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Living Radical Polymerization
活性自由基聚合
RAFT polymerization
Reversible addition-fragmentation chain transfer polymerization
ATRP polymerization
Atom transfer radical polymerization
NMRP polymerization
nitroxide mediated radical polymerization
Introduction
Reversible Addition Fragmentation Chain-Transfer (RAFT)
Polymerisation
a. Atom transfer radical polymerization (ATRP)
 Synthesize well-defined polymeric architectures with predictable MW and
PDI
 Supply a good technique to prepare well-defined protein-polymer
conjugate
b. RAFT polymerization

Polymerize more versatile monomers in more flexible reaction
conditions for a wide range of polymeric architectures

Get rid of the metal catalyst which might complex with some functional
groups on proteins and damage the protein bioactivity.
RAFT Agents and Functionalization
S
R
Z
S
S
(C)
关于RAFT聚合应掌握如下几点:
1.RAFT试剂都是二硫酯或三硫脂
2.RAFT试剂都有一个R和Z基团
3.所有的链增长都发生在R和S之间
4.相对较活泼的基团是R基团
5.一般来说，取代较多的基团是R基团
Reaction Conditions – Monomers and RAFT Agents
Typical RAFT Agents and their structural variety
S
Leaving group
S
R
Stabilizing group
Z
Z
R
Ph
CH2 Ph
CH3
CH2CN
NEt2
C(CH3)(CN)CH2CH2COOH
Xanthates
OEt
C(CH3)2Ph
Trithiocarbonates
SCH3
C(CH3)2CN
Dithioesters
Ditihocarbamates
(CSIRO)
(1)
Monomer
Pm
ki
I
(2)
Pm+
S R kadd Pm S
S
k-add
Z
1
(3)
(4)
(5)
I
decomposition
R
kb
k-b
Z
2
Pm S
S
+ R
Z
3
Monomer
Monomer
Pn
P1
kre-in
kp
Pn +
Pn
S R
S
S Pm
Pn S
Z
+ Pm
S Pm
Z
4
ktc
ktd
Pn S
S
Z
Pn+m
Pn= + PmH
Generally accepted mechanism for a RAFT polymerization
+ Pm
Reaction Conditions – Monomers and RAFT Agents
Typical RAFT Agents and their structural variety
S
Leaving group
S
R
Stabilizing group
Z
Z
R
Ph
CH2 Ph
CH3
CH2CN
NEt2
C(CH3)(CN)CH2CH2COOH
Xanthates
OEt
C(CH3)2Ph
Trithiocarbonates
SCH3
C(CH3)2CN
Dithioesters
Ditihocarbamates
(CSIRO)
Reaction Conditions – Monomers and RAFT Agents
The RAFT agent and monomer have to be carefully selected for an efficiently
functioning RAFT process:
Well chosen
O
O
O
O
S
O
+
S
S
Ph
O
Ph
Ph
S
+
S
+
S
S
Ph
Poorly chosen
O
O
O
O
S
O
+
S
S
S
Ph
Ph
Ph
O
S
Ph
S
S
O
t-BA/AIBN
S
S
OH
S
n
dioxane
O
S
NIPAM/AIBN
O
dioxane
n
mS
OO
NH
S
O
n
O
OH
mS
NH
S
OH
O
O
S
OH
CF3COOH
DCM
O
S
O
OH
O
OH
O
S
S
Ag
C
m
n
S
HN
O
HO
N
Cl
O
DCC/DMAP
COOH
S
S
C
Ag
N+
O
n
m
S
HN
O
O
O
=
COOH
O
O
N+
Cl
O
N
Functions
RAFT agents
Monomers
S
α-carboxylic
acid
CO2H
NAM
S
α-carboxylic
acid
NAM
S
CO2H
S
α-carboxylic
acid
CO2H
MMA, St.
