f: ;

 

TETRAHYDROFURFURYL SUBSTITUTED POLYLACTIDES

M.S.

This is to certify that the
thesis entitled

SYNTHESIS AND CHARACTERIZATION OF

presented by

Thomas L. Jurek II

has been accepted towards fulfillment
of the requirements for the

degree in Chemistry

 

 

4!

iv . J . "/7
£9321! U/WDM,‘

Manr I5rofe'ssor’s Signature
Augusv’ 3/, 20 l o

 

Date

MSU is an Affirmative Action/Equal Opportunity Employer

 

LIBRARY
Michigan State
University

 

 

 

“4,-‘M‘J.-.-.—.- _ _ .

 

 

 

'-'-,... '1'uv‘LLu-J—

‘0’.-.-l-O-l-I-l-l-0-0-0-l-I-.-O-D-l-I-I-l-t-

PLACE IN RETURN BOX to remove this checkout from your record.
TO AVOID FINES return on or before date due.
MAY BE RECALLED with earlier due date if requested.

 

DATE DUE DATE DUE DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5108 K1IProi/Acc8Pres/ClRC/DateDue,indd

SYNTHESIS AND CHARACTERIZATION OF TETRAHYDROFURFURYL
SUBSTITUTED POLYLACTIDES

By

Thomas L. Jurek II

A THESIS

Submitted to
Michigan State University
in partial fulfillments of the requirements
for the degree of

MASTER OF SCIENCE
Chemistry

2010

ABSTRACT

SYNTHESIS AND CHARACTERIZATION OF TETRAHYDROFURFURAL
SUBSTITUTED POLYLACTIDES

By

Thomas L. Jurek |l
Polylactides are widely used in biomedical applications due to their
degradability, and their value as commodity plastics is increasing due to their
attractiveness as “green materials." However, the use of polylactide in
biomedical applications is limited by its hydrophobicity, which reduces the
degradation rate. In structural applications, dimensional stability depends on
polymer crystallinity since the polylactide glass transition temperature is low (T9 =
50-60 °C). Modifying the polylactide structure while retaining the polyester
backbone, provides polylactide derivatives that retain desired attributes such as
biodegradability. The goal of this research was to synthesize a polylactide

derivative with an increased T9 and hydrophilicity.
We synthesized two new polylactide derivatives with pendant THF rings.
The stereochemical systems of poly(THFglycolide1) and poly(THFglycolide2)
were different, and the polymers had glass transition temperatures (Tg’s) of ~64
°C and 44 °C, respectively. No changes in T9 were observed when LiCl was
added to poly(THFglycolide1), but the T9 of poly(THFglycolide2) increased from
~44 °C to 64 °C. Static contact angle measurements showed that both polymers

were relatively hydrophilic compared to poly(rac-lactide).

ACKNOWLEDEMENTS

The journey I took in coming to graduate school seemed to be my true
American Dream Hunter S. Thompson so lavishly described in his literature. It
was the wave of life which brought me to this place with many people to thank
along the way. I would especially like to acknowledge my high school and
undergraduate professors for feeding that swell and providing an environment
conducive to the furthering of my education. However, no calm sea stays that
way forever. Once the wave broke and I woke up on the shores of the chemistry
building of Michigan State University, I realized I had washed up on the beaches
of some uncharted land of which I had always been afraid to explore and take
head on. I had grown many ways in my life but in this place I was still a child.
Growing up is one of the hardest things to do and if it weren’t for my wonderful
parents, loving brother, best friend(s), the Spirit and those within, and all of my
friends and family in Arenac county and everywhere else, I would have died a
well fed but beaten child on that rocky shore.

l faltered and fell many times along the path through graduate school,
more than most people would believe, and my boss Greg and all the members of
the Baker group along with some other scattered souls throughout the building
helped pick me back up many times and encouraged me to keep going. I thank
you all for the care and compassion. I especially want to thank Greg for allowing

me to be successful in my own way.

iii

And so as I sit here I realize the child has come a long way in the past few
years. He may not have grown up, but he has survived. So, to the eternal child
within me, thank you. I know you will never leave, for that would mean the death

of me.

iv

TABLE OF CONTENTS

LIST OF TABLES .................................................................................. vi
LIST OF FIGURES ............................................................................... vii
LIST SCHEMES ................................................................................... xi
LIST OF ABBREVIATIONS ..................................................................... xii
Chapter 1 Introduction ............................................................................ 1
Polylactides
1.1 The synthesis of polylactides ............................................................ 1
1.2 Glass transition temperatures of polylactides ........................................ 3
1.3 Hydrophilic polylactides ................................................................... 9
1.4 Furfural-based polymers ............................................................... 22
Chapter 2 Poly(tetrahydrofurfuryl glycolide)s ...................................................... 32
2.1 Monomer synthesis ................................................................................. 33
2.2 Synthesis of poly(THFglycolide)s ............................................................ 43
2.3 Physical properties of poly(THFglycolide)s ............................................. 46
2.4 Glass transitions of poly(THFglycolide)s ................................................. 48
Chapter 3 Experimental ..................................................................................... 58
3.1 General details ........................................................................................ 58
3.2 Materials synthesis .................................................................................. 59
Appendix .............................................................................................................. 67
References ........................................................................................................... 94

LIST OF TABLES

Table 1. Composition and T95 of poly(MMD-co-glycolide) ................................... 21
Table 2. Composition and Tgs of poly(lPMD-co-lactide) ..................................... 21
Table 3. Water contact angle at 20°C for various packaging materials .............. 26

Table 4. Glass transition temperature of poly(2-furyloxirane) as a function

of Mn ............................................................................................................. 31
Table 5. Polymer data before precipitation with the polymerizations in bulk at
160°C with monomer to initiator ratios ([M]/[l]) of 200 .................................. 45
Table 6. Polymer data after precipitation with [M]/[l] = 200 ................................ 46
Table 7. T9 data for poly(THFglycolides) ............................................................ 49

Table 8. Results from computational study performed on model poly(THF
glycolide) systems in Figure 30 ................................................................... 50

Table 9. Contact angle measurements for poly(THFglycolides) and polylactide
where saw-9,9, is the contact angle hysteresis ............................................. 57

vi

LIST OF FIGURES

Figure 1. Structure of polylactide ......................................................................... 1
Figure 2. lsomers of lactide .................................................................................. 5
Figure 3. Common lactide polymerization catalysts and initiators ....................... 6

Figure 4. Representative organocatalysts developed for the ROP of lactide ...... 7

Figure 5. For n-alkyl substituted polylactides, Tg decreases as the alkyl chain
increases ..................................................................................................... 10

Figure 6. Polylactides further illustrating the effects of dipole-dipole screening on

T9 ................................................................................................................. 11
Figure 7. Tg’s of aryl and cylcohexyl substituted polylactides ............................ 13
Figure 8. lsotactic, syndiotactic, and heterotactic polylactides ........................... 14

Figure 9. Star shaped poly(L-lactide) (Mn z 16,000-96,000 g/mol) and poly(D,L-
lactide) (Mn z 1,500-9,500 g/mol) ................................................................. 15

Figure 10. Branched copolymer with mevalonolactone/L-lactide 10:90
Mn = 23,000 .................................................................................................. 15

Figure 11. Examples of comb-like polylactides including poly(glycidol)-g-poly(L-
lactide) (Mn z 25,000-287,000 g/mol), poly(vinyl alcohol)-g-PLLA (M. =
76000-274,000 g/mol) and poly(vinyl alcohol)-g-PDLA (Mn = 125,000-
260,000 g/mol), and dextrin-g-PLLA(Mn z 110,000-350,000 g/mol) ............ 16

Figure 12. Examples of functional polymers with pendent ring or rings in the
polymer backbone structures: poly(L-lactide-co-benzyllPPTC) and poly(L-
lactide-co-IPPTC), poly(PAGYL) and poly(L-lactide-co-PAGYL), poly(N-
acetyl-4-hydroxyproline-co—mandelic acid), and poly(L-lactide-co—lPXTC)..18

Figure 13. T9 trends in homopolymers from AB monomers

Figure 14. Copolymerization of morpholine-2,5-dione derivatives with glycolide
and lactide) .................................................................................................. 20

vii

Figure 15. Removal of the protective benzyl groups from poly(lactic acid-alt-
Asp(OBn)) and poly((lactic acid-aIt-Asp(OBn)).co-Iactic acid) increase their

Tgs by 53 and 17 °C, respectively ................................................................ 22
Figure 16. Contact angle of a liquid drop on a solid surface and representation

of surface tensions at the three-phase contact point ................................... 23
Figure 17. PEG-grafted polylactide structures ................................................... 25

Figure 18. Hydrophilic polylactide derivative with pendant hydroxyl groups ...... 26
Figure 19. Structures of common packaging materials ...................................... 27

Figure 20. Furfural self-condensation products isolated from furfural heated

under neutral conditions ............................................................................... 29
Figure 21. Well defined polymers containing furfuryl groups ............................. 31
Figure 22. Furfural to poly(di-tetrahydrofurfuryl glycolide) ................................. 32

Figure 23. 1H NMR spectra showing (top) coupling between the o-hydroxy
proton and the methine proton on the adjacent carbon ............................... 36

Figure 24. Actual 1H NMR (top) and gNMR simulated 1H NMR (bottom) spectra
of the methylene protons of ethyl 2-(furan-2-yl)-2-hydroxyacetate. For the
simulation, the chemical shifts were 4.25 ppm and 4.28 ppm for Ha and H,
and coupling constants of 1JHH = 12 Hz and 3JHH = 7.2 Hz ......................... 37

Figure 25. 1H NMR spectra of RR/SS (top) and RS/SR (bottom) THFAHA ....... 39

Figure 26. X—ray crystal structure of RS/SR THFAHA (provided by Erin Vogel)41

Figure 27. X-ray crystal structure of RR/SS THFAHA (provided by ErinVogel).41

Figure 28. TGA analysis results for the different stereoisomers of
poly(THFglycolide)s. Samples were run in air at a heating rate of

10 °C/min ..................................................................................................... 47
Figure 29. TGA analysis results for substituted poly(glycolide)s run in air.

Heating rate: 10 °C/min ................................................................................ 48
Figure 30. Stereoisomers of poly(dicyclohexylglycolide)s and their Tgs ............ 49

viii

Figure 31. Model poly(THFglycolide) system used in computational study of
rotational barriers with stereocenters 1, 2, 3, and 4 (*defines the bonds
involved in the backbone rotation) ............................................................... 50

Figure 32. DSC analysis of poly(rac-lactide) with varying Lithium ion
concentrations. Heating rate: 10°C/min under nitrogen. The data are from
the second heating scan .............................................................................. 53

Figure 33. DSC analysis of poly(RRRR/SSSS, RRSS-THFglycolide) (M3) with
varying Lithium ion concentrations. Heating rate: 10 °C/min under nitrogen.
The data are from the second heating scan ................................................ 54

Figure 34. DSC analysis of poly(RSSR/SRRS, RSRS-THFglycolide) (M1M2)
with varying Lithium ion concentrations (Mn 3 7800). Heating rate:
10 °C/min under nitrogen. The data are from the second heating scan ..... 55

Figure 35. DSC analysis of poly(RSSR/SRRS,RSRS-THFglycolide) (M1M2)
with varying Lithium ion concentrations (Mn 3 20200) . Heating rate:
10 °C/min under nitrogen. The data are from the second heating scan ..... 56

Figure A-1. 1H NMR spectrum of 2-(furan-2-yl)—2-hydroxyacetonitrile ............... 68
Figure A-2. 13c NMR spectrum of 2-(furan-2-yl)-2-hydroxyacetonitrile .............. 69
Figure A-3. 1H NMR spectrum of ethyl 2-(furan-2-yl)-2-hydroxyacetate ............ 70
Figure A-4. 13C NMR spectrum of ethyl 2-(furan-2-yl)-2-hydroxyacetate ........... 71
Figure A-5. 1H NMR spectrum of 2-(furan-2-yl)-2-hydroxyacetic acid ................ 72
Figure A-6. 13C NMR spectrum of 2-(furan-2-yl)-2-hydroxyacetic acid .............. 73

Figure A-7. 1H NMR spectrum of R,S/S,R-2-hydroxy-2-(tetrahydrofuran-2-yl)-
acetic acid .................................................................................................... 74

Figure A-8. 13C NMR spectrum spectrum of R,S/S,R-2-hydroxy-2-
.(tetrahydrofu ran-2-yl)-acetic acid ................................................................ 75

Figure A-9. IR spectrum of R,S/S,R-2-hydroxy-2-(tetrahydrofuran-2-yl)-acetic
acid .............................................................................................................. 76

Figure A-10. 1H NMR spectrum of R,R/S,S-2-hydroxy-2-(tetrahydrofuran-2-yl)—
acetic acid .................................................................................................... 77

Figure A-11. 13C NMR of R,R/S,S-2-hydroxy-2-(tetrahydrofuran-2-yl)-acetic
acid .............................................................................................................. 78

ix

Figure A-12. IR spectrum of R,R/S,S-2-hydroxy-2-(tetrahydrofuran-2-yl)-acetic
acid .............................................................................................................. 79

Figure A-13. 1H NMR spectrum of RSSR/SRRS, RSRS-3,6-bis(tetrahydrofuran-
2-yl)-1,4-dioxane-2,5-dione (monomer 1) .................................................... 80

Figure A-14. 13C NMR spectrum of RSSR/SRRS,RSRS-3,6-bis(tetrahydrofuran-
2-yl)-1,4-dioxane-2,5—dione (monomer 1) .................................................... 81

Figure A-15. IR spectrum RSSR/SRRS/RSRS-3,6-bis(tetrahydrofuran-2-yl)-1,4-
dioxane-2,5-dione (monomer 1) ................................................................... 82

Figure A-16. 1H NMR spectrum of RSSR/SRRS, RSRS—3,6-bis(tetrahydrofuran-
2-yl)-1,4-dioxane-2,5-dione (monomer 2) .................................................... 83

Figure A-17. 13C NMR spectrum of RSSR/SRRS, RSRS-3,6-
bis(tetrahydrofuran-2-yl)-1,4-dioxane-2,5-dione (monomer 2) ..................... 84

