Thermosensitive Water-soluble Transition Polymers Brandon Spradlin Zhao Group University of Tennessee Dept. of Chemistry, Knoxville

Abstract. Three random copolymers were synthesized by atom transfer radical

polymerization with varying proportions of DEGMMA and DMAEMA. The DMAEMA

moieties were then modified with 1,3 –propylsultone to form zwitterionic pendant

groups. Polymeric sulfobetaines such as these typically exhibit an upper critical solution

temperature, in contrast to PDEGMMA, a known lower critical solution temperature-type

polymer. These monomer units were combined in order to tune the solubility of the

random copolymers in water. Molecular   weight,   composition,   and   degree   of  

quarternization  were  determined  by  1H  NMR  spectroscopy.      

  2  

Introduction

Thermosensitive polymers are an important subset of environmentally responsive polymer

systems and have been intensively studied in recent years. Temperature is unique as an external

stimulus due to its relative ease of manipulation, as compared to that of other external stimuli,

such as pH. Thermosensitive polymers are typically divided into two types: those exhibiting a

decrease in solubility leading to a phase transition above a lower critical solution temperature

(LCST) or below an upper critical solution temperature (UCST). A variety of applications of

materials with such properties have been reported, ranging from catalysis to drug delivery and

smart surfaces.

It has been established that incorporation of hydrophobic/philic moieties into a

thermosensitive polymer allow for relatively precise tuning of LCST or UCST values;

hydrophobic groups raise UCST’s and lower LCST’s while hydrophilic groups lower UCST’s

and raise LCST’s. Little attention, however, has been given to the combination of UCST and

LCST monomer units in a single random copolymer. Such a combination could lead to

interesting phase diagrams exhibiting both UCST and LCST transitions, as shown in Figure 1 on

the next page. In this work, methoxydi(ethylene glycol) methacrylate (DEGMMA), and 2-

(dimethylamino)ethyl methacrylate (DMAEMA) were used to synthesize such random

copolymers (figure 2). PDEGMMA typically exhibits an LCST of 25 °C, while PDMAEMA is

easily converted to 3-((2-(methacryloyloxy)ethyl)dimethylammonio)propane-1-sulfonate

(PADPS), a classic polysulfabetaine with a UCST of 8.5 °C at moderate molecular weights.1

This was accomplished using atom transfer radical polymerization (ATRP), an example of a

“living” polymerization technique, meaning that it employs an equilibrium between “dormant”

and “active” states to achieve uniform chain growth.2

  3  

   

Figure  1:  Possible  UCST  and  LCST  Phase  Diagrams3

Experimental

Materials: Methoxydi(ethylene glycol) methacrylate (DEGMMA, or di(ethylene glycol)

monomethyl ether methacrylate) and ethyl 2-bromoisobutyrate (EBiB, Aldrich) were dried over

calcium hydride and distilled under reduced pressure. CuBr (98 %, Aldrich) was purified with

glacial acetic acid, washed with ether and ethanol, and stored in a desiccator 1,1,4,7,7-

pentamethyldiiethylenetriamine (PMDETA, 97 %, Aldrich), dichloromethane (DCM), and

anisole (99 %, Acros) were used without further treatment; DCM, when referred to as dry, was

processed via the Grubbs system. N,N-Dimethylaminoethyl methacrylate (DMAEMA) (99 %,

Aldrich) was passed through a basic aluminum oxide column prior to use. Poly(ethylene glycol)

(HO-PEO-OH) with a molecular weight of 20,000 g/mol was obtained from Aldrich. All other

chemicals were purchased from either Aldrich or Fisher and used without further purification.

Characterization: 1H NMR (300MHz) spectra were recorded on a Varian Mercury 300 NMR

spectrometer and the residual solvent proton signal was used as the internal standard.