S
S
α-carboxylic
acid
HO2C
S
S
10
S
Et. A, AA, n-BA,
HEA, t-BMA, St,
MMA
α-carboxylic
acid
HO2C
S
AA,
n-BA,
NIPAAm
S
2
S
α-carboxylic
acid
HO2C
S
MMA
S
10
CN S
α-carboxylic
acid
S
HO2C
St.,
NIPAAm,
OEG-A, n-BA,
2-acryloyethyl
phosphorylcholin
e, AA
S
S
α,ω-carboxylic
acid
HO2C
S
CO2H
S
Et. A, AA, n-BA,
HEA, t-BMA, St
S
α,ω-carboxylic
acid
HO2C
S
S
CO2H
MMA, n-BA
S
α,ω-carboxylic
acid
HO2C
S
S
S
CO2H
n-BA
α-NHS
S
O
CN
O
NH
S
4-vinylbenzoic
acid
O
O
α-pentafluorop
henyl activated
ester
F
S
CN
O
S
F
O
α-mercapto-thi
ozaline
activated ester
F
F
F
HPMA
S
S
CN
N
S
NIPAAm, LMA,
OEG-MA,
DEG-MA, MMA
S
O
α-hydroxyl
MA, MMA
S
S
OH
CN
α,ω-hydroxyl
S
HO
O
2
S
O
S
O
O
S
St,
n-BA,
NIPAAm
S
N
O
α-amine
St,
2
O
α-amine
OH
MA,
NIPAAm
S
R
R = C4H9
O
S
Vac, NVP
S
N
O
O
α,ω-amine
O
S
S
N
S
NIPAAm,
n-BA
St,
NIPAAm,
n-BA
St,
O
N
O
α,ω-amine
O
O
S
N
O
O
S
S
S
S
S
N
O
α-epoxy
O
S
O
S
10
O
S
α-oxetane
St, Et A, n-BA,
AA, MA
O
S
O
S
10
S
O
α-allyl
St, Et A, n-BA,
AA
S
St, MA, MMA
CN
O
S
8
O
α,ω-allyl
S
α- fluorescent
St, n-BA
S
S
St
S
S
α- fluorescent
St, MA
S
S
Table 2. RAFT agents used for direct post-polymerization conjugation.
Functions
RAFT agents
α-pyridyl
disulfide
Monomers
OEG-A
O
N
S
S
S
O
S
2
S
ω-pyridyl
disulfide
S
S
ω-pyridyl
disulfide
OEG-A,
St.,
NIPAAm
O
S
S
O
S
N
OEG-A,
St,
NIPAAm
O
O
S
O
S
O
S
12
α-azide
S
S
N
O
NIPAAm
O
N3
S
O
S
11
S
α-azide
VAc
N3
O
S
S
α-azide,
pyridyl
ω-
O
N3
O
S
S
S
O
O
S
S
N
St.,
NIPAAm
Reaction Conditions – Monomers and RAFT Agents
The RAFT agent and monomer have to be carefully selected for an efficiently
functioning RAFT process:
Well chosen
O
O
O
O
S
O
+
S
S
Ph
O
Ph
Ph
S
+
S
+
S
S
Ph
Poorly chosen
O
O
O
O
S
O
+
S
S
S
Ph
Ph
Ph
O
S
Ph
RAFT试剂的合成
OH
Br
O
S
NH
S
O
O
OH
S
O
OH
(98%)
CS2, methanol, KOH
O
r.t., 6-8 h
N
H
SH
O
N
H
S
S
Cl
S-
OH
O
O
O
S
NH
S
O
Synthesis of RAFT agents using free thiol
O
S
O
OH
OH
O
O
S
S
NH
S
NH
S
S
O
S
O
O
O
O
S
O
S
S
S
O
H
N
O
OH
N
H
O
H
N
O
O
OH
O
OH
S
O
H
N
N
H
O
S
H
N
O
Scheme . Different peptide-macroRAFT agents.