Figure A-18. IR spectrum RSSR/SRRS/RSRS-3,6-bis(tetrahydrofuran-2-yl)-1,4-
dioxane-2,5-dione (monomer 2) ................................................................... 85

Figure A-19. 1H NMR spectrum of RRRR/SSSS,RRSS-3,6-bis(tetrahydrofuran-
2-yl)-1,4-dioxane-2,5-dione (monomer 3) .................................................... 86

Figure A-20. 13c NMR spectrum of RRRR/SSSS, RRSS-3,6-
bis(tetrahydrofuran-2-yl)1,4-dioxane-2,5-dione (monomer 3) ..................... 87

Figure A-21. IR spectrum RRRR/SSSS/RRSS-3,6-bis(tetrahydrofuran-2-yl)-1,4-
dioxane-2,5-dione (monomer 3) ................................................................... 88

Figure A-22. 1H NMR spectrum of poly(RSSR/SRRS, RSRS-
ditetrahydrofurfurylglycolide) (poly((M1M2)) ................................................ 89

Figure A-23. 13c NMR spectrum of poly(RSSR/SRRS,RSRS-
ditetrahydrofurfurylglycolide) (poly(M1M2)) ................................................. 90

Figure A-24. 1H NMR spectrum of poly(RRRR/SSSS,RRSS-
ditetrahydrofurfurylglycolide) (poly(M3)) ...................................................... 91

Figure A-25. 13C NMR spectrum of poly(RRRR/SSSS, RRSS-
ditetrahydrofurfurylglycolide) (poly(M3)) ...................................................... 92

LIST OF SCHEMES

Scheme 1. Pathways to polylactide from lactic acid ............................................. 4
Scheme 2. The synthetic equivalent route to polylactide ..................................... 4

Scheme 3. Mechanism of the DMAP-catalyzed ROP of lactide as proposed by

Hedrick ........................................................................................................... 8
Scheme 4. DMAP-catalyzed ROP of lactide proposed from intermediates

calculated by Bonduelle and co-workers ................................................ 9
Scheme 5. Formation of furfural from D-xylose .................................................. 28
Scheme 6. Synthetic route 1 to di-tetrahydrofurfuryl glycolide ........................... 33
Scheme 7. Vogel’s synthetic route to di-tetrahydrofurfuryl glycolide .................. 34
Scheme 8. Formation of the furfural cyanohydrins ............................................. 35
Scheme 9. Equilibrium between furfural and its cyanohydrins ........................... 35
Scheme 10. Synthetic routes to ethyl 2-(furan-2-yl)-2-hydroxyacetate .............. 35
Scheme 11. Basic hydrolysis of ethyl 2-(furan-2-yl)-2-hydroxyacetate .............. 38
Scheme 12. Hydrogenation of 2-(furan-2-yl)-2-hydroxyacetic acid .................... 38
Scheme 13. Synthesis of di-tetrahydrofurfuryl glycolides ................................... 42
Scheme 14. Synthesis of poly(THFglycolide)s ................................................... 45

xi

LIST OF ABBREVIATIONS

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Al(O-i-pr)3 aluminum triisopropoxide

BBA 4-tert-butylbenzyl alcohol

BEMP 2-tert-butylimino-2-diethylamino-1 ,3-
dimethylperhydro-1 ,3,2-
diazaphosphorine

br broad

d doublet

dd doublet of doublets

DMAP 4-(dimethylamino)«pyridine

DP degree of polymerization

DSC differential scanning calorimetry

dt doublet of triplets

EC ethylcellulose

El electron impact

9 gram

GPC gel permeation chromatography

HEC hydroxyethyl cellulose

HOTf trifluoromethanesulfonic acid

HPC hydroxypropyl cellulose

HPMC hydroxypropyl methylcellulose

Hz hertz

lPMD 3(S)—isopropylmorpholine-2,5-dione

IR infrared

J coupling constant

LDPE low density polyethylene

LLDPE linear low density polyethylene

M molar

m multiplet

m/z mass of ion(atomic units)/charge of
Ion

M1 monomer 1

M2 monomer 2

M3 monomer 3

MC methylcellulose

MMD 6-methylmorpholine-2,4-dione

 

 

xii

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Mn number average molecular weight
mp melting point

MS mass spectrometry

MW weight average molecular weight
NHC N-heterocyclic carbenes
NMR nuclear magnetic resonance
OCAs O-carboxyanhydrides

PDl poly dispersity index

PEO polyethylene oxide

PET poly(ethylene terephthalate)
PMMA poly(methyl methacrylate)
PP poly(propylene)

ppm parts per million

PPY 4-pyrrolidinopyridine

PS polystyrene

psi pound per square inch
PTFE poly(tetrafluoroethylene)
PVC poly(vinyl chloride)

rac racemic

ROP ring opening polymerization
s singlet

Sn(Oct)2 tin(ll)-2-ethylhexanoate

t triplet

TBD triazabicyclodecene

ten tertiary

Tg glass transition temperature
TGA thermal gravimetric analysis
THF tetrahydrofuran

THFAHA tetrahydrofuran alpha hydroxy acid
THFglycolide tetrahydrofuran glycolide

wt weight

6 chemical shift

8 contact angle '

urn micrometer

v wavenumber

 

 

xiii

 

CHAPTER 1

Introduction
1.1 Poly(lactide)s

Most commodity plastics are derived from petroleum, a limited resource.
However, biodegradable polyesters derived from renewable resources may be
viable replacements for petroleum based plastics. Polylactide (Figure 1), which
is emerging as a high volume “green material”, is biodegradable, bioassimible,
and can be recycled and composted.1 Unlike its petrochemical counterparts,
polylactides sequester carbon dioxide from the atmosphere through its
production through photosynthesis.2 Polylactide also can mimic poly(vinyl
chloride) (PVC), linear low density polyethylene (LLDPE), polypropylene (PP),
and polystyrene (PS)3 because a wide range of physical properties can be

obtained through manipulating polylactide’s stereochemistry, crystallinity, and

Per.

Figure 1. Structure of polylactide

architectu re.4

Initially, polylactides were limited to biomedical applications such as
bioassimable sutures, biodegradable implants and orthopedic devices such as
ligating clips and bone pins.5 Production costs for polylactides were greater than
$2/lb in 2000,6 much higher than commodity plastics such as polystyrene, which

ranged between $0.40 - '$1.00/lb from 2007-2009.7 Polylactide costs have

steadily declined since 2000, and polylactides offer benefits (from renewable
sources, degradable, ...) that petrochemical-based polymers do not.

Polylactide is commonly described as biodegradable, but the word must
be defined. The use of the word “biodegradable" should only be applied to living
cell-mediated degradation and not abiotic enzymatic degradation. In the case of
polylactides, simple chemical hydrolysis breaks down the polymer backbone into
oligomeric degradation byproducts. Once small enough, microorganisms may
then biochemically process the polylactide byproducts, or the partially degraded
polymer may enter the food chain and be processed indirectly by animals such
as earthworms. However, certain enzymes such as proteinase K have been
shown to cleave the main chain.8 Polylactides eventually degrade to carbon
dioxide, water, and humus.6 The bioassimibility of polylactides stems from the
lactic acid’s presence in nearly every form of life. In humans and animals its
primary function is related to the supply of energy to muscle tissue. In the
average adult male the turnover of lactic acid, the Cori cycle, has been estimated
at 120-150 g per day.9

Lactic acid and therefore polylactide can be derived from many renewable
resources such as cornstarch, cassava starch, cottonseed hulls, Jerusalem
artichokes, corn cobs, corn stalks, beet molasses, wheat bran, rye flour,
sugarcane press mud, barley starch, cellulose, carrot processing waste, spent
molasses wash, and potato starch.10 There has been increased interest in the
fermentive production of lactic acid from these feedstocks owing to their low cost

and environmental friendliness. Two microorganisms valuable in the fermentation

of biomass to lactic acid are the amylolytic bacteria Lactobacillus amylovorus
ATCC 33622 and Lactobacillus helveticus. L. amylovorus has been reported to
effect full conversion of liquefied cornstarch to lactic acid with a productivity of 20
g L'1 h" while high cell density L. helveticus (27 g L") has a maximum
productivity of 35 g L'1 h'1 and complete conversion of 55-60 g L‘1 lactose present
in whey.
1.2 The synthesis of polylactides

As shown in Scheme 1, there are multiple pathways to high molecular
weight polylactide. Polycondensation of lactic acid, with concomitant removal of
water to drive the polymerization reaction towards completion, usually provides
low molecular weight oligomers and with forcing, higher molecular weight
polymer with polydispersities near 2.0.11 Since driving the equilibrium to high
molecular weight is slow, low molecular weight polylactide oligomers may be
converted to high molecular weight polymer by using chain coupling reagents.
Alternatively, oligomers may be thermally cracked to lactide, the lactic acid dimer,
using a catalyst such as zinc oxide, and then ring opening polymerization (ROP)
of lactide can provide high molecular weight polymers with excellent control over
the molecular weight. Lactide also can be obtained directly from dimerization of

lactic acid.

 

Bacterial Azeotropic dehydration O
fermentation O and condenstion HQ O/kn/O R

 

  
 
  

——> HO w T O
OH 4120 n
Polylactide
-H20 -H20
ROP

 

 

 

 

 

0 Thermal O O
HO O O H r cracking _ I I
‘ o o
O n
prepolymer
O

Ho Ogre R
O n

Mn » 5000
Polylactide

 

Chain coupling

Scheme 1. Pathways to polylactide from lactic acid6

Another route to polylactides is the polymerization of activated lactide
equivalents such as the decarboxylation polymerization of 1,3-dioxolane-2,4-
diones, or O—carboxyanhydrides (OCAs). The organo-catalyzed ROP of
carboxyanhydrides derived from lactic acid (lacOCA), provides high molecular
weight polymers with controlled molecular weights and narrow polydispersities

under mild conditions.12 Molecular weights up to 60,000 g/mol have been

achieved using the methodology illustrated in Scheme 2.12

0 o ROH/DMAP O o
:Ofio — R0 H + coz

n

 

Scheme 2. The synthetic equivalent route to polylactide

 

The thermodynamics for the polymerization of lacOCA was predicted to be more
favorable than the ROP of lactide for both enthalpic and entropic reasons, the
liberation of C02 being a considerable driving force.12

Lactic acid is one of the smallest chiral organic molecules. Naturally
occurring lactic acid is mainly L(+), while the D(-) isomer is uncommon.9
Dimerization of rec-lactic acid leads to three lactides, L-lactide, D-lactide, and
mesa-lactide (Figure 2). D and L lactide are optically active while the meso
lactide is inactive. A 1:1 mixture of L and D lactide is called D,L-lactide, or

racemic or rec-lactide

010T” O O O O 2"”

(S,S) L—lactide (R,R) D-lactide R,S-lactide

 

\ j
W J
rec-lactide
mesa-lactide

Figure 2. lsomers of lactide

Polymerization of the different stereochemical forms of lactide provides polymers
with different properties. For example, rac-lactide polymerizes to an amorphous
polymer with a glass transition temperature, T9, of 50-60 °C while polylactide
synthesized from stereochemically pure D or L lactide generally is highly
crystalline with a melting transition Trn around 180 °C.13 Common catalysts

and/or initiators include Sn(2-ethylhexanoate)2 (Sn(Oct)2) paired with an alcohol

 

initiator such as benzyl alcohol or p-tert-butylbenzyl alcohol (BBA), and aluminum
triisopropoxide (Al(O-i—Pr)3) which acts as both a catalyst and initiator Figure 3.
Recently, organocatalysts such as 4-(dimethylamino)pyridine (DMAP) have
been developed which yield high molecular weight polymers under mild

conditions5 and eliminate the use of toxic metal catalysts.

OH
O
/Oi-Pr I\ N/ I
i-PrO—Al\ 0‘53“") \ N/
Oi-Pr O l
Al(O-i-Pr)3 Sn(Oct)2 BBA DMAP

Figure 3. Common lactide polymerization catalysts and initiators

It is widely accepted that these catalyst and initiator systems operate by a
coordination-insertion mechanism.14 With Sn(Oct)2, at least one of the 2-
ethylhexanoate ligands is exchanged with the initiating alcohol to form a tin
alkoxide initiator. Ring opening of the monomer forms an ester from the initiating
alcohol, and a new metal alkoxide derived from the ring-opened lactide.
Propagation proceeds through successive steps of ring opening and formation of

tin alkoxides.1517

The catalyst/initiator systems utilized in this work were
Sn(Oct)2/BBA as well as DMAP/BBA. As described below, ROP of alkyl-
substituted monomers using the DMAP/BBA system15 may follow a different

mechanism.

 

Since Hedrick and co-workers reported the first organocatalytic ROP of
lactide with DMAP and PPY (4-pyrrolidinopyridine),18 new organocatalysts have
been developed including N-heterocyclic carbenes (NHC’s),
trifluoromethanesulfonic acid (HOTf), thiourea/amine combinations, guanidines,

and phosphazenes (Figure 4).19

[—5

Mes’NvN‘Mes HO-g-CF3 / I

\

N
NHC HOTf PPY
CF3 /
N N. ,N-t-Bu
JSL A C 'P‘NEt
‘N N CF3 N {:1 N\ 2
NHZH H
TBD BEMP

Figure 4. Representative organocatalysts developed for the ROP of lactide19

The mechanism by which DMAP effects ROP of lactides is only
superficially understood. Two proposed mechanisms, illustrated in Schemes 3
and 4, were evaluated via computational studies at the B3LYP/6-31G(d) level,
with solvent effects (dichloromethane) taken into account through PCM/SCRF

single-point calculations at the B3LYP/6-31G(d) level of theory.