Synthesis of P(DEGMMA-co-DMAEMA) Random Statistical Copolymer: Below is a typical

procedure for the synthesis of P(DEGMMA-co-DMAEMA). First, DEGMMA (2.008g, 10.68

  4  

mmol) and EBiB initiator (15.6 mg, 8.0 x 10-5 mol) were combined in a three neck round bottom

flask. Anisole (3.018 g) and CuBr (12.2 mg, 8.5 x 10-5 mol) were added next. Then, DMAEMA

(1.699 g, 10.82 mmol) and PMDETA (20.1 mg, 11.6 x 10-5 mol) were added to the flask. The

solution was quickly stirred after the addition of the last two reagents, then immediately frozen to

ensure no radicals had formed before the remaining oxygen had been displaced. Once completely

frozen, ‘freeze, pump, thaw 3x3’ (FPT 3x3) was performed. During this process, the solution is

completely frozen, placed under high vacuum, then nitrogen gas is pumped in, and the solution is

allowed to melt. This is done 3 times to make sure no oxygen is left in the reaction flask. After

FPT 3x3 had been performed, the solution was added to a 55°C oil bath. The polymerization was

monitored by 1H NMR spectroscopy and was stopped after 150 minutes by opening the flask to

air. The final monomer conversion was found to be 50.25% by integration of the monomeric and

polymeric ester peaks at 4.20 – 4.35 ppm and 4.03 – 4.20 ppm, respectively. This conversion

corresponds to a degree of polymerization (DP) of 135. A similar procedure was carried out with

monomeric feed ratios of 80% DMAEMA and 20% DMAEMA, as shown below. The former

was found to have a final monomer conversion of 85.52 % and the latter 94.7 %, corresponding

to DP’s of 259 and 281. The final NMR spectrum of each polymerization is shown below (NMR

1-3).

The polymer was dissolved in methylene chloride, then precipitated in a 90% hexane-10%

diethyl ether solution a total of three times. The remaining hexane/diethyl ether solution was

removed via rotary evaporation, and the polymer was placed under a high vacuum overnight. 1H-

NMR spectroscopy was conducted to ensure the desired polymer had been made. The following

tables show the three random statistical copolymers that were synthesized using a similar

procedure.

  5  

50% DMAEMA Name Mass (g) mMoles Actual Amount (g) DEGMMA 188 10.68 2.008 DMAEMA 157.2 10.81 1.6987 EBiB 195.1 0.08 0.0156 CuBr 143.5 0.09 0.0122 PMDETA 173.3 0.12 0.0201 Anisole 4.318

20% DMAEMA Name Mass (g) mMoles Actual Amount (g) DEGMMA 188 16.66 3.1318 DMAEMA 157.2 4.131 0.6494 EBiB 195.1 0.07 0.0136 CuBr 143.5 0.09 0.0122 PMDETA 173.3 0.13 0.023 Anisole

2.9974

80% DMAEMA Name Mass (g) mMoles Actual Amount (g) DEGMMA 188 4.24 0.7971 DMAEMA 157.2 17.0 2.6671 EBiB 195.1 0.0743 0.0145 CuBr 143.5 0.0836 0.012 PMDETA 173.3 0.1143 0.0198 Anisole

3.0133

Synthesis of P(DEGMMA-co-ADPS) Random Statistical Copolymer: Below is the synthesis

of P(DEGMMA-co-PADPS) by post-polymerization modification of the polymer that consist of

80% DMAEMA. The procedure is representative of those used for the other random

copolymers. 1,3-propanesultone (0.600 g, 4.91 mmol) was added to the polymer containing 80%

DMAEMA in a three neck round bottom flask and dissolved in THF. Once the sultone was

added, the polymers were sealed under N2 gas and stirred overnight at room temperature. The

polymers were then purified by crystallization in diethyl ether, and the excess ether was rota-

  6  

vaped off. Percent-weight samples of the purified polymer were then made using distilled water,

and temperature-dependent-solubility tests were conducted.

Synthesis of Br-PEO-Br Macroinitiator: Initially, PEO (20.2595g, 1.013 mmol) and toluene

(200mL) were added to a three neck round bottom flask. The solution was heated so all PEO

would be dissolved. This was followed by azeotropic distillation to remove trace amounts of

water in the PEO. Once distillation was complete, the flask was removed from the oil bath and

cooled to about 40°C. Triethylamine (1.3727 g, 13.59 mmol) was added. A gas flow adapter and

septum were attached, the solution was placed under nitrogen gas, and then 2-bromo-2-

methylpropanoyl bromide (BMPB) (3.7532g, 0.0163 mol) was cautiously added dropwise under

a closed fume hood. Finally, the flask was sealed completely, placed under nitrogen gas, and put

in a 35°C oil bath. The reaction proceeded overnight and was complete by morning. It was

quenched with methanol and deionized water, then transferred to an oil bath to initiate

precipitation. The PEO was then precipitated in diethyl ether from DCM three times. Next, 250

mL deionized water was adjusted to a pH of about 8-9, and used to dissolve the PEO. It was

transferred to a separation funnel and left to settle overnight due to an emulsion. Once separated,