O
OH
O
N
H
+H3N
O
P
O-
O
O C15H31
O C15H31
O
S
H
N Lipid
S
O
S
H2N
S
HN
O
S
NH
S
S
NH
O
S
O
N
HN
O
O
NH
O
O
O
O
NH2
O
OO
S
S
NH
O
Chemical modification of ester activated RAFT agent by biocompounds, such as
phospholipid, biotin, carbohydrate
NC
S
S
NC
C1 2H2 5
HOOC
HN
O
NHS, DCC
DMF, 14 h
HN
NC
NH
S
n
HN
S
O
HN
O
S
S
H2N
C1 2H2 5
O H
NN
H O
DMF, r.t., 18 h
C1 2H2 5
S
ACVA, 4 h, 25 C
O
S
n
o
S
HOOC
NIPAAm
S
O
HN NH
O
NC
O
O
HN
O
O
S
n
N
S
HO
N
O
S
C1 2H2 5
S
Post-polymerization functionalization of poly(NIPAAm) with
biotin via NHS-ester activation.
O
S
O
N
2O
O
S
O
S
S
C12H25
S
O
N
S
S
C12H25
2O
O
SH
BSA
O
O
O
O
S
12
S
S
O
O
S
S
N
O
S
O
12
S
S
O
S
S
O
Synthesis of BSA-macroRAFT agent by two
different routes: thiol-maleimide addition and
thiol-pyridyl disulfide exchange
O
NC
NaBH4, water
2h
N
n
O
N
O
O
S
S
NC
NC
N
Ellman's reactant
n
O
N
SH
O
O
HO2C
O2N
SS
N
S
S
N
n
NO2
CO2H
HO2C
NO2
O
NC
O
hydrolysis, 50 oC NC
N
n
O
N
O
H
n
S
S
NC
N
water, pH 4-10, 16 h
O
N
OH
120 oC, 1 mBar, 20h
RAFT聚合物的进一步改造
n
O
N
O
S
R
N
S
R
X
Y
n
Z
SS
N
X
Y
N
HS
G
S
X
n
Aminolysis
S
G
S
R
X
Y
S
R
G
n
G = Biocompounds
RAFT聚合物的进一步改造
Y
n
S
G
CN
S
CN
S
+
CO2H
O
HO2C
S
S
n
O
O
O
S
S
S
N
S
N
SH
CN
HO2C
S
S
n
O
O
S
S
RAFT聚合物的进一步改造
S
O
S
S
S
O
O
H 2N
O
O
n
NH
On
O
N(Et)3, DMSO
O
O
NO2
O2N
RAFT聚合物的进一步改造
Z
n Acetic acid
O
Z
n
O
O
OH
O
OH
HIO4
n
O
Z
O
H
NH2 R
n
RAFT聚合物的进一步改造
Z
O
NH
R
S
S
S
S
S
O
O
On
O
S
n
TFA
O
DCM / H2O
O
O
O
O
O
O
H
H 2N
O
S
S
n
O
O
RAFT聚合物的进一步改造
N
H
S
O
n
S
O
C
S
N
S
O
(a)
S
O
O
8~9
O
O
O
S
n
16
O
R
S
O
S
S
S
N
(b)
O
R = NIPAAM or PEG-A
O
NH
H
HN
H
S
O
C
O
n
S
O
O
S
NH
O
O
(c)
O
NH
H
HN
H
N
S
S
O
H
N
CN
O
N
H
S
O
O
O
O
NH
(d)
O
O
NC
NC
N
n
N
N
n
S
OS
NC
N
H
n
N
N
O OH
O
O
n
O
O
S
S
n
O
N
O
O
N
(e)
(f)
O
O
N3
O
N
n
O
N
S
S
C12H25
m
O S
(g)
O
N3
O
S
n
S
O
S
S
S
O
N
(h)
Reaction Conditions – Monomers and RAFT Agents
• Typical RAFT reaction conditions are identical to those of
the associated conventional FRP
• Nearly all monomers can be polymerized in a living
fashion via the RAFT process – provided the RAFT agent is
judiciously chosen
• Purification of the resulting polymers is simple – they are
however coloured (red, yellow, pink)
各种各样的单体
R
HN
O
O
B
O
HN
O
O
O
O
O
O
O
OH
O
NO
HN
O
O
N
O
O
R
O
O
O
OH
O
O
O
R
O
O
O
O
F
O
F
O
O
H
F
N3
F
F
O
O
O