 

Scheme 3. Mechanism of the DMAP-catalyzed ROP of lactide as

proposed by Hedrick”19
m / l
O (CD/\N/ ‘\LB!\ 9 / ’g\
o’ufi/ DMAP 028/ ” <0 N /
/l\n,o Afro ‘— 0.1g/
0 O NO
0

0 II
ROH _ O
+ R'OrLokrOL— egg
0 / _
G 0
07A
0

Hedrick et al. proposed that DMAP acts as a nucleophile, attacking the carbonyl

/
Z
\

23

carbon and forming a zwitterionic acylpyridinium intermediate (Scheme 3).
Addition of alcohol to the acylpyridinium carbonyl carbon forms an ester,
regenerates DMAP, and generates a new alcohol species to propagate the
polymerization. This route was found to be less favorable than DMAP acting as
a base that activates nucleophilic attack by an alcohol as proposed in Scheme
4.19 In this mechanism, the optimized intermediates and transition states, found
through theoretical calculations, invoke a central role for multiple hydrogen
bonding, and the possibility of DMAP acting as a bifunctional catalyst through its
basic nitrogen center and the acidic ortho-hydrogen via non-classical hydrogen

bonding.19

Scheme 4. DMAP-catalyzed ROP of lactide proposed from intermediates
calculated by Bonduelle and co-workers19

 

\N/ \N/
./ ./
\N| \6i
0 ,. i4:
0 DMAP,ROH _ Fido ~————'- H\‘ 8
No ' 9 O R’0
R /l\lfo o
o o No
0
a
9,H \N
0 /
on H

 

O O O>LT/
proton H 0]
transfer O N0

O
O \N/
R’Ojl/LOJKrOH + / I
O \N

1.3 Glass transition temperatures of polylactides

The T9 is a physical property that depends tacticity, crystallinity, molecular
weight, polymer architecture, and the presence of plasticizers. At Tg a polymer
transforms from a rigid amorphous solid state to a melt state. The reptation
model is often used to describe the movement of polymer chains entangled in
networks such as polymer gels, melts, and concentrated polymer solutions. In
the melt state, the movement of a single chain can be described as a snakelike

motion constrained in a tube defined by entangled neighboring polymer

 

molecules.20 Using the reptation model, qualitative conclusions can be drawn

about the relationship between polymer structure and T9 in polymers such as

polylactides.
O H O O
Wow/k0}, PTOWXOIV o 4/
H O n O n o n
poly(glycolide) poly(lactide) poly(ethylglycolide)
Tg-7’? °C 55°C Tg=15°C
poly(hexylglycolide) poly(octylglycolide)

T9: -37 °C Tg= -46 °C
Figure 5. For n-alkyl substituted polylactides, Tg decreases as the alkyl chain

increases. 21

A homologous series of n-alkylpolyglycolides was synthesized and the
measured Tg decreased with increasing alkyl length. Simple considerations of the
rotational barriers would predict that Tg should increase as the alkyl chain length
increases. However, the observed decrease in T9 suggests that the dominant

effect is to screen dipole-dipole interactions between ester groups on adjacent

10

 

chains. Another possibility is that alkyl groups are acting as internal plasticizers
and lower T9.21

Another series of polylactides supports dipole-dipole screening as the
mechanism for lowering T9. These polyglycolides are substituted with isopropyl
and isobutyl groups as shown in Figure 6. For isopropyl glycolide, one would
expect that the increased the steric bulk of the isopropyl groups will increase

rotational barriers about the polymer backbone and increase Tg, but the the T9 of

tort. Mi

poly(lactide) ‘ poly(isobutylglycolide)
T9: 55°C T9: 15°C

PEN text.

poly(isopropylglycolide) poly(tetramethylglycolide)
1'9: 56°C Tg= ?? °C

Figure 6. Polylactides further illustrating the effects of dipole—dipole screening21
poly(isopropylglycolide) is almost identical to poly(lactide). Dipole-dipole

screening apparently compensates for any chain stiffening caused by the

increased rotational barriers. Similar effects are seen in poly(isobutyl glycolide).

11

Extending the isopropyl groups one more carbon from the polymer backbone
increases screening effects and markedly lowers the T9 to 23° 0.21

Screening effects are also observed in aryl-substituted polylactides. Two
aromatic polylactide systems, poly(phenyllactide) and poly(mandelide), were
synthesized from naturally occurring o-hydroxyacids. These aryl analogues of
polylactide were expected to have high glass transition temperatures due to the
steric bulkiness of aromatic rings, as well as the possibility of it-n interactions.
However, the Tgs of high molecular weight poly(phenyllactide) and
poly(mandelide) were 50 and 100 °C, respectively. The low T9 of
poly(phenyllactide), comparable to poly(lactide), mirrors the poly(isobutyl
glycolide) system. In both cases, moving the sterically demanding group one
carbon from the polymer backbone decreased the rotational barriers and
increased screening effects.4

Poly(mandelide) would seem to be an ideal high Tg biodegradable
material with polystyrene-like polymers, however each repeat unit has a labile
methine proton, at to a carbonyl and an aromatic ring, making it relatively acidic.
Consequently, the poly(mandelide) epimerizes, discolors, and is prone to thermal
and photochemical degradation. Replacing the aromatic ring of mandelide with a
cyclohexyl group stabilized the methine proton in both the monomer and the
corresponding polymer while maintaining chain rigidity.22 As shown in Figure 7,
the T93 of the resulting poly(dicyclohexylglycolide)s are 98 °C, for rac-

poly(dicyclohexylglycolide) and 104 °C and no signs of crystallization for

12

poly(R,R-dicyclohexylglycolide) (greater than 98% stereochemical purity,

determined by integration of 13C NMR).22

$235.3 .552 .55

poly(phenyllactide) poly(p-tolyllactide) poly(mandelide) poly(cyclohexylglycolide)
Tg= 50°C Tg= 59°C Tg= 100°C Tg= 98°C

Figure 7. T93 of aryl and cylcohexyl substituted polylactides

Tacticity can have an affect the preferred chain conformations of a
polymer and therefore the polymer T9.” lsotactic polylactide synthesized from
stereochemically pure D or L-lactide is generally crystalline with T93 of ~60 °C
and Tms around 180 °C.23'24 Through the use of selective catalysts, heterotactic
as well as syndiotactic polylactides have been prepared (Figure 8). Syndiotactic
polylactide synthesized from mesa-lactide and annealed at 95 °C for 60 minutes
exhibits a T9 of 34 °C and a Tm at 152 °C.25 Heterotactic polylactide made from
rec-lactide polymerizes to an amorphous polymer (T9 = 49 °C) despite its
stereoregularity.26

Although not all stereoregular polymers form crystalline phases,
stereoregularity generally enables polymer chains to pack in a regular fashion

and crystallize. As the degree of crystallinity increases, the chain mobility in the

13

amorphous phase becomes restricted, thereby increasing T9.13 The effects of
crystallinity on polylactide Tgs have been explored by Gupta et al. using oriented
fibers with draw ratios from 1-12. As the draw ratio increased, the degree of
crystallinity increased, the melting transition increased from 176 to 180 °C, and
the Tg increased from 61 to 72 °C.27 Uryama et al. examined the effects of
crystallinity on the polylactide Tg by deliberately adding defects to poly(L-lactide).
In a series of poly(L-lactide-co—D,L-lactide) copolymers with the L-lactide content
ranging from 75-100%, the polymer Tgs decreased from 61 °C for poly(L-lactide)
to 53 °C for a copolymer 75% poly(L-lactide). In addition, polymers with 585%

poly(L-lactide) content were amorphous.28

H o o R o o R
O§}o§)‘o H 056Lo§2Lo

n n
lsotactic polylactide Syndiotactic polylactide
T9 » 60 °C Tm »180 °C Tg=34°C Tm=152 °C

0 o O 0
H °¥°T¥0$0§2Lo R
: 3 n

Heterotactic polylactide T9 = 49 °C

23,24

Figure 8. lsotactic, syndiotactic25 and heterotactic26 polylactides

Linear polylactides joined to form different polymer architectures have
varying Tgs. Figures 10-12 show examples of star-shaped, branched, and comb-

like polymers, all exhibiting differing properties. For each architecture, increasing

14

the composition of L-Iactide in the polymer increases both T9 and Tm, as

 

 

 

expected.
CH3
O
Rag/OVoi’iJKl/OVO i“ FAR/Otmhk Hot,”
X CH30 X CH3O
\ j J
Y V
R R
Star—shaped poly(L-lactide) Star-shaped poly(D,L-lactide)
Tg ~ 17-38 °C, T9 ~125—155 °C Tg ~ -29-27 °C

Figure 9. Star shaped poly(L-lactide) (M = 16,000-96,000 g/mcl)29 and

poly(D,L-lactide) (Mn z 1,500-9,5oo g/mcl)30

flaw—OM?“

Branched poly(L-lactide-co-mevalonolactone)

Figure 10. Branched copolymer with mevalonolactone/L-lactide 10:90

M, = 23,00031

15

HO—T—‘CHZ

Dex-g-PLLA GHQ-0):: NM
1ft

Tg ~16-19 °C Tm ~ 103- 140 °C
/(’\(O HWO:
\n’ \(YLOJH’OiH 001% in
O m

 

H

O
poly(glycidol)-g-PLLA

PVA-g-PLLA Tg ~ 46-57 °C Tm ~ 130-174 °C T9 ~ 28-41 °C Tm ~119-168 °C

PVA-g-PDLA Tg ~ 38-44 °C

Figure 11. Examples of comb-like polylactides including poly(glycidol)—g—poly(L-
lactide) (Mn z 25,000-287,000 g/mol),32 poly(vinyl alcohol)-g-PLLA (Mn = 76000-
274,000 g/mol) and poly(vinyl alcohol)-g-PDLA (M, z 125,000-260,000 g/mcl),33

and dextrin-g-PLLA(Mn z 110,000-350,000 g/mol).34'35

Copolymerization is commonly used to alter the polylactide and achieve

higher Tg materials. Copolymer Tgs vary with composition and fall between the

16

T93 of the two homopolymers. For homogeneous copolymers, the Tg can be

described empirically by the Fox equation36 as:
1 2
1/ Tg = w, / Tg + w2 / Tg Equation 1
where W1 and w2 are the mass fractions of components 1 and 2, respectively. To

obtain a high polylactide Tg, lactide must be copolymerized with a monomer that
yields a higher Tg polymer. Accordingly to the guidelines outlined earlier, the
required monomers are those that provide polymers with restricted rotational
barriers or a stiff backbone. The examples shown in Figure 12 incorporate

pendant rings that restrict backbone flexibility and stiffen the polymer chain.

17

OX0 n OX" n

poly(L-lactide—co-benzyllPPTC) T9 = 60-69 °C poly(L-lactide-co—IPPTC) T9 = 58 °C

llW’Lll .5?)

HO OH
poly(L-lactide—co-IPPTC) T9 = 52 °C

X 0 O Y n
/)'O OX0
poly(DIPAGYL) T9 = 95 °C poly(L-lactide-co-PAGYL) T9 = 73 °c

 

 

 

o
o
/ N O
W’Rx
_ o

poly(N-acetyl-4-hydroxyproline-co-mandelic acid) poly(L-lactide-co-IPXTC) T9 = 60—89 °C
R=CH3, T9 = 53-119 °C; R=OCH2Ph, T9 = 54 ° C

 

 

/ Virgil

D

Figure 12. Examples of functional polymers with pendent ring or rings in the
polymer backbone structures: poly(L-lactide-co—benzyl|PPTC) and poly(L-lactide-
co-IPPTC), 37 poly(PAGYL) and poly(L-Iactide—co-PAGYL),38 poly(N-acetyl-4-

hydroxyproline-co-mandelic acid),39 and poly(L-lactide-co-IPXTC).4o

18

A class of polylactides analogous to copolymers is homopolymers derived
from AB monomers. AB monomers are unsymmetrical lactides synthesized from
two different glycolic acid units. The T95 of polymers synthesized from AB
monomers are roughly the average of the T93 of the two homopolymers. The
examples shown in Figure 13 were synthesized in the Baker lab with the

exception of the n-hexyl derivative reported by Trimaille et al.41

w M w

9:??° -_-_ °
C T9 11 C

Figure 13. T9 trends in homopolymers from AB monomers21
Cross-linking increases the T9 of polymer systems, and is usually
attributed to a decrease in configurational entropy as the distance between
cross-links decreases.”43 In polylactide systems, cross-linking is accomplished
by a number of methods including post-synthesis addition of polymerizable
cross-linking agents, end-capping polylactides with cross-linkable acrylates or
other polymerizable groups, and the synthesis of lactide-based cross-linking

agents that can be copolymerized with lactide.13 When the cross-linking is less

19

than 10 mol%, Tg usually increases less than 10 °C. Most examples reported in
the literature involving high molecular weight polylactide fall into this category.
Larger increases in T9 usually require cross-linking low molecular weight
oligomers to high molecular weight polymer.13

Inter and intrachain hydrogen bonding can also increase polymer Tgs.
Hydrogen bonding makes the polymer chains “sticky", restricting their movement
through the tube described in the reptation model. Morpholine-2,5-dione
derivatives, glycolides where an o-hydroxyacid group has been replaced by an 0-
amino acid, place amides in the polymer backbone (Figure 14). As expected,
the data in Tables 1 and 2 show that the copolymer Tg increases with the amide
concentration, illustrating the effects of hydrogen bonding and the higher

rotational barrier of the amide bonds.

0 o
o o
o HN’UN/ _ H o
Kn’o + o 0 TAO
o o x o y n

O
6-methylmorpholine- poly(MMD-co-glycolide)
2,5-dione (MMD)

0 o
jib; HNJH o H o
+ ..Ktro N OYL
o o
0. w 0 Y‘
3(S)-i50propyl

morpholine-2,5-dione
(lPMD)

 

poly(lPMD-co-Iactide)

Figure 14. Copolymerization of morpholine-2,5-dione derivatives with

glycolide“ and lactide).45

20

 

Table 1. Composition and T93 of poly(MMD-co-glycolide)

 

 

lVlole fraction of MMTS T (°C)
in copolymer (%) 9

0 43

9 54
20 63
26 68
35 72
45 75
66 75
85 86
100 91

 

Table 2. Composition and T93 of poly(lPMD-co—lactide)

 

Mole fraction of lPMD

 

in copolymer (%) T9< C)
O 40
7 41
9 42
29 45
46 48
7O 56
100 74

 

When pendant carboxylic acid groups are added to polylactides, Tg increases
significantly due to hydrogen bonding (Figure 15). Feng et al. polymerizated
benzyl-protected morpholine-2,5-diones (poly(lactic acid-aIt-Asp(OBn)) and their
copolymers with D,L-Iactide (poly((lactic acid-aIt-Asp(OBn lactic acid)—co-lactic

acid) 30 mol % aspartic acid, as determined by 1H NMR). The Tgs were 34 °C

21

and 47 °C, respectively.“6 Removal of the protective benzyl groups provides
poly(lactic acid-aIt-Asp(OBn)) and poly((lactic acid-aIt-Asp(OBn))-co-lactic acid)

with Tgs of 87 °C and 64 °C, respectively.