PEO was precipitated in diethyl ether 3 times and vacuum filtered. The wet PEO was placed in

an Erlenmeyer flask and vacuum-oven dried for two hours, then left to air-dry overnight. 1H-

NMR spectroscopy was conducted to ensure the desired polymer had been made. The following

table shows the reagents used to synthesize Br-PEO-Br.

Br-PEO-Br Name Mass (g) mMoles Actual Amount (g) PEO 20,000 1.013 20.2595 BMPB 229.9 16.33 3.7532 Toluene 92.14

174

Triethylamine 101.19 13.6 1.3727

  7  

Synthesis of P(DMAEMA-b-PEO-b-DMAEMA): To synthesize P(DMAEMA-b-PEO-b-

DMAEMA), first Br-PEO-Br macroinitiator (0.5046g, 0.0252 mmol) was added to a three neck

round bottom flask. Next, DMAEMA (0.8193g, 5.212 mmol) was added, followed by an

addition of anisole (2.3303g, 0.0213 mol) as a solvent. The solution was slightly stirred before

PMDETA (0.0076g, 0.0439 mmol), and CuBr (0.0079g, 0.0551 mmol) were added. The

solution was quickly transferred to liquid nitrogen and frozen. Upon thawing, the reagents

crashed out, therefore more anisole (2.1248g, 0.0196 mol) was added and the solution was

heated using a heat gun to ensure all reagents were dissolved. After heating, FPT 3x3 was

performed. The flask was then transferred to a 45°C oil bath for approximately two hours. 1H-

NMR spectroscopy was conducted and monomer conversion was found to be 17.19 %,

corresponding to a DP of 18 for each A block. The following table shows the reagents used to

synthesize P(DMAEMA-b-PEO-b-DMAEMA).

pDMAEMA-b-PEO-b-pDMAEMA Name Mass (g) mMoles Actual Amount (g) Br-PEO-Br 20,000 0.025 0.5045 DMAEMA 157.21 5.212 0.8193 Anisole 108.14 41.2 4.4561 PMDETA 173.3 0.04 0.0076 CuBr 143.45 0.0079

  8  

8 7 6 5 4 3 2 1

δ (ppm)  

NMR  1:  Final  NMR  for  synthesis  of  P(DEGMMA-­‐co-­‐DMAEMA)-­‐80%  amine  

8 7 6 5 4 3 2 1

δ (ppm)  NMR  2:  Final  NMR  for  synthesis  of  P(DEGMMA-­‐co-­‐DMAEMA)-­‐20%  amine  

  9  

8 7 6 5 4 3 2 1

δ (ppm)  NMR  3:  Final  NMR  for  synthesis  of  P(DEGMMA-­‐co-­‐DMAEMA)-­‐50%  amine  

  10  

Discussion

P(DEGMMA-co-DMAEMA) Random Statistical Copolymer

 

Figure  2:  Synthesis  of  P(DEGMMA-­‐co-­‐DMAEMA)  

DEGMMA, EBiB initiator, anisole, CuBr, DMAEMA, and PMDETA were added to the flask.

The solution was quickly stirred after the addition of the last two reagents, then immediately

frozen to ensure no radicals had formed before the remaining oxygen had been displaced. Once

frozen, FPT 3x3 was performed. After FPT, the solution was added to a 55°C oil bath. The

polymer was dissolved in methylene chloride, then precipitated in a 90% hexane-10% diethyl

ether solution a total of three times. The remaining hexane/diethyl ether solution was removed

via rotary evaporation, and the polymer was placed under high vacuum overnight. Three

different polymers were synthesized using the following ratios of reagents: (1) 50%

DEGMMA/50%DMAEMA, (2) 20% DEGMMA/80%DMAEMA, and (3) 80% DEGMMA/

20% DMAEMA. The purified polymers were dried under vacuum and analyzed using 1H NMR

spectroscopy. By integrating the peaks corresponding to the methyl (OCH3) of the DEGMMA

