epoxy
TAD-diene
CuAAC
25 min
15 s
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
56.4
59.5
63.0
64.5
64.2
64.9
68.3
70.2
53.5
55.1
57
1.06
1.09
1.10
1.13
1.11
1.06
1.09
1.11
1.03
1.04
1.03
1.04
1.05
1
3
1
3
b
HBP(F /tBu-b-F )-c-Ph
HBP(F -b-F )-c-Ph
1 3
1
3
b
HBP(F -b-F /nBu)-c-Ph
HBP(F -b-F )-c-Ph
12 hr
12 hr
15 s
1
3
1
3
a
HBP(F /tBu-b-F /nBu)-c-Ph
HBP(F /tBu-b-F )-c-Ph
1 3
1
3
b
HBP(F /tBu-b-F /nBu)-c-Ph
HBP(F -b-F /nBu)-c-Ph
1 3
1
3
a
HBP(F -b-F )-c-Glu
HBP(F -b-F )
25 min
15 s
1
3
1
3
b
HBP(F /Boc-b-F )-c-Glu
HBP(F -b-F )-c-Glu
TAD-diene
thiol-epoxy
CuAAC
1
3
1
3
a
HBP(F /Boc-b-F /SAc)-c-Glu
HBP(F /Boc-b-F )-c-Glu
36 hr
40 min
8 hr
1
3
1
3
a
HBP(F -b-F )-c-Ph
HBP(F -b-F )
2
1
2
1
b
HBP(F /iBu-b-F )-c-Ph
HBP(F -b-F )-c-Ph
alkoxyamine-ketone
TAD-diene
TAD-diene
alkoxyamine-ketone
CuAAC
2
1
2
1
b
HBP(F -b-F /tBu)-c-Ph
HBP(F -b-F )-c-Ph
15 s
2
1
2
1
b
HBP(F /iBu-b-F /tBu)-c-Ph
HBP(F /iBu-b-F )-c-Ph
15 s
57.1
58.1
60.6
61.9
2
1
2
1
a
HBP(F /iBu-b-F /tBu)-c-Ph
HBP(F -b-F /tBu)-c-Ph
8 hr
2
1
2
1
HBP(F -b-F )-c-(PEO0.42nBu0.58
)
HBP(F -b-F )
a
40 min
1 min
1.05
1.06
2
1
2
1
HBP(F -b-F /Ph0.75nBu0.25)-c-(PEO0.42nBu0.58
)
HBP(F -b-F )-c-(PEO0.42nBu0.58)b
TAD-diene
2
1
2
1
HBP(F /Dan0.16nBu0.84-b-F /Ph0.75nBu0.25)-c- HBP(F -b-F /Ph0.75nBu0.25)-c-
2
1
2
1
alkoxyamine-ketone
18 hr
>99
63.8
1.08
(
PEO0.42nBu0.58
)
(PEO0.42nBu0.58)a
a
HBP(F -b-F ’)-c-Ph
HBP(F -b-F ’)
CuAAC
thiol-epoxy
40 min
12 hr
8 hr
>99
>99
>99
>99
>99
>99
>99
59.9
58.6
60.8
61.3
62.5
60.6
61.5
1.05
1.06
1.05
1.06
1.06
1.06
1.05
3
2
3
2
b
HBP(F /nBu-b-F ’)-c-Ph
HBP(F -b-F ’)-c-Ph
3 2
3
2
b
HBP(F /nBu-b-F ’ꢀ/iBu)-c-Ph
HBP(F /nBu-b-F ’)-c-Ph
alkoxyamine-ketone
esterification
CuAAC
3
2
3
2
b
HBP(F /nBu/ene-b-F ’ꢀ/iBu)-c-Ph
HBP(F /tBu-b-F ’/iBu)-c-Ph
36 hr
40 min
36 hr
12 hr
3
2
3
2
a
HBP(F -b-F ’)-c-EtHex
HBP(F -b-F ’)
3
2
3
2
b
HBP(F /Gly-b-F ’)-c-EtHex
HBP(F -b-F ’)-c-EtHex
thiol-epoxy
3
2
3
2
b
HBP(F /Gly-b-F ’ꢀ/DEG)-c-EtHex
HBP(F /Gly-b-F ’)-c-EtHex
alkoxyamine-ketone
3
2
3
2
a Precursor that was directly post-functionalized via sequential addition of reactants in one pot without any purification process. b Precursor that was purified
prior to use. c Conversion of reactive groups in the purified product determined by 1H NMR spectroscopy. d Apparent number-average molecular weight and
dispersity of crude product measured by DMF SEC with RI detector, calibrated with linear PMMA standards. All copolymer precursors were synthesized from
st
CuAAC polymerization with m = 100 for the 1 monomer and m = 200 for the 2nd monomer.