0 H O H
H /Pd
0 n O n

BnO O HO O
poly(Lactic acid-alt-Asp(OBn)) poly(Lactic acid-aIt-Asp)
Tg=34°C Tg= 87°C
0 O H O O H
H lPd
o n o m _ o n o m
BnO O HO O
poly(Lactic acid-co-Asp(OBn)) poly(Lactic acid-co—Asp)
Tg= 47°C Tg=64°C

Figure 15 Removal of the protective benzyl groups from poly(lactic acid-alt-
Asp(OBn)) and poly((lactic acid-aIt-Asp(OBn))-co-lactic acid) increase their Tgs

by 53 and 17 °C, respectively.

1.4 Hydrophilic polylactides

Adding hydrogen bonding to polymers increases their Tgs, and can impart
other properties such has hydrophilicity. Polylactides are typically hydrophobic,
but hydrophilic polylactides may exhibit useful properties such as the ability to
form micelles, lower critical solution temperature (LCST) behavior, and water

solubility. These properties could prove useful in medical applications such as in

22

drug delivery, where a hydrophilic polylactide may have accelerated degradation
rates in vivo or resist protein fouling.“7

The usual method for evaluating the hydrophobicity/hydrophilicity of
materials is contact angle measurements. In 1805, Young described the
relationship between the surface tension at the three-phase contact line between
a smooth, rigid, solid phase 8, a liquid L, and its vapor V (Figure 16).

Liquid drop

  

YLV

 

'st

Solid surface

Figure 16. Contact angle of a liquid drop on a solid surface and representation
of surface tensions at the three-phase contact point.“8

The contact angle, 0, is defined by the equation:

YLV'COSG = st - YSL Equation 2

where yLv, ysv and Ya are the surface tensions (or free energy per unit area) of

the liquid-vapor, solid-vapor and solid-liquid interfaces.“9

The value of 0 indicates the hydrophobicity of a surface. A large 0
corresponds to a hydrophobic surface while a small 0 implies a hydrophilic
surface."8 The range of contact angle measurements are from 0-180°. Materials
that are completely wetted have a contact angle of 0°, while the other extreme,

180°, is not possible because it would imply a total lack of interaction between

23

 

the liquid and the solid. Vogler differentiated “hydrophilic” and “hydrophobic"
surfaces by their water contact angle. Materials with contact angles > 65° were
considered to be hydrophobic, and a contact angle < 65° indicated a hydrophilic
material.50

The usefulness of contact angle measurements is quite apparent in drug
delivery systems where they can be used to determine the behavior of a
substance in a particular environment, to improve processability and
bioavailability, and to control process and product quality. The wettability,
determined from contact angle measurements, can be used to predict and
determine the rate of release or interfacial interactions between components.51
For example, protecting proteins from gastric hydrolysis requires a hydrophobic
polymer.

Polylactides are hydrophobic by nature. The reported contact angles for
poly(D,L-lactide) range from 87° to 69°,52 while a contact angle of 100° for
poly(hexylglycolide) was attributed to the added hydrophobicity of the hexyl
groups.‘7 If a hydrophobic group increases the contact angle of polylactides,
then adding a hydrophilic side group should have the opposite effect. Hydrophilic
polylactides have been synthesized by grafting polyethylene oxide (PEO)
segments to the polymer backbone via a hexyl spacer as shown in Figure 17.
The polymers contain n = 1,2,3, and 4 PEG units, and all had weak Tg values at
~-25 °C."7 When n = 1 and 2, the contact angles were between 50-75°. Although
hydration of the hydrophilic side chains prevented precise measurements, the

increased hydrophilicity was obvious compared to more hydrophobic polylactide

24

examples. When n = 3 or 4 the polymers were water-soluble and formed clear

solutions below their LCST.“7

WW
OWN).

“‘7‘g‘x
Figure 17. PEG-grafted polylactide structure"7

Other examples of hydrophilic polylactides include polymers with pendant
alcohol groups. Poly(DlPAGYL) (Figure 18) is derived from glycolic acid and D-
gluconic acid with its alcohol functional groups protected with propylidene
groups. The protected polymer is insoluble in hydrophilic solvents such as
methanol, ethanol, and water. After deprotection, (maximum deprotection
achieved was 60%) the polymer was soluble in methanol and ethanol and
partially soluble in water.38 Poly(3-benzyloxymethyl-1,4-dioxane-2,5-dione)
(PBMG), synthesized by Yang et al., shows similar behavior. Removing the
benzyl group revealed the hydroxyl group (poly(3-hydroxymethyl-1,4-dioxane-
2,5-dione, PHMG)) and greatly increased the polymer hydrophilicity, as
confirmed by a decrease in the water contact angle from 90° to 20°. The polymer
remained insoluble in water, but the polymer absorbed approximately 58 wt%
water after only 8 hours.

Adding pendant carboxylic acid groups to polylactides have similar affects.
The hydrophilicity of poly(Lac-aIt-Asp) and poly((Lac-aIt-Asp)—co-Lac)) (Figure
15) were soluble in methylene chloride before deprotection, but insoluble in water

or methanol. However, after deprotection, poly(Lac-aIt-Asp) was soluble in water

25

and methanol, but not in methylene chloride, while poly((Lac-aIt-Asp)Lac-co-
Lac)) (30 mol % aspartic acid) is insoluble in water and methanol but soluble in
methylene chloride. The results clearly show the correlation between higher

hydrophilicity and the carboxylic acid content in poly(Lac-alt-Asp).46

+O/figofifl PROYV} H2, Pd/C Pkg)? r0];
373 o o 00 n
7< f)

PO'Y(D'PAGYL) PBMG: PHMG:
60% free hydroxy groups contact angle ~ 90° contact angle ~ 200

Figure 18. Hydrophilic polylactides with pendant hydroxyl groups”53

Table 3. Water contact angle at 20°C for various packaging materials

 

 

material 65mm material 85%,,
LDPE 94 Filter paper 15
LDPE 97 Starch 32

PET 81 Starch + 20% glycerol 53
PMMA 80 HPMC 70
PMMA 74 MC 54
PMMA 65 HPC 70

PP 100 HEC 38
PS 91 EC 85
Parrafin 108

 

(LDPE: Low density polyethylene; PET: poly(ethylene terephthalate); PMMA:
poly(methyl methacrylate); PP: polypropylene; PS: polystyrene; HPMC:
hydroxypropyl methylcellulose; MC: methylcellulose; HPC: hydroxypropyl

cellulose; HEC: hydroxyethyl cellulose; EC: ethylcellulose

26

N N El 111

poly(ethylene) poly(propylene) poly(styrene) poly(methyl methacrylate)

TZHMJE lg? l

poly(ethylene terephthalate) n i

R = CH2CH(OH)CH3 = hydroxypropyl methylcellulose .. .
R = CH3 = methylcellulose if:
R = CH2CH2CH20H = hydroxypropylcellulose

R = CH2CH20H = hydroxyethylcellulose

R = CH2CH3 = ethylcellulose

 

Figure 19. Structures of common packaging materials

The contact angles of most synthetic polymers are greater than 65°,
classifying them as hydrophobic materials. The contact angles of common
packaging materials are listed in Table 3. The measured contact angles can be
rationalized from their structures, as shown in Figure 20. Aliphatic polymers such
as polypropylene and polyethylene have large contact angles owing to their
hydrophobic nature. The cellulosic materials have contact angles ranging from
38° to 85° depending on the hydrophobicity or hydrophilicity of the ether group

which directly corresponds to the presence of hydroxyl groups.

27

1.5 Furfural-based polymers

Furfural has been a commodity chemical for many decades due to its easy
access from corn cobs, oat and rice hulls, sugar-cane bagasse, cotton seeds,
olive husks, wood chips, and a vast array of other pentose-containing materials.54
Furfural is formed from aldopentoses when exposed to aqueous acid and
elevated temperatures, as shown in Scheme 5 for its formation from D-xylose.55

The worldwide production of furfural in 2005 was ~250,000 tons/year with a

market price around $1000/ton (USD).56

Scheme 5. Formation of furfural from D-xylose55

 

 

 

 

CHO CHOH CHO
H—-OH '—0H -H20 I OH
HO——H =2 Ho——H —’ H
H—-OH Ha—OH H OH
-H2O
CH0
0 lo -H20 0
l / l H
H
CHZOH

28

The full scope of furfural and furfural-containing polymers is too large to
summarize in this work. Instead, examples of well-defined polymers containing
furan rings will be discussed due to their inherent link to the tetrahydrofurfuryl
substituted polylactides described in Chapter 2. Homopolymerization of the
furfural carbonyl is thermodynamically unfavorable, but furfural can be a
comonomer in polymerizations.54 However, modifying the furfural structure
provides polymerizable monomers. Of these, only a handful of well-defined
homopolymers have been synthesized as the reactivity of the furan ring often
leads to crosslinking.

Furfural’s tendency to form cross-linked products has been knoWn for
decades, induced by acids, bases (including zeolites“), and to a much lesser
extent under neutral conditions at high temperatures.54 The classical product of
these processes is a black, insoluble mass. When highly purified anhydrous
furfural was sealed in an evacuated ampoule and subjected to prolonged heating
(100-250 °C) in the dark, a difuryl ketonic aldehyde and a trifurylic dialdehyde

were formed (Figure 20).

 

Figure 20. Furfural self-condensation products isolated from furfural
heated under neutral conditions
Further condensation of these products undoubtedly led to the formation of the

both soluble oligomers and insoluble resins, in which the net result was the slow

29

but progressive accumulation of a black crosslinked product.”59 The significance
of isolating structures such as the trifurylic dialdehyde is that it shows the
formation of a labile tertiary hydrogen atom attached to a carbon bearing three
furyl moieties. This hydrogen atom can be abstracted as a free radical, as a
hydride in acidic media, or as a proton in basic media, which would lead to
further resinification of the material.54

Several well-defined furfuryl polymers are shown in Figure 21. Their Tgs
depend on the details of their structure. The T9 of poly(furfuryl acrylate) is
reported to be 48 °C, but there was no mention of the polymer molecular

t.60

weigh Poly(2-furyloxirane) has a T9 which varies greatly with molecular

weight (Table 4).61 The relationship between T9 and M, has been confirmed for

many polymers and is often described by the Fox-Flory relationship:

T9 = Tgoo - K/Mn Equation 3

Where Tgoo is the glass transition temperature at infinite number average

molecular weight (Mn) and K is a constant that depends on the polymer

structu re.‘32

30

Cl
HO nOH n
/O O O
EEO
\

poly(2-furyloxirane) T9 ~ -52 to 14 °C poly(furfuryl acrylate) Tg ~ 48 °C

0 o/\/
O /\/ O /{, O o

\/\O "\/ n

poly(5-hydroxymethyl furfurylidenester)

poly(2,5-furylene vinylene) T9 = ’7
Tg ~ 45 °C, Tm = 180 °C

WWO, va1

T9 = 325 °C Tg ~100 °C, T9 = 180- 225 °C
Figure 21. Well defined polymers containing furfuryl groups.60'51'63'65

Table 4. Glass transition temperature of poly(2-furyloxirane) as a function of Mn61

 

M n x 10'3 (g/mol) Tg (°C)

 

1.0 -52
2.0 -31
3.2 -14
4.0 -3
5.0 5

8.2 11
10.1 14

 

31

Chapter 2 Poly(tetrahydrofurfuryl glycolide)s

As petroleum reserves are depleted, analogues of materials derived from
petroleum must be devised from renewable resources. Polylactide is one such
material, but it has its limitations. lts low Tg (50-60 °C) limits its use as rigid, clear
replacement for large-volume thermoplastics such as polystyrene (Tg ~ 100 °C).
In drug delivery systems, its hydrophobicity slows in vivo degradation rates. New
materials must be synthesized which address these issues.

The abundance and low cost of furfural makes it an attractive building
block for new materials. However, the high reactivity of the furan ring limits its
use in the synthesis of well-defined materials, and it must be modified, usually by
hydrogenation. The goal of this work was to synthesize and characterize a
polylactide derivative based on furfural (Figure 22). Our motivation for the
synthesis was that a furan-based polylactide might have unique physical
properties. In particular, the T9 trends seen in polylactides with differing pendant
alkyl and aryl groups suggest that a pendant THF ring should stiffen the polymer

backbone, increase the T9, increase polymer hydrophilicity, and increase the

029:. ° °
\/ _. o O
o on

Figure 22. Furfural to poly(di-tetrahydrofurfuryl glycolide).

degradation rate.

32

2.1 Monomer synthesis
Di-tetrahydrofurfuryl glycolide was synthesized by the dimerization of 2-
hydroxy-2-(tetrahydrofuran-2-yl)acetic acid. Two approaches were explored for

the synthesis of the hydroxyacid from furfural. (Schemes 6 and 7).

 

 

 

 

 

O 0 p, 0 OH 0 o
I/ / H2 dC> DJ [0] DJ
OH O
1. KCN _ o hydrolysis _ WW
2. H3o+ ’ We“: ' OH
0
p-TsOH_ O
r o o
o
0

Scheme 6. Synthetic route 1 to ditetrahydrofurfuryl glycolide

Scheme 6 was based on reducing the furan ring early in the synthesis to avoid
furan's tendency to form undesired condensation products. Hydrogenation of
furfural was uneventful, but oxidation of the tetrahydrofurfuryl alcohol to
tetrahydrofurfural proved difficult, and the desired aldehyde was obtained in low
yields. In addition, it was difficult to scale-up the oxidation methodology to
provide sufficient quantities of the aldehyde. Therefore, Scheme 6 was
abandoned in favor of the protocol shown in Scheme 7, developed by Dr. Erin

Vogel.