N
O
F
O
F
F
F
F
O
O
OH
O
O
O
O
O
HO
HO
O
O
O
OH
O
O
HO
HO
O
O
HO
HO
O
OH
O
O
O
G2
G1
O
OH
OH
OH
O
O
O
HO
HO
OO
G3
G4
G5
OH
O
OH
HO
HO
H
N
O
OH
O
O
N
H
OH
OH OH
O
OH
HO
HO
OH
O
O
O
O
AcO
AcO
OH
(CH 2)n
O
O
G10
NH
O
O
O
G9
O
O
O
O
O
G8
O
O
O
OH
G7
OAc
O
O
OH
O
O
O
HO
HO
HO
H
N
H
N
O
O
OH
O
G6
O
O
HO
HO
O
O
OO
O
NH
OH
O
O
O
O
OAc
O
O
O
O
O
G11
G12
G14
G13
OAc OAc
O
H
OO
O
O
O
OAc
O O
OH
HO
HO
O
O
G18
OH
O
O
O
O
OAc
OH
O
O
O
O
AcO
AcO
O
O
G15
OAc
O
O
O
HO
HO
G17
O
NH
G19
G16
O
NH
NHAc
G20
OH
O
O
OH
H
N
HO
HO
OH OH
O
HO
OH
O
O
O
G22
O
O
OH OH
OH
O
G21
O NH
O
OH
O
O
HO
OH
O
OH
O
HO
OH
G23
O
O
H
N
O
G24
Functions
RAFT agents
Monomers
S
α-carboxylic
acid
CO2H
NAM
S
α-carboxylic
acid
NAM
S
CO2H
S
α-carboxylic
acid
CO2H
MMA, St.
S
S
α-carboxylic
acid
HO2C
S
S
10
S
Et. A, AA, n-BA,
HEA, t-BMA, St,
MMA
反应温度: 常温引发 (常温引发剂,光引发,微波引发,
辐射引发; 热引发
反应介质: 水相, 有机相,本体
高分子分离纯化: 分离纯化简单, 沉淀法, 透析法等
反应温和易控:
Block Copolymers, Nano/Micro-spheres, Micelles and Stars
ABA triblock copolymers via difunctional RAFT agents
S
S
Ph
S
S
butyl methacrylate
S
S
BMA
n
Ph
BMA
m S
Ph
Ph
S
Ph
Mn = 35 500, PDI = 1.09
methyl methacrylate
S
S
MMA
x
BMA
n
Ph
BMA
Ph
m
MMA
y
S
S
Ph
Mn = 112 200, PDI = 1.14
(CSIRO)
Introduction
Methods to Prepare Biomolecule -polymer Conjugates
b) In situ polymerization
In situ polymerization
Biomolecule
Biomolecule -polymer conjugate
Advantages
 Less steps
 Less-purification
 Easy to control
 High yield
ITO glass
5. pH-Detachable Polymer Brushes Formed Using
Titanium-diol Coordination Chemistry and
RAFT Polymerization
OEt
O
O Si
O Si
O OEt
O
Ti
O
N
H
O
O
S
CN S
O
HO
HO
O
O
O
NH
NH
N
H
CN
Styrene
AIBN, 75 0C
pH 9.0
S
n
Ti(OH)4
aqu. solution
S
Jingquan Liu*, Wenrong Yang, Hadi M. Zareie, J. Justin Gooding
and Thomas P. Davis, Macromolecules, 2009, 42 (8), pp 2931–2939.
7. Biodegradable Three-armed Star Polymeric
Architectures
S
SH
S
C
S
O
C
N
S
O
Mo
no
O
O
O
TMPMP
O
HS
PDEBP
S
60
-7 5
O
me
r/
AIB
N
0
C
SH
O
CH
Cl 2
2
S
N
S
S
S
One-armed polymer
O
S
O
S
S
O O
O
O
O
O
S
O
S
S
O
S
S
SS
S S
O
S
MOo
no
me
r /A
I
60
-75
0
C
TH
F
SH
O
BN
S
O
S
HS
O O
O O
O
O
O
O
O
S
S
O
SH
S S
Three-armed polymer
DTT/GSH
SH
O
O
O
HS
O
O
SH
O
SH
*
Jingquan Liu , Huiyun Liu, Zhongfan Jia, Volga Bulmus and Thomas P. Davis,
Chemical Communications, 2008, 6582-6584.