The “living” CuAAC polymerization allows sequential addition of
functional monomers in one pot and renders the possibility to
place desired reactive groups in specific domain while
minimizing the synthetic effort. Three types of segmented
proton peak at δ = 1.48~1.12 ppm. Subsequent addition of n-
butyl thioglycolate in basic condition into the polymer solution
disappeared the characteristic proton signal of epoxide at δ =
3.08 ppm but quantitatively produced a new peak at δ = 0.78
hyperbranched copolymers HBP(F
1
-b-F
3
)-c-Ph, HBP(F
2
-b-F
1
)-c-
3
ppm, representing the CH - protons from the n-butyl group
Ph, HBP(F
3
-b-F
2
’)-c-Ph, with different monomer placement
(Figure 2C). In both reactions, the reactive groups were
compatible in the other reactions and did not introduce any side
st
sequences were prepared by sequential addition of the 1
monomer in m = 100 followed by chain-extension polymerization
of the 2nd monomer (m = 200) and end capping using 1 equiv. of
phenylacetylene to the azido groups (Table 2, Figure 2A). No
loss of functional group was observed in all cases. 1H NMR
characterization (Figure S21) confirmed that the molar ratios of
the two monomer units and the terminal phenyl units exactly
matched the feed ratio of 1:2:3 in each copolymer. Sequential
functionalization was carried out on each copolymer. For
product. The sequential functionalization of HBP(F
1
3
-b-F )-c-Ph
was also successful to produce HBP(F /tBu-b-F /nBu)-c-Ph in
1 3
either synthetic pathway as demonstrated by 1H NMR
spectroscopy with molar ratio of ftBu: fnBu ≈ 1:2 and SEC
measurements (Mn,app = 64.5k, M
64.2k, M /M = 1.11, Route II, Table 2, Figures 2B, S22). To
demonstrate that our strategy is applicable for other guest
3
molecules with tunable reactivity and polarities, HBP(F -b-F )
w n
/M = 1.13, Route I, or Mn,app =
w
n
1
example, treating the HBP(F
1
-b-F
monomer units) completely disappeared the diene peaks
δ = 6.21~5.42 ppm, Figure 2C) and introduced the t-butyl
3
)-c-Ph with equimolar tBuTAD
was capped with glucose, modified with a Boc-protected amine
derived TADs and thiol acetic acid which could be easily
transformed to amine and thiol groups (Figure S23).
(
(
to F
1
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Chemistry - A European Journal
10.1002/chem.201800683
FULL PAPER
Hyperbranched polymer with a radial polarity gradient could also
well as tedious synthetic procedure of traditional dendrimers,
this development will become a useful toolbox that enables a
facile access to unlimited types of polytriazoles with desired
functions. We envisage that many other functionalization
techniques could be possibly compatible with the current CuAAC
polymerization, which may further enrich the elements in this
toolkit for preparing advanced materials.
be prepared through three-step modifications by using HBP(F
3
-
b-F ’) as the parent scaffold (Figure S24). In all cases, complete
2
conversions of functional groups were achieved with no side
reactions (Table 2). In another example, tetra-functionalized
polymer (Mn,app = 61.3k, M
w
/M
n
= 1.06) was synthesized through
-b-F ’)-c-Ph with n-butyl
sequential modification of the HBP(F
3
2
thioglycolate, O-i-butyl hydroxylamine, and 4-pentenoic acid for
reacting with epoxy, carbonyl and hydroxyl groups (after epoxide
ring-opening reaction), respectively (Table 2, Figure S25).