33

1. NaHSOg,

 

 

 

 

 

o /o 5 equiv. KCN _ o 0” 1. EtOH, dry “019), I o OH
w H20, 0 °C, 15 min 7 ”03“] 4 days, 4 00 W0
2. conc. HCI 2. H20 0151
2-5 MOI N30”: | O OH H2, 5 % Rh on alumina A 0 0H
3 HOUR» 01° ’1 WC 1150 psi, EtOH, 48 hrs, rt We
HCI workup OH OH
O
p-TSOH O
> O O
toluene, reflux O
4 days
0

Scheme 7. Vogel’s synthetic route to ditetrahydrofurfuryl glycolide

The initial step of the synthesis is the formation of the furfural cyanohydrin, as
shown in Scheme 8. The intermediate bisulfite addition complex provides a
desirable sodium sulfate leaving group while protonating the oxyanion. ln acidic
conditions, the furfural cyanohydrin is in equilibrium with furfural as shown in
Scheme 9. Since evolution of HCN drives the equilibrium toward furfural, a large
amount of 12.1 M HCI was carefully added to the reaction mixture just prior to
isolating the cyanohydrins by extraction. Since 5 equivalents of KCN are used in
this step, copious amounts of HCN is produced and extreme caution must be

used.

34

1. NaHSO3, 5equiv. KCN 0 OH 0H

0 ° EH .—
/ _ | , _ _____. 0 ~
I / V—— / S’O C¢N

H20, 0 °C, 15 min ‘0’ “O \ I

 

Scheme 8. Formation of furfural cyanohydrins

EH“ —-'“* .0 /°
0. +H, / +HCN
‘N

Scheme 9. Equilibrium between furfural and its cyanohydrins

The furfural cyanohydrin was recovered as a slightly unstable black oil and
was used without purification. Direct hydrolysis of the nitrile to the acid under
acidic and basic conditions proved unsuccessful. Boatright and Degering
encountered similar problems in their attempts to synthesize 2-(furan-2-yl)-2-
hydroxyacetic acid,66 but they successfully converted the nitrile to the ortho
ester, and then isolated ethyl 2-(furan-2-yl)-2-hydroxyacetate. A modified version

of their synthesis was used (Scheme 10).

 

OH
O 1. EtOH, HCI(g), H20 1 O OH
C“. = /
\ l N 4days, 4°C W0
EtO
Boatright and Degering
isolated yield 46%
OH O OH

1. EtOH, Ham, 0 OH

O 2. H20 I /
c, o l / 0
\ I N 4days.4 C E)—<C(0Et)3 EtO

 

Isolated yield 58%

Scheme 10. Synthetic routes to ethyl 2-(furan-2-yl)-2-hydroxyacetate

35

Ethyl 2—(furan-2-yl)-2-hydroxyacetate was recovered as a highly viscous
brown/black oil which solidified upon standing. While recrystallization failed to
provide the pure ester, sublimation gave white powdery crystals with a melting
point (mp 40-41 °C), comparable to the literature value (39 °C).66 1H NMR
spectra taken before and after sublimation show only minor differences (Figure
23). Prior to sublimation, the signal for the d-hydroxy proton appeared as a
singlet due to proton exchange, but after sublimation and loss of water, the
signal evolVed into broad doublet (J = 5.5 Hz) from coupling with the adjacent

methine.

 

After sublimation T d

 

d Before sublimation

 

_.JL - °

5.1 4.9 4.7 4.5 4.3 4.1 3.9 3.7 3.5 3.3
fl (ppm)

 

 

 

 

 

 

 

 

 

v I ‘v I v r I’

Figure 23. 1H NMR spectra showing (top) coupling between the d-hydroxy

proton and the methine proton on the adjacent carbon.

36

The methylene protons of the ethyl ester show an interesting splitting
pattern. The difference in the chemical shifts of the diastereotopic methylene
protons (z 0.03 ppm or 9 Hz) is comparable to their coupling constants (1JHH z 12
Hz) leading to a higher order pattern, as shown at the top of Figure 24. The
chemical shift and coupling constant values were determined by gNMR
simulations performed by Dr. Daniel Holmes of the Max T. Rogers NMR facility.

The simulated spectrum is shown at the bottom of Figure 24

 

|o OH III I‘ II .
We .1 l l
O><Ha III II I II
”°C “b ll l I I l"
.. ll 1 I l ' " \ I ,1
III “I I ‘ I \r! j I ’1
Ill II: III j I‘ 1,1 U I 1V 1/ \d/ /,\\
F6435 ‘ _ _4630 T 14.25 T 64.20 f—

I

I l l 1 l l l
/ 1 1 \ l \ I 1 l l‘
I II I1 “1 l; U j \j \ \l l; .
_/\-_ _ ,__,/’/\~-_./ \./ \J \j \/ \U/‘L “A . .- ..

4.35 4.30 > 4.25 4.20
ppm

 

Figure 24. Actual 1H NMR (top) and gNMR simulated 1H NMR (bottom) spectra

of the methylene protons of ethyl 2-(furan-2-yl)-2-hydroxyacetate. For the

37

simulation, the chemical shifts were 4.25 ppm and 4.28 ppm for Ha and Hb and

coupling constants of 1JHH = 12 Hz and 3JHH = 7.2 Hz

Ethyl 2-(furan-2-yl)-2-hydroxyacetate was hydrolyzed in aqueous sodium

hydroxide (Scheme 11). The reaction proceeded cleanly and no purification was

 

necessary.
0 OH 2.5 Mol NaOH 0 OH
W = l /
O 3 Hours, 0°C to rt o
'30 HCI workup OH
Isolated yield 90%

Scheme 11. Basic hydrolysis of ethyl 2-(furan-2-yl)—2-hydroxyacetate

Hydrogenation of the furan ring, as shown in Scheme 12, resulted in two
sets of diastereomers, R,R/S,S and R,S/S,R 2-hydroxy-2-(tetrahydrofuran-2-

yl)acetic acid (THFAHA).

 

I 0 OH H2, 5 % Rh on alumina _ O OH
WC 1150 psi, EtOH, 48 hrs, rt W0
0H Crude yield 83% OH

Isolated RR/SS yield 25%
Isolated RS/SR yeild 24%

Scheme 12. Hydrogenation of 2-(furan-2-yl)—2-hydroxyacetic acid

The diastereomers were separated by recrystallization from EtOAc/hexanes; the
RR/SS isomers had a melting point of 76-77 °C while the RS/SR diastereomers

melted at 1265-1275 °c (lit. 129 "0).67 The 1H NMR spectra of the compounds

38

were different, as expected (Figure 25). Proton Ha is shielded in the RR/SS
stereoisomer while proton H, is deshielded and its signal is located farther
downfield. The opposite was true for the RS/SR stereoisomers; Ha proton was

downfield and the Hb proton upfield.

 

RR/SS _2
Ho H

W
a

1.35 4.30 4.25 4.20 4.15 4.10 4.05 4.00 3.95
f1 (ppm)

 

 

 

 

 

 

 

 

 

Figure 25. 1H NMR spectra of RR/SS (top) and RS/SR (bottom) THFAHA

An examination of the crystal structures of the diastereomers explains the
chemical shift difference for protons H8 and Hb. Dr. Erin Vogel obtained single
crystal X-ray diffraction data and determined the stereochemistry of the
diastereomers. In the RS/SR THFAHA structure (Figure 26), proton Ha is
attached to C(5) and oriented toward 0(1) of the THF ring, while proton Hb,
attached to C(6), points down and away from 0(1) of the THF ring. In RR/SS
THFAHA (Figure 27), H, is attached to C(6) and oriented toward 0(1) in the THF

ring while Ha, attached to C(5), points away from 0(1) of the THF ring. As

39

observed in the 1H NMR spectra of the various stereoisomers, protons oriented
toward the 0(1) of THF ring are shifted farther downfield (increased deshielding
by oxygen) while protons oriented away from 0(1) are less deshielded and their

chemical shifts are upfield.

4O

 

“3
$3311)
019’ 01101
x . l9
#7} \-=.\\\"
0131
O
'2’:
C(6)
‘
a“, 0171
0

0m :7? o
e
O . Ciel 'Q’él
‘ ’4 3—2
Cl6l “V («a
1!
01101

 

Figure 27. X-ray crystal structure of RR/SS THFAHA (provided by Erin Vogel)

41

After separating the o-hydroxyacid diastereomers, they were dimerized
separately in refluxing toluene with p-TsOH as a catalyst. The reaction was
driven to completion by azeotropic removal of water via a Dean-Stark trap

(Scheme 13).22

 

 

RSSR/SRRS
RSRS
RS/SR o
O OH
2 p-TsOH ; O
O toluene, reflux O O
HO 4 days 0
-2H
20 O
isolated yield 41%
RRRR/SSSS
RR/SS RRSS
O
O OH
2 p-TsOH : O
O toluene, reflux 0 0
H0 4 days 0
-2H
20 O
isolated yield 29%

Scheme 13. Synthesis of di-tetrahydrofurfuryl glycolides

Dimerization of RS/SR acids provided ditetrahydrofurfuryl glycolide
(THFglycolide) stereoisomers (meso and rec) in low yields, likely due to the
harsh reaction conditions and the competing formation of low molecular weight
oligomers. Recrystallization from acetone gave products enriched in the mesa or

rac isomers, but neither pure meso or rac products were obtained. These results

42

and the characterization data are summarized in the experimental section of this
thesis. The stereochemistry of the separated monomers was not determined, but
rec-glycolides usually have higher melting points than mesa-glycolides. The
higher melting monomer, denoted as M1, was a stereochemically pure racemic
mixture of either RSSR/SRRS or RSRS and melted at ZOO-201°C. The lower
melting monomer, M2, (mp 146-150°C) could not be fully purified by
recrystallization, and 1H NMR showed that it was contaminated with ~ 6% of the
higher melting M1. For melt polymerizations, the monomers were combined to
obtain a lower melting point. A ~2:1 mixture of RRRR/SSSS and RRSS (denoted
as M3) melted at 144-154°C while a M1/M2 mixture melted at 145-147°C.
2.2 Synthesis of poly(THFglycolide)s

The polymerization of the monomers posed problems. Both THFglycolide
mixtures, RRRR/SSSS RRSS and RSSR/SRRS RSRS, were insoluble in
toluene, partially soluble in THF, and fully soluble in dichloromethane. Attempts
to polymerize them in THF and dichloromethane, as solutions or slurries, resulted
in no conversion to polymer. However, bulk polymerizations of both mixtures
were successful at 160°C using different catalyst/ initiator systems (Scheme 14).

Polymerization of RRRR/SSSS RRSS THFglycolide (M3) proceeded
nicely using the Sn(Oct)2/BBA methodology, however, 1H NMR showed that the
conversion to polymer was only 80 % at 30 minutes. Longer reaction times may
have provided higher conversions. The RSSR/SRRS RSRS THG glycolide M1
(mp 200-201 °C) was heated at an oil bath temperature of 215 °C for 30 minutes

but failed to provide polymer. 1H NMR analysis showed signs of degradation.

43

Mixtures of M1 and M2 (mp of M1/M2 was 145-147°C), were polymerized at 160
°C with the Sn(Oct)2/BBA system several times, but reached only 10-15%
conversion for reaction times up to 1.5 hrs. We speculated that the RSSR/SRRS
RSRS THF-substituted glycolide might be more sterically demanding than its
stereoisomeric counterpart, and therefore, we used DMAP as the catalyst since it
is known to polymerize sterically hindered glycolides.15 With the DMAP/BBA
system, conversions of monomer to polymer 97-100% were attained after 2.5 hrs
at 160 °C.

Both polymers were light brown. Prior to precipitation, their
polydispersities (PDls) ranged from 1.47-2.15 (Table 5), and the number average
molecular weights (M) were lower than predicted by the monomer to initiator
ratios ([M]/[l]). The target degree of polymerization (DP) was 200 for all entries
except for the last entry (([M]/[l] = 500). The highest DP achieved was 65, which
suggests intramolecular chain transfer or a low molecular weight impurity, likely

water, that acts as a competing initiator in the system.

44

RRRR/SSSS RRSS

 

 

o
o o
O O Sn(Oct)2, BBA ‘ O POIYM3
0 160° C, 35 min 0 O
O n
o o
RSSR/SRRS RSRS
o
o
o o DMAP, BBA > 0 PolyM1M2
o 0 150°C, 2.5 hrs 0 O
0 H
o 0

Scheme 14. Synthesis of poly(THFglycolide)s
Table 5. Polymer data before precipitation with the polymerizations in bulk at

160°C with monomer to initiator ratios ([M]/[l]) of 200

 

 

-3 -3
sample catalyst _ rxn . % conv*** M" X 10 wa 10 M Mn DP
time (min) (g/mol) (g/mol) from M n
poly(lactide)* Sn(Oct)2 37 97 5.1 8.2 1.63 35
poly(M3) Sn(Oct)2 30 75 16.8 25.9 1.54 65
poly(M3) Sn(Oct)2 31 82 15.2 25.8 1.63 59
poly(M1 M2) DMAP 150 97 6.3 13.3 2.11 24
poly(M1M2) DMAP 150 100 7.9 16.9 2.15 30
poly(M1M2)** DMAP 361 97 3.4 5 1.47 13

 

* Polymerization carried out at 130°C
** [M]/[I] = 500
*** Determined by 1H NMR spectroscopy
After precipitation, the polymer molecular weights increased significantly
but the PDls improved only modestly. In contrast, the PDI of lactide improved

from 1.63 to 1.13 after two precipitations (Table 6.). The increase in molecular

45

weight was expected since the more soluble lower molecular weight species are
preferentially removed during re-preciptation. Two poly(THFglycolide)s,
poly(RRRR/SSSS RRSS THFglycolide) (poly(M3)) were precipitated twice to
remove the catalyst and residual monomer (less than 1% by 1H NMR) while
poly(RSSR/SRRS RSRS THFglycolide) (poly(M1M2)) required one precipitation
to remove all residual monomer and catalyst.

