NIPAM homopolymer Above 32oC LCST phase transition where it goes from a swollen hydrated state to a shrunken dehydrated state. Copolymers can reversibly form aggregates upon heating above the LCST. Will a norbornene NIPAM analogue show similar behaviour?

O

NH O NH

n

O

OH

NHO

OHO

mn

Thermo-Responsive Polymeric Materials: Norbornene NIPAM Analogues Baseem Taraz, Matt Thompson, Nathan Gianneschi

Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0378

Due to the toxicity and solubility of many drug molecules used in the treatment of diseases it is advantageous to use a material as a carrier/delivery vehicle. Materials that form vesicles known as micelles can be used to deliver these drug molecules to the desired site. More important than the delivery itself is the extent to which scientists can manipulate the structure and activity of these micelles through changes in pH, temperature, light and biological stimuli. Here we attempt to synthesize thermo-responsive materials that can change morphology based on changes in temperature. .

Thermo-Responsive Systems

Polymerization – Homopolymer Unsymmetric

HNO

Ph

OHN

1) "Ru" Gen 32) EVE

CD2Cl2

m

-0.1

0.1

0.3

0.5

0.7

0.9

1.1

20 22 24 26 28

Inte

nsity

Time (min)

LS

RI

UV

Mn = 3081

PDI = 1.084 M:I = 20 DP = 17

NIPN-EAN Block-copolymer

HNO

Ph

N HNO

OH

O O

1) "Ru" Gen 3

2)

3) EVEDMF

N

O

OOH

mn

0

0.2

0.4

0.6

0.8

1

1.2

10 15 20 25

Inte

nsi

ty

Time (min)

LS Homo

RI Homo

UV Homo

LS Co

RI Co

UV Co

Polymer Solubility Water n DCM n MeOH mostly THF slightly DMF y DMSO y

Homo Mn = 1835

PDI = 1.048 M:I = 20 DP = 10

Copolymer Mn = 13730

PDI = 1.002 M:I = 40 DP = 57

Dialysis of the copolymer results in micellar particles with a diameter ranging from 32 nm to 71 nm (filtered samples). Heating the MES F sample does not result in a significant change in the diameter of the particles

0

10

20

30

40

50

60

70

10 14 21 32 48 71 107 159 237 354 529 789

% In

tens

ity

Diameter (nm)

MES UF

MES F

0

10

20

30

40

50

60

70

10 14 21 32 48 71 107 159 237 354 529 789%

Inte

nsity

Diameter (nm)

Tris Slow F

Tris Fast F

0

5

10

15

20

25

30

35

10 14 21 32 48 71 107 159 237 354 529 789

% In

tens

ity

Diameter (nm)

DMF F

DMSO UF

DMSO F

Ph

N HNO

OH

O O

mn DMF or DMSO

H2OMES pH 4.0Tris pH 8.5

Dialysis PEG-NIPN Copolymer

N OO

O4

Ph

NO O

1) "Ru" Gen 318

DMF

O4

N

O

O

NH

O

2)

3) EVE

2)

3) EVE

N HNO

O O

1618

NO O

1518

NO O

O

O

4

4

Ph

Ph

0

0.2

0.4

0.6

0.8

1

1.2

20 22 24 26 28

Inte

nsity

Time (min)

LS PEG RI PEG LS PEG-Symm-NIPN

RI PEG-Symm-NIPN LS PEG-Unsymm-NIPN RI PEG-Unsymm-NIPN

Polymerization - Homopolymer

NO O

Ph

NO O

1) "Ru" Gen 32) EVE

mCD2Cl2

-0.1

0.1

0.3

0.5

0.7

0.9

1.1

20 22 24 26 28

Inte

nsity

Time (min)

LS

RI

UV

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)

-2.0

-1.5

-1.0

-0.5

0

0.5

1.0

1.5

Nor

mal

ized

Inte

nsity

DICHLOROMETHANE-d2

1.201.

231.

331.

341.

451.

47

2.57

3.20

4.254.

274.29

4.31

4.32

5.32

6.27

0 min

1 min

2 min

3 min

5 min

Monomer undergoes complete polymerization in 5 minutes as seen by the disappearance of monomer olefin 1HNMR signal (6.27 ppm). Polymer molecular weight was determined using size-exclusion chromatography coupled with multi-angle light scattering.

NIPN: Monomer Synthesis

OO O

H2N

NO O

OO

NO

O

H2N

HNO

OO O

H2N OH

O

NO O

OH

O

H2N

NO O

HN

O

Toluene, Reflux32%

Dipea

CH2Cl283%

Toluene, RefluxHBTU, Dipea

DMF

NEt3

The top symmetrical monomer is not expected to display thermo-responsive

behaviour whereas the other two monomers should as they have an available

proton for hydrogen bonding.

Monomer undergoes complete polymerization in 2 minutes as seen by the disappearance of monomer olefin 1HNMR signal (6.12 ppm).

6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)

-1.0

-0.5

0

0.5

1.0

1.5

Nor

mal

ized

Inte

nsity DICHLOROMETHANE-d2

1.10

1.11

1.12

1.13

1.23

1.271.

291.

671.68

1.86

1.87

1.911.921.93

1.941.94

2.852.86

3.973.

993.994.01

4.02

4.04

5.32

5.325.

576.08

6.096.10

6.116.12

6.12

6.13

0 min

2 min

5 min

MES pH 4.0

Water Tris pH 8.5

Summary and Acknowledgments Air Force Office of Scientific Research, Department of Defense – PECASE – FA9550-11-1-0105 Army Research Office, Department of Defense – W911NF-11-1-0264

Norbornene analogues of NIPAM were synthesized and used to make homo and block copolymers. These polymers are not soluble in water however dialysis from DMSO into water gives micellar aggregates . The thermo-responsive properties of these systems are still being explored

Gianneschi Group

Mn = 5658

PDI = 1.015 M:I = 25 DP = 28

Polymer backbone may be limiting the solubility of the polymers in aqueous media.

Hydrophilic Block

Thermoresponsive Block

Hydrophilic Block Copolymer

+ Temperature

- Temperature

Hydrophilic Block

Hydrophobic Block

Amphiphilic Block Copolymer

Micelle

Mn = 9373

PDI = 1.001 M:I = 25 DP = 15

Mn = 9138

PDI = 1.023 M:I = 25 DP = 16

Mn = 6246

PDI = 1.026 M:I = 25 DP = 18