Experimental Section
For advanced applications (e.g. catalysis, diagnosis and
therapy), it is often desirable to formulate the dosages of
multiple reactive species into one nanostructure.[23] In our study,
the three efficient click reactions between alkyne and azide,
triazolinediones and diene, hydroxylamine and ketone provide
possibility to use mixed substrates for one reaction to
simultaneously introduce two functional groups into one domain.
Preparation of segmented HBP(F -b-F )-c-Ph via CuAAC
2
1
polymerization in one pot. The inner core HBP(F
synthesized at molar ratios of [F :[B :[CuSO ·5H O] :[ascorbic acid]
00:1:10:10. (305.3 mg, 0.7 mmol), (3.6 mg, 7.0 μmol),
CuSO ·5H O (17.5 mg, 70.0 μmol) and 1.2 mL DMF were charged in a
0 mL schlenk flask equipped with a magnetic stirring bar. The flask was
2
) was firstly
2
]
0
3
]
0
4
2
0
0
=
1
F
2
B
3
4
2
1
subjected to three freeze-pump-thaw cycles, back-filled with nitrogen and
immersed in a thermostatic oil bath at 45 oC. The reaction was initiated
To test this versatility, the HBP(F
2 1
-b-F ) (mtotal = 300 with
theoretical ratio of F :F as 1:2) immediately after polymerization
2
1
by quickly addition of a degassed solution of ascorbic acid (12.3 mg, 70.0
was functionalized in situ via end-capping reaction with a
mixture of alkynyl-terminated poly(ethylene glycol) with average
molar mass 350 g/mol (ay-PEG350) and propynyl n-butyrate at
μmol) in 0.2 mL DMF ([F ] = 0.5 mol L-1 in total amount of DMF). After 4
2
0
min, 98% monomer conversion was reached, and a 2nd batch of
1
deoxygenated F monomer (624.7 mg, 1.4 mmol, m = 200) in 2.4 mL
DMF was added into the system and allowed to react for 40 minutes to
reach completion.
The chain-end azido units of the resulted hyperbranched polymer were
subsequently modified by adding deoxygenated phenylacetylene (214.3
0
.4:0.6 molar ratio (1 equiv. to the azido groups on polymer).
The polymer after purification was further functionalized on the
shell using a mixture of PhTAD: nBuTAD at molar ratio 0.75:0.25
(
totally 1 equiv. to the diene units) and in the core using a
mg, 2.1 mmol) to the mixture via a 1 mL syringe, and allowed to react at
mixture of dansyl (Dan)-hydroxlamine and O-nBu hydroxylamine
o
4
5 C for another 40 min before dilution with 10 mL CH
2
Cl
2
.
at molar ratio 0.3:0.9 (1.2 equiv. to the ketone units, Figure 3A),
The Cu catalyst was then removed by adding two equivalents of 2,2′-
bipyridyl (bpy) ligand followed by passing through a flash neutral alumina
0
.16
0.84
producing
final
product
HBP(F
2
/Dan nBu -b-
F
1
/Ph0.75nBu0.25)-c-(PEO0.42nBu0.58) (Mn,app = 63.8k, M
/M
w n
= 1.08, column. The catalyst-free solution of hyperbranched polymers were
1
precipitated into 40 mL diethyl ether three times, dried in vacuo to a
Table 2, Figure S27). The evolution of H-NMR spectra after
individual modification exhibited complete consumption of the
clickable groups, the ratio of guest molecules incorporated via
CuAAC and TAD-diene reactions exactly matched with the initial
feed ratio (Figure 3B).
constant mass, yielding 1.06 g product as a white solid (93%), which was
o
stored in a freezer at -20 C before further usage.