Table 6. Polymer data after precipitation with [M]/[l] = 200

 

M, x10'3 wa10'3

 

sample M w/M n DP from Mn
(g/mol) (glfimol)
poly(lactide) 22.0 24.8 1.13 152
poly(M3) 22.4 30.9 1 .54 87
poly(M3) 22.5 32.6 1.63 87
poly(M1M2) 11.0 17.1 1.73 42
poly(M1M2) 7.8 11.9 1.51 30
poly(M1M2)* 20.2 25.4 1.25 78

 

* [M]/[l] = 500
2.3 Physical properties of poly(THFglycolide)s

The poly(THFglycolide)s were characterized by thermal gravimetric
analysis (TGA), differential scanning calorimetry (DSC), and contact angle
measurements. The TGA data for poly(RRRR/SSSS, RRSS-THFglycolide),
shown in Figure 28, show an onset for weight loss at ~250 °C followed by rapid
degradation. Compared to data from alkyl lactides (Figure 29), the degradation
profile has a plateau that persists to >500 °C. Decomposition of
poly(RSSR/SRRS, RSRS-THFglycolide) shows a similar trend to its stereoisomer
counterpart, but over a larger temperature range. Shoulders in TGA curves in
other polymer systems are attributed to slow degradation of thermostable cross-

linked products, formed by oxidative reactions at elevated temperatures.68

46

100

 

  
  
  
 

 

 

80 RSSR/SRRS RSRS
g _
f5) 60 _
g _
g shoulders
CE" 40 —
(0
co - /'

20 —

RRRR/SSSS RRSS
O 1 1 1 1 1 1

 

100 200 300 400 500 600
Temperature (°C)

Figure 28. TGA analysis results for the different stereoisomers of

poly(THFglycolide)s. Samples were run in air at a heating rate of 10 °C/min

47

 

 

 

 

 

1 00 Poly(methylphenylglycolide)
g 80 -
d)
U,
5 Poly(ethylmethylglycolide)
: 60 '-
Q,
2
Q,
Q.
E 40 - Poly(trimethylglycolide)
.9
Q,
3

20 -

l
O ‘ _
0 200 400 600

temperature ( °C)

Figure 29.21 TGA analysis results for substituted poly(glycolide)s run in air.

Heating rate: 10 °C/min.

2.4 Glass transitions of poly(THFglycolide)s

The Tgs of the different poly(THFglycolide)s were determined by DSC and
are summarized in Table 7. Interestingly, the Tg values for the different
poly(THFglycolide) stereoisomers differ by 20 °C, suggesting that
stereochemistry plays a role. As previously reported for amorphous

poly(cyclohexylglycolide) systems (Figure 30), the stereochemistry of the main

chain made little difference in the T9 of the polymers.22

48

Table 7. T9 data for poly(THFglycolides)

 

Mn x10'3 wa10'3

 

sample (g/mol) (g/mol) M1,/M n Tg( C)
poly(rac -lactide) 22.0 24.8 1.13 50
poly(M3) 22.5 32.6 1.63 64
poly(M1M2) 7.8 11.9 1.51 43
poly(M1M2) 20.2 25.4 1.25 44

 

Q
ofigo£

poly(meso-dicyclohexylglycolide)
T9 = 96 °c

.3; .9
9 O R 0m“
0 n O n

poly(rac-dicylohexylglycolide) poly(R,R-dicyclohexylglycolide)
7'9 = 93 °c T9 = 104°C

 

Figure 30. Stereoisomers of poly(dicyclohexylglycolide)s and their T95

49

Theoretical calculations performed on the poly(THFglycolide)s do not seem to
support the experimental Tg data obtained. The maximum rotational barriers
were calculated for the model system shown in (Figure 31). Methyl groups were
used as “end caps” for the model system with the assumption they would

contribute little or no interaction.

0 * 1O
/U\o 2 *o 3
* 4
O O
1234 = RRRR, RRSS, RSSR, RSRS

Figure 31. Model poly(THFglycolide) system used in computational study of
rotational barriers with stereocenters 1, 2, 3, and 4 (*defines the bonds involved

in the backbone rotation)

Table 8. Results from computational study performed on model poly(THF

glycolide) systems in Figure 30

 

 

Stereocenters 1234 rotational barrier (kcal/mol)
RRRR ~0
RRSS ~0
RSSR ~14
RS RS ~13

 

As shown in Table 8 the rotational barrier for the RRRR and RRSS systems was

approximately zero. These results are interesting, especially since the T9 of

50

poly(RRRR/SSSS, RRSS-THFglycolide) is ~20° higher than poly(RSSR/SRRS,
RSRS-THFglycolide). The expectation was that the higher rotational barrier
would correspond to the higher T9, but the exact opposite was observed.

Li+ ions and To

An interesting experiment was performed in order to alter the T9 of the
polymers. Since the pendant group of the new polyester is a THF ring and it is
known Li+ coordinates to the oxygen of the THF ringeg, Li+ was added to the
polymer to see if it would have any effect on T9 due to Li" coordination. The
general procedure for the experiment was carried out as follows. Approximately
3-5 mg of polylactide (the control experiment) or poly(THFglycolide) was added
to a sample vial flushed with N2. The number of oxygen atoms in each sample
(including ester oxygens) was calculated based on the mass of the sample.
Then anhydrous LiCl in a 0.5 M THF solution was added in an inert N2
atmosphere corresponding to the desired Li+:O ratio desired for the sample. The
THF was removed under vacuum and the DSC samples were prepared in air.
The Li+:O ratios used for this experiment were 1:1, 2:1, 3:1, and 4:1. The results
are summarized in the following Figures 32-35.

As can be observed in Figure 32. The T9 of poly(rac-lactide) is not altered
at all by the addition of Li+ as is the same case for poly(RRRR/SSSS, RRSS-
THFglycolide) (Figure 33). However, the T9 of poly(RSSR/SRRS, RSRS-
THFglycolide) does change after the addition of LiCl. The lower molecular
weight species of M, of ~7800 with a larger PDI 1.51 shows an increase of T9

with increasing Li+ concentration from ~43 °C to ~63 °C (Figure 34). The higher

51

molecular weight species with M, of ~20,200 with a PDI of 1.25 shows the same
increase in T9 from ~44 °C to ~64 °C (Figure 35). However, the higher molecular
weight species does not show the gradual increase in T9 with increasing
concentration of Li+. Instead, the Tg increases directly to the higher temperature
with a 1:1 ratio of Li+ to oxygen. This may be a result of the increased number of
chain ends in the lower molecular weight polymer with a higher PDI. The
polymer is not fully saturated with Li+ at lower ratios while the higher molecular
weight polymer is. As to the question why one stereochemical system
coordinates to Li” and the other doesn't; we speculate it may be due to the
formation of pockets Li+ can fit into between the THF ring oxygens and the

carbonyls of the ester backbone in one system versus the other.

52

 

Li+:O = 4

 

L1*:O=3

 

   

 

 

Heat flow (exo up)

 

 

 

Li+:O=0

 

 

 

25 50 75
Temperature (°C)

Figure 32. DSC analysis of poly(rac-lactide) with varying Lithium ion
concentrations. Heating rate: 10 °C/min under nitrogen. The data are from the
second heating scan.

 

 

 

 

 

 

 

 

 

 

 

 

 

Li”:O = 4
\
\ Li+: O = 3
a
3
O .
g \ L'+: O: 2
5
c
H
8
I Ll+1 O = 1
/ V-
1.1+: O = 0
\
25 50 75

Temperature (°C)

Figure 33. DSC analysis of poly(RRRR/SSSS, RRSS-THFglycolide) (M3) with
varying Lithium ion concentrations. Heating rate: 10 °C/min under nitrogen. The
data are from the second heating scan.

54

 

 

 

 

 

 

 

 

 

 

 

\ Li*:0 = 4
A Li“: 0 = 3
g \
o \
x \
‘9' Li*' 0- 2
3 ' '-
O \
a:
a; ‘4
a: Li”: 0 = 1
I -\

Li“: 0 = 0
25 50 75

Temperature (°C)

Figure 34. DSC analysis of poly(RSSR/SRRS, RSRS-THFglycolide) (M1M2)
with varying Lithium ion concentrations (M, = 7800). Heating rate: 10 °C/min
under nitrogen. The data are from the second heating scan.

55

 

 

 

 

 

 

 

 

 

 

 

 

 

 

\ Li+:0 = 4
a LI+2 O = 3
:3 \
3
1;, \ L1“: 0: 2
O
1.1:
‘5' Ll”: O = 1
0 ‘
I
Ll“: O = 0
\
25 50 75

Temperature (°C)

Figure 35. DSC analysis of poly(RSSR/SRRS,RSRS-THFglycolide)
(M1M2) with varying Lithium ion concentrations (M, = 20200) . Heating
rate: 10 °C/min under nitrogen. The data are from the second heating
scan.

56

Contact angle measurements were also taken for the different
poly(THFglycolide)s and the results are summarized in Table 9. As indicated by
the contact angles attained both poly(THFglycolide)s are slightly hydrophobic

with more hydrophilic character than polylactide.

Table 9. Contact angle measurements for poly(THFglycolides) and polylactide
where Sam-0,3, is the contact angle hysteresis

 

 

sample estatic eadvancing ereceding eadv'erec
poly(rac-lactide) 82 98 74 24
poly(M3) 68 35 53 32
poly(M1M2) 67 86 49 37

 

57

Chapter 3
Experimental
3.1 General details
Unless otherwise specified, ACS reagent grade intermediates and
solvents were used as received from commercial suppliers without further
purification. EtOH was dried by refluxing with'Mg0 and CCI4. House nitrogen
was used in air and moisture sensitive reactions.
1H NMR (300 or 500 MHz) and 13C NMR (75 or 125 MHz) spectra were
acquired using either a Varian Gemini 300 spectrometer or a Varian UnityPlus
500 spectrometer, with the residual proton signal from the CDCI3 solvent used as
the chemical shift standard. IR spectra were taken with a Mattson Galaxy 3000
FT-lR. Elemental analyses were determined using a Perkin-Elmer 2400 CHNS/O
Analyzer, and mass spectral analyses were carried out on a VG Masslab Trio-1.
Melting points were taken on an Electrothermal capillary melting point apparatus

and are uncorrected.

Polymer molecular weights were determined by gel permeation
chromatography (GPC) at 35 °C using two PLgel 10p mixed-B columns in series
(manufacturer-stated linear molecular weight range of 500-10x106 g/mol). The
eluting solvent was THF at a flow rate of 1 mL/min, and the concentration of
polymer solutions used for GPC was 1 mg/mL. GPC data were obtained using
GPC-MALLS (Multi-Angle Laser Light Scattering) at 35 °C using THF as the

eluting solvent at a flow rate of 1 mUmin. An Optilab rEX (Wyatt Technology

58

Co.) and a DAWN EOS 18-angle light scattering detector (Wyatt Technology Co.)
with a laser wavelength of 684 nm were used to calculate absolute molecular
weights. Differential Scanning Calorimetry (DSC) analyses of polymers were
obtained using a TA DSC Q100. Samples were run under a nitrogen atmosphere
at a heating rate of 10 °C/min, with the temperature calibrated with an indium

standard.

Contact angle measurements were taken by making polymer solutions
containing 1-5 wt % of the desired polymer.dissolved in toluene and filtered
through Whatman 0.2 pm PTFE filters. The samples were then spin-coated onto
silicon wafers and the advancing, static, and receding contact angles were

measured using dionized water and reported as an average of 5 measurements.

3.2 Material synthesis

Synthesis of 2-(furan-2-yl)-2-hydroxyacetonitrile. Danger: This preparation
generates copious amounts of HCN. All manipulations must be carried out
in a fume hood. A 3L, 3 neck flask was charged with 500 mL of de-ionized
water and 452 g of KCN. The mixture was stirred for 30 minutes at 0 °C, and
then freshly distilled furfural (100 mL, 115.9 g, 1.207 mol) was added drop-wise
to the solution over a period of 10 minutes. After the furfural addition was
complete, saturated NaHSO3 (375 mL) and 400 mL of ice-cold water were
quickly added, and the mixture was stirred for 15 minutes. Then, 700 mL of
concentrated HCI (12.1 M) was added slowly added to the solution. (This step
generates copious amounts of HCN!) The solution was extracted with ether

(6X600 mL), washed with saturated brine solution (600 mL) and dried overnight

59

with NaZSO4. Gravity filtration and removal of the solvent by rotary evaporation
gave a dark brown oil (70.55 g). 1H NMR analysis showed that the oil was a
mixture of the desired furfural cyanohydrin (68.33 9, 0.5554 mol, 46%) and the
starting aldehyde (2.22 g.) 1H NMR (CDCI3): 6 (ppm) 7.41 (s, 1H), 6.5 (dd, 1J =
3.3 Hz, 2J = 0.9 Hz 1H), 6.35 (dd, 1J = 2.1 Hz, 2J = 1.8 Hz, 1H), 5.5 (s, 1H), 3.5-
4.5 (br s, 1H). 13C NMR (CDCI3): 6 (ppm) 147.3, 144.2, 116.9, 110.8, 110.0,
56.7. (Lit.70 1H NMR: (CDCI3, 300 MHz): 6 (ppm) 7.47 (d, J = 1.9 Hz, 1H), 6.58
(d, J = 3.4 Hz, 1H), 6.41 (d, J = 1.8 Hz, J = 3.4 Hz, 1H), 5.53 (s, 1H), 4.25 (br s,
1H)).