O

O

O

O

2-(2-methoxyethoxy)ethyl methacrylateDEGMMA

O

N

O

2-(dimethylamino)ethyl methacrylateDMAEMA

+

O

O

O

N

OO

nx 1-x

z

DEGMMA-co-DMAEMA

ATRP

Anisole, 55oC

Br

  11  

units at 3.4 ppm and the two methyl groups (N(CH3)2) at 2.28 ppm, the exact proportion of

amine-bearing units was found to be 50.0 % (1), 19.8 % (2), and 79.8 % (3).

4 3 2 1

δ (ppm)  

NMR  4:  NMR  for  purfied  P(DEGMMA-­‐co-­‐DMAEMA)  –  80  %  amine  

4 3 2 1

δ (ppm)  

NMR  5:  NMR  for  purified  P(DEGMMA-­‐co-­‐DMAEMA)  –  50  %  amine  

  12  

4 3 2 1

δ (ppm)  

NMR  6:  NMR  for  purified  P(DEGMMA-­‐co-­‐DMAEMA)  –  20  %  amine  

  13  

P(DEGMMA-co-ADPS)

 

Figure  3:  Synthesis  of  P(DEGMMA-­‐co-­‐ADPS)

The purpose of modification with 1,3-propane sultone into the P(DEGMMA-co-DMAEMA)

random statistical copolymer is to attach a zwitterionic pendant groups to the DMAEMA

monomer units through a nucleophilic attack upon the sulfonic ester carbon, hopefully imparting

UCST behavior to the polymer in water. Sultone was added to the polymer solutions in THF.

Once the sultone was added, the polymers were sealed under N2 gas and stirred overnight. The

polymers were later purified by crystallization in diethyl ether. Samples of each polymer were

then stored for further analysis. NMR 7 shows the 20% DMAEMA polymer after the addition of

the 1,3- propane sultone; the shifting of the DMAEMA methyl peaks from 2.25 to 3.15 ppm

suggest a successful quarternizition of all amine moieties.

Various percent-weight samples of the purified P(DEGMMA-co-ADPS) polymer were

used to conduct temperature-dependent solubility tests. Three different percent-weight polymer

solutions were created for each random copolymer and the results can be seen in Table 1 below.

Each test solution was 0.5%, 2%, and 5% polymer by weight, dissolved in deionized water. All

O

O

O

N

OO

nx 1-x

z

DEGMMA-co-DMAEMA

THF, room temp.

O

O

O

N

OO

nx 1-x

z

S OO

O

S O

OO

1,3 propane sultone

P(DEGMMA-co-ADPS)

BrBr

  14  

of the test solutions were sonicated in ice water. After warming to room temperature, each was

exposed to the heat gun to detect UCST solubility changes. No change was detected in the 80%

or 50 % zwitterion-containing polymer, but a small decrease of light scattering (red

monochromatic laser) was observed for the 20 % ADPS. Each test solution was then put into an

ice bath for approximately 40 minutes to detect any cold-induced transition. Again, no change

appeared to occur in the 80 % ADPS or 50 %, but the 20 % ADPS appeared to have an increase

in light scattering.

 

 

 

 

 

 

 

 

 

Table  1:  Solubility  Tests  of  Random  Statistical  Polysulfatone  Copolymers  

 

0.5 % Test Solution Ice Bath Room Temp Heat Gun 80% ADPS No Change Clear No Change 50 % ADPS No Change Clear No Change 20% ADPS No Change Clear Slightly Cloudy 2 % Test Solution Ice Bath Room Temp Heat Gun 80% ADPS No Change Clear No Change 50 % ADPS No Change Clear No Change 20% ADPS Increase

Scattering Clear-Yellow Decrease

Scattering 5 % Test Solution Ice Bath Room Temp Heat Gun 80% ADPS No Change Cloudy

White No Change

50 % ADPS No Change Clear No Change 20% ADPS Increase

Scattering Cloudy Yellow

Decrease Scattering

  15  

5 4 3 2 1

δ (ppm)  

NMR  7:  Final  NMR  for  20%  Zwitterion  

 

 

 

 