8. Biodegradable Star Polymers Functionalized With β Cyclodextrin Inclusion Complexes
S
S
S
S
HO
COOH
OH
S
[1]
Cl
S
DCC , DM AP
THF
S
S
O
C
S
S
O
OH
O
S
Cl
Cl
O
S
[2]
S
S
O
S
S
O CO
S
S
Styrene / PEG-A
DMA P
O
THF
O
O
S
S
S
O
O
S
O
S
S
AIBN / dioxane
O
O
O
C
O
S
O
SS
OC
S
O
O
S
O
S
O
S
S
S
S
S
S
[3]
= polySt or polyPEG-A
S
S
S
S
Tailoring the end groups and cleavage tests
Cholesterol Attachment and cyclodextrIn Complex
*
Eki Setijadi, Lei Tao, Jingquan Liu , Cyrille Boyer, Zhongfan Jia and Thomas P. Davis,
Biomacromolecules, 2009, 10 (9), pp 2699–2707.
9. Synthesis of six-armed biodegradable star polymers
O
COOH
HO HO
OH
Cl
H2N
OH
Cl
O
NH
O
O
O
O
COOH
O
O
O
O
O
THF/MeOH
Cl
1
O
H
N
HO
O
HO
O
DMAc, 45 oC
HN
OH
O
OH
2
HOOC
NH
H
N
O
O
O
O
O
O
S
S
S
S
O
O O
O
O
SS
O
O
O
C
O
O
O
O
HN
S
S
S
S
S
O
O
O
C
O
C
S
S
O O
S
O
C
O
S
S
O
O
O
O
NH
O
O
S S
2. PEG-A, AIBN, 70 oC
O
S
O
O
S
S
O
O
O
4
C
O
AP
M
NH
O
O
/D
C
DC
HO
O
O
O
O
S
S
C
O
H
N
1. styrene, AIBN, 75 o C
S
S
O
O
O
S
O
S
S
O C
S
S
O
SS
O
COOH
S
O
O
3
S
O
O
C
O
H
N
O
O
O
O
S
O
O
OC
O
O
O
O
O
O
O
HN
O
C
O
S
O
Jingquan Liu*, Lei Tao, Jiangtao
Xu, Zhongfan Jia, Cyrille Boyer and
Thomas P. Davis, Polymer, 2009,
50, 4455–4463..
S
S
HS
DTT/GSH
S
S
S
S
S
COOH
O
HOOC
S
O
HN
S
HS
SH
S
S
HS
HS
SH
SH
10. Thermosensitive graphene-polymer composites
Characterization of thermosensitive graphenepolymer composites
Jingquan Liu, Wenrong Yang, Lei Tao, Dan Li, Cyrille Boyer and Thomas P. Davis,
Journal of Polymer Science Part A: Polymer Chemistry, 2010, 48, 425-433.
（IF，3.821） .
11. pH sensitive graphene-polymer composites and
self-assembly
pH sensitivity of the graphene-polymer composites
of PDMAEA (a) and PAA (b) at different pH.
180
160
Frequency/ Hz
140
y
120
100
z
80
y
60
40
z
20
x
0
0
20
40
60
Time/ min
Jingquan Liu, Lei Tao, Wenrong Yang, and Thomas P. Davis,
Langmuir, 2010, 26, 10068-10075. （IF，4.079）
80
100
120
12. Highlight of RAFT polymerization
Boyer C., Bulmus, V., Davis T. P., Ladmiral V., Liu J., Perrier S. Chemical
Review 2009, 109, 5402-5436.
(作者按姓氏字母顺序排列。本人负责Bioconjugates 部分的编写)