Synthesis of ethyl 2-(furan-2-yl)-2-hydroxyacetate. This procedure was
adapted from Boatright and Degering.66 Dry EtOH (750 mL) was charged into a
3 L, 3 neck flask protected with nitrogen, stirred and cooled to 0 °C. Over 30
minutes, HCI gas, produced by slowly dripping concentrated H2804 (500 mL, 18
M) over 452 g of NaCl, was bubbled into the EtOH. Then, over 30 minutes, a
solution of the furfural cyanohydrin (68.33 9, 0.5554 mol) in 250 mL of dry EtOH
was added dropwise to the stirred EtOH/HCI mixture. After the addition of the
furfural cyanohydrin was complete, stirring was discontinued, and HCl(g, was
bubbled through the solution for an additional 3.5 hours at 0 °C. The reaction
vessel was transferred to a refrigerator at 4 °C. After 4 days, the flask was
removed from the refrigerator, and warmed to room temperature. De-ionized
water (500 mL) was added to the mixture, and after stirring for 10 minutes, the
solution was extracted with ether (5 X 750 mL, and then washed with de-ionized

water (3 X 400 mL) until the pH was neutral. The ether was dried with NaZSO4

6O

overnight. Gravity filtration and removal of the solvent by rotary evaporation
gave the crude product as a dark brown liquid which eventually solidified (72.19
9, 0.4246 mol, 76.46%). Sublimation of the dark brown solid (50 °C, 20 mtorr)
over a period of three days gave the desired product as white powdery crystals
(55.29 9, 0.3252 mol, 58.56%). 1H NMR (CDCI3): 6 (ppm) 7.38 (s, 1H), 6.32-6.37
(m, 2H), 5.14-5.18 (d, J = 5.5 Hz, 1H), 4.20-4.33 (m, J = 3.6 Hz, 2H), 3.31-3.35
(d, J = 5.5 Hz, 1H), 1.22-1.29 (t, J = 7.2 Hz, 3H). 13C NMR (CDCI3): 6 (ppm)
171.5, 150.9, 144.0, 110.5, 106.7, 66.9, 62.6, 14.1. Anal. Cald. for C3H1004: C
56.47; H, 5.92 Found: C, 56.46; H, 5.84. MS (EI) m/z 170, 97 (100), 69. mp
4041 °c (Lit.66 mp 39 °C). (Lit71 1H NMR data: (CDCI3) 6 (ppm), 7.40 (m, 1 H)
6.35 (m, 2 H), 5.20 (s, H), 4.25 (q, J = 7 Hz, 2 H), 3.55 (s, OH, 1 H), 1.20 (t, J = 7
Hz, 3 H))

Synthesis of 2-(furan-2-yl)-2-hydroxyacetic acid. This procedure is adapted
from Boatright and Degering.66 A 3L 3-neck flask protected with nitrogen was
cooled to 0 °C and charged with 2-(furan-2-yl)-2-hydroxyacetate (55.29 9, 0.3252
mol). 2.5 M NaOH (800 mL) was added to the flask, and after the mixture was
stirred for 1 hour at 0 °C, the ice bath was removed and the stirred reaction was
allowed warm to room temperature over a period of 2 hours. Concentrated HCI
(250 mL, 12.1 M) was added to adjust the pH to ~1-2, and then the resulting
solution was extracted with EtOAc (4 X 600 mL). After drying the combined
EtOAc layers overnight with Nast4, gravity filtration and removal of the solvent
by rotary evaporation gave the desired hydroxyacid as light brown crystals (41.64

9, 0.2932 mol, 90.17%). 1H NMR (acetone-d5): 6 (ppm) 7.52-7.53 (dd, J = 0.9

61

Hz 1H), 6.41-6.44 (m, 2H), 5.24 (s, 1H). 13C NMR (De-acetone): 6 (ppm) 171.5,
152.5, 142.6, 110.4, 106.0, 66.5. Anal Calcd. for C6H504: C, 50.71; H, 4.26.
Found: c, 50.40, H, 4.19. mp 109-111 °c (Lit. mp 108-111 °c72, 115 °c65). (Lit.
NMR data”: 1H NMR (acetone-de): 6 (ppm) 7.60 (d, J = 0.3, 1H), 7.50 (d, J =
1.8, 1H), 6.40 (dd, J = 1.8 and 0.8, 1H), 5.25 (s, 1H); 13C NMR (acetone-d6): 6
(ppm) 172.6, 153.5, 143.6, 111.4, 109.0, 67.6)

Synthesis of 2-hydroxy-2-(tetrahydrofuran-2-yl) acetic acid. A Parr
hydrogenation bomb was charged with a solution 2-(furan-2-yI)-2-hydroxyacetic
acid (41.64 9, 0.2932 mol) in 250 mL of anhydrous EtOH, and 1.0 g of 5% Rh on
Al203 (Engelhard Lot # C003081). The bomb was pressurized to 1500 psi H2 and
the reaction stirred for 48 hours. The reaction was monitored by 1H NMR and
when the reaction was complete, the bomb was opened and the reaction mixture
was filtered through Celite to remove the catalyst. Removal of the solvent by
rotary evaporation gave the desired acid as a light brown solid (35.64 9, 0.2441
mol, 83.25%). Crystallization of the product in a minimal amount of EtOAc
provided the R,R/S,S product as white crystals (5.06 9, 0.0347 mol, 23.6%) and
R,S/S,R as white crystals (5.30 9, 0.0363 mol, 24.8%) (stereochemistry
determined by x-ray crystallography)

R,R/S,S: 1H NMR (acetone-dB): 6 (ppm) 4.20-4.23 (d, J=4.2 Hz, 1H), 4.09-4.15
(m, 1H), 3.77-3.86 (m, 1H), 3.63-3.72 (m, 1H), 1.76-1.97 (m, 4H). 13C NMR (Dr;-
acetone): 6 (ppm) 173.5, 80.5, 73.0, 69.0, 26.3, 26.3. IR (NaCl): v (cm'1) 3710-

3068, 2983, 2967, 2900, 2696-2466, 1737, 1218, 1137, 1062. Anal. Calcd. for

62

C5H1004: C, 49.32; H, 6.90. Found: C, 49.37; H, 6.83. MS (El) m/z 147.1
(0.11), 128 (0.97), 110.0 (4.86), 101.0 (8.63). mp = 76-77 °C.

R,S/S,R: 1H NMR (acetone-d6): 6 (ppm) 4.18-4.27 (dt, 1J = 6.9 Hz, 2.1 = 2.4 Hz,
1H), 4.03-4.09 (d, J = 2.4 Hz, 1H), 3.75-3.84 (m, 1H), 3.61-3.69 (m, 1H), 1.75-
2.08 (m, 4H). 13C NMR (acetone-ds): 6 (ppm) 174.0, 80.0, 72.3, 69.2, 22.7, 22.6.
IR (NaCl): v(cm'1) 3430, 3397, 2971, 2967, 2935, 2661-2495, 1735, 1215, 1137,
1049. Anal. Calcd. for C5H1004: C, 49.32; H, 6.90. Found: C, 49.38; H, 7.10.
MS (EI) m/z 128.1 (0.57), 111.0 (2.65), 110.0 (1.28), 101.1 (24.49). mp = 126.5 —
127.5 °c (Lit.67 mp 129 °C).

Synthesis of RSSR/SRRSIRSRS 3,6-bis(tetrahydrofuran-2-yI)-1,4-dioxane-
2,5-dione. A 2 L, 2 neck flask protected with N2 and equipped with a Dean-Stark
trap and a jacketed water condenser was charged with R,S/S,R-2-hydroxy-2-
(tetrahydrofuran-2-yl)-acetic acid (5.30 9, 0.0363 mol), p-TsOH (0.340 g, 1.79
mmol), and 900 mL of toluene. The flask was heated to the reflux temperature,
and the reaction was monitored by 1H NMR. When the oligomeric by-products
became noticeable (~5 days), the reaction solution was filtered while hot and
then the toluene was removed by rotary evaporation. The resulting solid was
dissolved in CH2Cl2 and washed with aqueous saturated sodium bicarbonate (3 x
200 mL) followed by saturated brine solution (1 x 200 mL). After drying over
Na2SO4 and gravity filtration, the solvent was removed by rotary evaporation.
Two recrystallizations of the crude product from acetone gave colorless crystals
of 3,6-bis(tetrahydrofuran-2-yl)-1,4-dioxane-2,5-dione (1.36 g, 531 mmol, 29.2%)

as a statistical mixture of the RSSR/SRRS and RSRS isomers. The monomers

63

were purified and almost completely separated by crystallization from acetone.
The stereochemistry was not determined for the mixtures of monomers. The
monomers were labeled M1 and M2. Monomer M1 was isolated in its pure state
as flake like colorless crystals. Characterization for M1: 1H NMR (CDCI3): 6
(ppm) 4.84-4.88 (d, J=3.6 Hz, 1H), 4.48-4.56 (dt, 1J= 6.9 Hz, 2J=2.4 Hz, 1H),
3.77-3.91 (m, 2H), 1.82-2.16 (m, 4H). 13'c NMR (CDCI3): 6 (ppm) 164.6, 78.5,
78.3, 69.2, 27.8, 26.0. IR (NaCl): v (cm'1) 2992, 2875, 1766, 1232. Anal. calcd.
for C12H1506: C, 56.18; H, 6.29. Found C, 56.23; H, 6.00. MS (EI) m/z 256.1
(0.12), 238.1 (0.14), 186.1 (1.79), 128 (3.55). mp 200-201 °C. Characterization
for M2: 1H NMR (CDCI3): 6 (ppm) 4.94-4.97 (d, J=3.0 Hz, 1H), 4.47-4.54 (dt,
1./=9.0, 2.1: 3.0, 1H), 3.73-3.39 (m, 2H), 1.31-2.14 (m, 4H). 13c NMR (CDCI3): 6
(ppm) 165.1, 79.1, 77.9, 69.8, 27.1, 26.1. IR (NaCl): v (cm'1) 2989, 2964, 2877,
1754, 1378, 1275, 1058. Anal. calcd. for C12H1506: C, 56.18; H, 6.29. Found C,
56.39; H, 6.54. MS (EI) m/z 256.0 (0.03), 238.1 (0.02), 186.1 (0.96), 156.0
(0.23), 129.0 (0.85). mp 146-150 °C.

Synthesis of RRRRISSSS/RRSS 3.6-bis(tetrahydrofuran-2-yl)-1,4-dioxane-
2,5-dione. A 2 L, 2 neck flask, protected with N2 and equipped with a Dean
Stark trap and a jacked water condenser, was charged with R,R/S,S-2-hydroxy-
2-(tetrahydrofuran-2-yl)acetic acid (5.06 g, 363 mmol) and p-TsOH (0.340 g, 1.79
mmol) and 900 mL of toluene. The reaction was heat to reflux and the reaction
was monitored by 1H NMR. When the oligomeric by-products became noticeable
(~5 days), the reaction solution was filtered while hot and then the toluene was

removed by rotary evaporation. The resulting solid was dissolved in CH2Cl2 and

64

washed with saturated aqueous sodium bicarbonate (3 x 200 mL) followed by
saturated brine solution (1x200 mL). After drying over Na2SO4, and gravity
filtration, the solvent was removed by rotary evaporation. Crystallization of the
product twice from acetone gave 1.81 g (70.7 mmol, 40.8%) of a statistical
mixture of RSSR/SRRS and RSRS stereoisomers of 3.6-bis(tetrahydrofuran-2-
yl)-1,4-dioxane-2,5-dione as colorless crystals. 1H NMR (CDCI3): 6 (ppm) 5.17-
5.21 (d, J=3.0 Hz, 1H), 5.04-5.08 (d, J=3.0 Hz, 1H), 4.52-4.59 (dt, 1J=3.0 Hz, 2J=
6.0 Hz, 1H), 4.40-4.57 (dt, 1J=3.0 Hz, 2J= 6.0 Hz, 1H), 3.73-3.99 (m, 4H), 1.80-
2.20 (m, 8H). 13C NMR (CDCI3): 6 (ppm) 164.4, 164.2, 79.5, 78.7, 77.0, 76.9,
- 69.4, 69.4, 26.7, 26.20, 26.0, 25.7. IR (NaCl): v (cm'1) 2971, 2935, 2875, 1751,
1253, 1068. Anal. calcd. for Cr2H1605: C, 56.18; H, 6.29. Found C, 56.54; H,
6.55. MS (EI) m/z 256.3, 213, 186.1, 149.0, 128.0. mp 144-154 °C

Bulk Polymerization of Substituted Glycolides. Solvent-free polymerizations
were carried out in sealed ampoules prepared from 3/8 in. diameter glass tubing.
Ampoules were charged with monomer and a stir bar and connected via a Cajon
fitting to a T-shaped vacuum adapter fitted with a stopcock and an air-free Teflon
valve. A septum was attached to the outlet of the stopcock, and the apparatus
was connected to a vacuum line and evacuated through the Teflon valve. After 2
h, the ampoule was backfilled with nitrogen, and a syringe was used to add pre-
determined amounts of Sn-(2-ethylhexanoate)2 or DMAP solutions, and 4-tert-
butylbenzyl alcohol solutions to the ampoules through the stopcock. The solvent
was removed in vacuo and the ampoule was flame-sealed and immersed in an

oil bath. At the end of the polymerization, the ampoule was cooled, opened, and

65

 

 

the polymer was dissolved in CH2CI2. A portion of the solution was evacuated to
dryness and analyzed by NMR for conversion. The remaining polymer solution
was precipitated 1-2 times into cold methanol until residual monomer and

catalysts were removed.

66

Appendix

67

$5.... 65.896
So 963 650 ..mtoumE 95.68 .9355 QEEQoomtAxBc>z-~é>-m-cm5t-m 6 :55on E22 IF . _..< 6.59“.

 

 

 

 

 

 

 

 

 

 

 

Eaa
m.o 3 me om Wm om mm 34 34 co mam o.o no cs 2 od Om 0.3 Om
l - $11 :11- 1 ljjil -jalla a
* * * *
o
o a
2,4 § / o a
On 0 6
was a
I F was oméémd
IF w .om.m
m._.n\.~.w.NuP I_. no mmd n ”.000 EoZom
mdnsmddnb Ir no omd IF «32032
T: u. a: 0.8 6.32853
€58 NIS. com 6:63.32”.

3.: s .E. .655 E55255 08-6666 55> .5528...

 

68

cmtofiE 9:th .mStat o_E_coHoom>xo.o>crmrA_>-~-:me-N ho E2663 m=22 02 .~.< 959“.

Egg
o or on on ov om cm on om om o9 o: oww one 03 omw 09 0: cm? om? com

h b 1— b D F P D h b 1?