Br-­‐PEO-­‐Br  

 

Figure  4:  Synthesis  of  Br-­‐PEO-­‐Br  Macroinitiator  

Br-PEO-Br macroinitiator was prepared for the synthesis of the random statistical

copolymers with an ABA architecture, which would allow further investigation of this polymer’s

aqueous behavior, particularly through gelation. PEO and toluene were added to a flask and

water was removed by azeotropic distillation. Triethylamine was added, followed by addition of

O H

Br

OBr

TEA, Toluene; 55oC

HO O

OO

OmBr

Br

m

Br-PEO-BrHO-PEO-OH

  16  

2-bromo-2-methylpropanoyl bromide. The reaction ran overnight, and was quenched the next

morning. The product was a di-halogen PEO macroinitiator, which permits the addition of

polymeric groups in place of the bromines. The polyethylene oxide chain will become the B

block, which gives a characteristic flexibility within the macromolecule. Copolymers formed

using a PEO macroinitiator will be water soluble because of the long ethylene oxide chain

present. The following NMR shows the product of the above reaction.

8 7 6 5 4 3 2 1

δ (ppm)  

NMR  8:  Final  NMR  for  purified  Br-­‐PEO-­‐Br  macroinitiator  

 

   

  17  

P(DMAEMA-­‐b-­‐PEO-­‐b-­‐DMAEMA)    

 

Figure  4:  Synthesis  of  P(DMAEMA-­‐b-­‐PEO-­‐b-­‐DMAEMA)  Copolymer  

PEO macroinitiator was used to synthesize P(DMAEMA-b-PEO-b-DMAEMA). The goal

of the synthesis was to test micelle and gel behavior in water of PADPS-b-PEO-b-ˆPADPS,

which could be synthesized in a manner described above. The flexibility of the PEO B block

gives the molecule the ability to stretch out or clump together, so adding DMAEMA as the two

A blocks gives them the ability to be close together, or far apart depending on the local

environment. The long ethylene oxide chain increases the solubility of the polymer in water,

which is the goal of synthesizing PADPS-b-PEO-b-ˆPADPS. Testing the behavior of

P(DMAEMA-b-PEO-b-DMAEMA), gives an idea of the behavior of the PADPS-b-PEO-b-

ˆPADPS, that is, the addition of a zwitterionic group to the DMAEMA copolymer block. 1H

NMR spectroscopy was used to find a DP of 18 for each A block, as calculated from monomer

conversion (located on the next page).

OO

OO

Br O

O

n nO

O

N

OO

PDMAEMA-b-PEO-b-PDMAEMA

m

N N

ATRP

Br

Br-PEO-BrO

OO

OmBr

Br

Anisole, 54oC

  18  

8 7 6 5 4 3 2 1

δ (ppm)

NMR  9:  Final  NMR  for  purified  P(DMAEMA-­‐b-­‐PEO-­‐b-­‐DMAEMA)  

   

  19  

Conclusion and Future Research

Three random copolymers of P(DEGMMA-co-ADPS) were synthesized successfully, first by the

ATRP of DEGMMA and DMAEMA and then by post-polymerization modification with 1,3-

propane sultone. The newly formed zwitterionic groups generally increased the solubility of the

polymers. Future synthesis of P(DEGMMA-co-ADPS) can be carried out with varying amounts

of ADPS units; it is likely that more extreme values are needed to observe significant

temperature effects. Other facets of these systems that need to be explored are those of

concentration and molecular weight, both of which are known to have a large effect on many

UCST type systems.

PEO macroinitiator and an amine-containing ABA tri-block copolymer were also

synthesized as a starting point for studies of UCST/LCST hybrid gelation systems. Upon further

study of the random copolymers, the use of a large macroinitiator will likely allow for the

fabrication of hydrogels with unique temperature induced phases.

 Works  Cited    1.   Woodfield,  P.  A.;  Zhu,  Y.;  Pei,  Y.;  Roth,  P.  J.  Macromolecules  2014,  47,  750-­‐762.  2.   Matyjaszewski,  K.;  Xia,  J.  Chemical  Reviews  2001,  101,  2921-­‐2990.  3.   Seuring,  J.;  Agarwal,  S.  ACS  Macro  Letters  2013,  2,  597-­‐600.