Preparation of HBP(F
2 1
-b-F /tBu)-c-Ph via TAD-diene reaction. 408.7
mg purified HBP(F -b-F
2
1
)-c-Ph (750.0 μmol of total monomer units) was
dissolved in 1.5 mL anhydrous DMF in a 10 mL round-bottom flask
equipped with a magnetic stirring bar. To this stirring solution was added
dropwise a freshly prepared solution of 77.5 mg tBuTAD (500.0 μmol, 1.0
equiv. to the diene groups) in 1.5 mL anhydrous DMF at room
temperature, with instant disappearance of the characteristic reddish
color of TAD. The resulting pale yellow solution was evenly separated
into two portions, with one precipitated into 20 mL ethyl ether three times
to remove the DMF and then dried in vacuo, yielding 238.1 mg pale
brown solid (98%), while the other half was directly used for next-step
reaction.
Conclusions
In this study, we developed a robust polymer platform to
construct structurally defined hyperbranched polymers with an
array of densely functionalized groups at different spatial layers.
The employed chain-growth CuAAC polymerization of three
types of AB
2
-F
x
(x = 1, 2, 2” and 3) functional monomers and
2 1
Preparation of HBP(F /iBu-b-F )-c-Ph via alkoxyamine-ketone
reaction. To the above solution was sequentially added O-i-
butylhydroxylamine hydrochloride (18.8 mg, 150.0 μmol, 1.2 equiv. to the
various types of subsequent orthogonal modifications, including
ultrafast TAD-diene reaction, alkoxyamine-ketone reaction, and
thiol-epoxy reaction, were all conducted under mild conditions
with high efficiency. In addition, successful combination of four
chemo-selective reactions allowed accurate and quantitative
allocation of several model guest molecules within one polymer
nanostructure at different placements. By simply varying the
monomers, the guest molecules and their ratios, all structural
and compositional parameters within these hyperbranched
polymers could be adjusted. Considering the extensive
applications of dendritic polymers, increasingly demanding
requirements of complexity for high-performance polymers, as
ketone groups), Et
(
3
N (15.2 mg, 150.0 μmol) and p-phenylenediamine
32.4 mg, 300.0 μmol, 0.2 mol L-1 in DMF) under nitrogen atmosphere.
The mixture was stirred continuously for 8 hours at room temperature,
before being precipitated into 20 mL of ethyl ether three times,
redissolved in 5 mL CH Cl and passed through a flash neutral alumina
2 2
column. After dried in vacuo to a constant mass, the product was 236.9
mg in pale brown solid (94%).
Acknowledgements
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Chemistry - A European Journal
10.1002/chem.201800683
FULL PAPER
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Figure 3. A) The HBP(F
2
/Dan0.16nBu0.84-b-F
1
/Ph0.75nBu0.25)-c-(PEO0.42nBu0.58
)
12092-12098.
synthesized from sequential loading of mixtures of guest molecules on
segmented HBP(F -b-F ) polymers, conditions: 1. PEO350-alkyne (0.4 equiv.),
propynyl n-butyrate (0.6 equiv.), 45 oC, no purification after polymerization in
situ; 2. PhTAD (0.75 equiv.), nBuTAD (0.25 equiv.), DMF, r. t., with purified
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3
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[
The authors thank the National Science Foundation (CHE-
554519) for financial support. X. Cao thanks the supported
1
1
from American Cancer Society (ACS) Institutional Research
Grants (IRG) from Notre Dame. Y. Shi acknowledges the partial
financial support from the Center of Sustainable Energy at Notre
Dame via the ND Energy Postdoctoral Fellowship Program. We
thank W. Liu and Prof. B. Smith for assistance with the UV-Vis
absorption and fluorescence emission spectra.
Keywords: Click Chemistry
• Hyperbranched Polymer •
Functionalization • Layered Structure
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Entry for the Table of Contents
COMMUNICATION
Xiaosong Cao, Yi Shi, Weiping Gan,
Haifeng Gao**
Loads on stations
like an airplane
Page No. – Page No.
Tandem Functionalization in One
Highly Branched Polymer with
Layered Structure
Orthogonal selective reactions in one highly branched polymer
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