 

 

 

 

 

 

 

 

II 1 i ll 11 L— l. 1 _l l 11111 l 1 r 1 l 1
u
C
o n
. /
2,70 ~ 0 M
New C o o
od: :0
wd: a.
adv F 600 Eozow
N63... 9 m OmF mam—0:2
m5; 6 00mm 9.3anth
€53 6 N15. mu 6:63—32".

55 .3626 825566 56> 26526:.

 

69

€o_.m_:E_m m22m .3 6658.566 3:99.06 955:8
US... 9.26. _mo_Eo..o 6:63:68 05206.9me 1.. o.m.oom>xo.U>:-N-A_>-N-cm..:brw $56 50 £26on «.22 I. .n.< 6.59".

:55
md 0.. 0. ON 0N o.m m.m o6 m4 oh Wm 06 00 ON m.» o.m Ow o.m Om

_. — p ~5—L _ h p p plr _ p p p . FLP . _ p.L _ h _ . ~1brp

, .1 e s ,

 

 

 

 

 

 

 

 

m
a o
x
o o . m
o a
U \ _ o+n
IO O m
m
N. ..m . mm.
m... I. .6 8.9.2.”
3 u 114...“. u II_.. I. E .8...
N. u .5... .N. u :13 I. E .3... .
Eo>_om
mo 1. o 8.3.... .08
...N E 8.6.9,... I. 96.32
I. m we. 6.. mm 9398.5.
m €53 N15. com 65:06..”—

.n.... s ..e. .25 55.8.5.6 82550 coeo> 865.6...

70

rEI r 33.1»? .T 3. ... .. . L4

9300ngn>c-~-:>-m-cm5¢-m 355 be 828me ”:22 02 .v.< 0.52”.

can
0 or cm on 9» om om os om om 03 o: omr cm? 03 cm? cm: at 8F 02 com

F \P F D — xP _ F P b — r h n — I b I — D - F hr D I Ll

F

 

 

 

 

 

 

_‘.v_‘ 0+9
0N0

ado
5.00.. 5
m6: E m m

. cg o
o 3: . A .80 . . w
mdmv E O n 02 320:2
m. E m \ _ 9. mm 2383.5...
AEQQV IO c O m NIS. mu 5.53—5E

czm _8_E2_o oom-_c_Emo cmEm> EoEaas

 

71

20m o:mom>xo.u>c-mé>-m-cm._SYN D6 828on «:22 IF .m..< 959“.

Ema

— P — L — h — b F I D I - L - L _ hL b P r — b b

md oé m._. ON 0N Qm Wm o6 m6 Qm mb 0.0 Wm 0.x. ms 0d 9w od md

 

 

 

 

 

 

 

 

1 A ‘ W {
0 0I u
a
c \ _ m
I0 0 m
0+2

um co>o
I? w wmfi mcoflmom D u . . m
IN E $8-3.o IF 2.22.2
mo IF 8 8.»ng oomN EBEoEEfl
€38 NIS. com 35:69.".
ANI. s ..E .965 Eamagefio oom-E_Emo :m_.m> EwEEfiE

 

 

72

 

Eon o:mom>x9n>n-~-c>-~-cm._BYm No 826on E22 02 .o.< 959".

 

 

 

 

 

Eng
9. om om ow on 8 on ow om 09. 0: cm? 02 o: 09 cm: 0: owe 02 com
o N
m
o+n
m8 0* oIo
2: g3

MINUS I0 0 a 8038-6 2528
0N2 0: 322.2
met oomN seeaefl
E68 N12 mm 55:69.".
55.8320 oom-_EEmo EwEm> EoEEfiE

 

 

73

. I . Saul!
firuii:fll’ibhf‘ M.

 

.998... 3:6 .528 5:2me L 20m o_.mom-c>-~-:93.9n>cmhmu-m.>x9n>c-w-m.m\m.m .0 .550QO «:22 I. .h.< 23mm

can
md o.. m. QN 9N Qm 0m oé 0v oh Om 0.0 m6 0.. ms 0... Wm od md

_ . — p — p _ h u p p p p p — + _ _ p — P — - L p — p p p _ . _ . P

 

 

 

 

 

 

 

 

IV E modhfi.

I _. E mod- .05

I _, E vwdumhd

IN I. n @0418...

...NH ..N dd" 3. I. 6 Rim...“

€53
0+9 m o 3:. N. - ..E 3.65 5.5 REESE

O O: o n 80.8me .:w>_om
m I. 9.20:2
IO o O N 0° mm «5.83:8...

 

 

NIS. com >053..qu
m.m\w.m m oom-_:_EmO cmtm> 59:25:.

 

74

 

200 0_.000A_>-N-:9EEPEm..00-~.>x90>c-~-mdad .0 E26000 52.0000 E22 on. .0.< 0.50....—

 

 

 

 

 

 

 

 

 

 

 

 

E00
0 0. 0m 00 00 on 00 on 00 00 00. 0.. 0m. 00. 0.. om. 00. on. 00. 00. com
ii; -FIN - ”III-Ii J 114:; y - ‘Liw- MAI —1-4t¥
0 0 .
0
+0 m
.OI
oufj.
. 0
0 mm IO 0 O m
NNN
. m.m\w.m
WWW 009000-00 .:0>_om
0.00 0.”. 030.032
QE. Comm 05.800E0...
0:03 NI_2 mm 5:03.02“.
Ezw 50:02.0 00045800 cmtm> .5825...

 

75

00¢

20... 0_.mom-0>-m-cm.29039.00-N->x903-9w..m6.m 82.0000 m. .m.< 059....
2.-.:00 50:02:05;

coo. coo. comm comm oowm

 

7

 

 

 

 

 

 

 

 

 

 

 

eouquosqv

76

28 0082..-NEEEE033.25...on3.3-0.0.0.0 .0 E233 022 I. .0..< 2:0...

 

 

 

 

 

 

 

 

 

 

 

E00
0.0 0.. 0.. 0.N 0.N 0.0 0.0 0... 0... 0.0 0.0 0.0 0.0 0... 0.. 0.0 0.0 0.0 0.0
m 0 I. E 5.0...
I. E 3.0-00.0
I. E 000-500
0+0 . I. E 0..v.00.v
Nv I. 0 mm Vow...
AEQQV
.NI. 5 .E. .290 £00 _~u_E2_0
CI
0 0 0
0
IO .0 O a 0:900me u:0>_om
. . I. 000.002
mem 0.. 0w 05.0.0050...
NIS. 000 5000000....
0 000-_c_E0O :0_.0> 20.0.50...

 

77

 

28 008m..._>-N-._E3.2029000-N..x9_0.3-0.00..m .0 E22 0.. ....< 2:0...

 

0+0

 

0.0N
0.0N
0.00
0.0.
0.00
0.0..
«E03
.020 _8_Eo._0

 

 

 

00

 

om

E00

00.

F

0.. ON. 00. CV. 00. 00. on. 00. 00. com

F r by P L I by L! F b —

.P

 

. 0...
Eng.
0
I0 .0 o m
0.0.0.0
009000-00
02
0.. 0m
NI... 05

002550 .555

E0200
000.032
05.0.0050...

5:03.000“.
$08.50...

78

28 2.89.30-53.93;9.2.058.250-00&0 52.8% m. .2-.. 2:9”.

..-Eo. 0.00E::0>0>>
oov coo? 80F comm comm oovm ooov

u u _ 4 A _ d d A u q — - a q u d — q q q u - — _ _ u u d — 1 4 q _ _ o

 

3
l
‘-
O

 

 

1
‘9.
o

 

 

 

#
°°.
O

 

eouquosqv

 

 

 

l
N.
‘—

4
V.
v-

 

 

 

 

 

 

w...

79

.. 5050505. 050.30-806.04. .-.3.0-5.555055.000.000-003 00.00.0000. .0 55.0000 «:22 I. .0..< 0.00....

.500...
0.0 0.. 0.. 0.0 0.0 0.0 0.0 0... 0... 0.0 0.0 0.0 0.0 0.. 0.. 0.0 0.0 0.0 0.0

L

 

 

 

 

 

 

 

 

_ 0
O n
N U 0
O I 0 O
0
0 O 0 O
0
0+2 0 U
n O
0
0
Iv E 0..N-N0..
I0 5 .00-...0 M500 .5200
«Nu 00 .00"... I_. .0 00.0.0.0...q I. 030.032
0.0"... I. c 00.10... 0.. mm 0.3.0.0050...
€33 NIS. com 5:03.00”.

3... s ..5 .0520 500.00.50.00 000.5500 5......3 505.505

80

.. 5050505. 050.000-006.00. .000-50..0.20.50000030000000.00.10.0000. .0 52.0000 «:22 on. .0..< 0.50.”.

5.00.
o o. cm on 0... cm 00 o... 00 cm oo. o: ow. 00.. o: om. 00. o: 00.. om. com

r I — r F P - b F L! p r .P L b L F b F .- L 0’ P F I F L! F — L, —

 

 

 

 

 

 

 

 

 

O
O
O O
O
O
odm
0.3 _
WWW # 0.000 “20200
m.®N . 00w ”aw—0:2
0.00. 0.. 00 05.800505
€53 NIS. 00 >0:03U0.£

:50 00.5000 000.5500 c000> 5052.05

 

 

81

 

.. 505085. 050.000-806.00.13-0.0525030500050.0-0000000.0.0000..0 55.0000 0: 0.-< 050.”.
..-Eo. 0.0083520;

oov cow. ooom comm

. 7 . d . _ q . 8 J . 4 . J fl 1 . P.o

 

 

u Nd

 

 

 

 

 

 

 

 

eaueqmsqv

u vac

 

 

 

 

 

 

 

 

 

 

0.0

82

23:39:. 20:55:...
.0 050005. 000.30-050.85... ..3-0-5520.0508.05-00-00.0m 00003000 .0 55.0000 «.22 I. .0..< 050.“.

 

 

 

 

 

 

 

 

 

.500...
0.0 o. 0.. 0.0 0.0 0.0 0.0 o...» 0.0 0.0 0.0 0.0 0.0 0.. 0.. 0.0 0.0 0.0 0.0
of ..
m
0 n
.0 o
Om
0+0 0 0 O
0 0 o
m o
0 n O
m
:0 5 0.0.0..
:0 5 000.000 m.000 50200
0.01000"... I. .0 00.10... 1. 000.002
0.0"... I. .0 3.1.00.0 0.. 0w 0.3.0.00E0...
.EQQ. NIS. com 3:03.00.”—
.~:. 0 ..5 .0000 050.00.50.00 0005.500 5050> 5052.0...

 

 

83

3.50.... F 8.00:0... 20 0x03 00.30.00 N
55085. 25.50 «-8985-.. F.s-m-cm.:.o.u>cm..o..ms- 0 0- 000m. 00003000 .0 55.8% «.22 on. t-< 230.".

 

 

 

 

 

 

 

 

:20 5252.0

 

 

.53.:
0 0. 00 00 0v 00 00 0. 00 00 00. 0: our 00. 0.: 00F 00. 0: 00F 00. 000
O
. 0
row 0 0
FR 0
0.00
0... o ”.000 52,30
Tmh OmF 2.0—0:2
v.00? 0000 2303050...
.qu. N15. 05 3:302”.
000-_:_Emo :m_.m> 2.05.505

 

84

.N 55935. mco_o0.m-mcmxo.u-v. 7.3.0.55252.55.20.00000000009000... .0 55.080 0. .03. 2:0...

...Eo. 0.0080520;

00.... com? Doom comm
. . 1 4 . . . . _ . q . . _ . . _ F.O

 

 

 

 

 

 

 

 

 

 

 

‘ u NNd

 

 

 

 

 

 

r vmd

 

I 0N6

 

 

 

0N0

85

.0 850005. 000.50.886.50. l3-0-0550.0.558.050.000500000000 .0 55.8% 0.22 I. .03. 0.00.0

.500...
0.0 0.. 0.. 0.0 0.0 0.0 0.0 0.0 0... 0.0 0.0 0.0 0.0 0.. 0.. 0.0 0.0 0.0 0.0

— r p b P LP _ p P p — p F F P r — p — b — b — b r r h p — h

 

 

 

 

 

 

 

 

 

i .0111 0
0
O n
0 o
00
0 o 0 o
O
0 U
0+2 0 m n O
0
I0 E omNdwé
Iv E madéNm
o.©ufi~.o.mufi. IF :0 N97000:... 0
0.0"..N.0.0u0. I. .0 00.100... .000 .8200
0.0 T: 0 00.0-3.0 0. 000.002
Qm IF U 56-5.6 00 mm 95082.59?
.800. N15. 000 >0:0:am.£

.01... .5. .0090 0.00.8505 0005.500 50..0> 5055.00.

86

.0
850005. 000.500-086.50. .-.$0505.50...5.000.000-0000 0000.0000 .0 55.8% 0.22 0.... .00.< 0.00.0

.500. ..
0. 00 00 00 00 00 00 00 00 0: 00. 00. 0: 00.

— P h * h D I P F b — L — fi — P — n — I — F — Br — p P h — h P

 

0.00
0.00
0.00 O
0.00 O
0.00
0.00 o o
0.00
.0 o
0.0. 0.000 50200
0.00. 0.... 000.002
0.00. 0.. 0m 23800:.0...
.Eaa. 01.2 00 5:03.020
Ecm 30.5.0.5 00005.50 :0_.0> 0:08:30...

 

 

 

 

 

 

87

 

.0 0050005. 000.000-086.00. 7.3-0-00.0.0.05000..0.00.0-000000000000 .0 55.8% 0. ..0.< 0.00.0

..-Eo. 0.0005090;
00.0 000. 0000 0000

fi 4 d d a I 4 a d — d 4 a a fi fi 1 N O

 

.2-
I

(O

O

 

 

 

CD
0
eou quosqv

 

 

 

 

 

 

0..

88

.0.2 ..2 850005. 02.820.05.50.05000000000 00000000500 .0 55.8% 0.22 I. .00.< 0.00.0

 

 

 

 

 

 

 

 

.500. ..
00 Q. 0. Q0 00 Q0 Q0 Q0 00 Q0 Q0 Q0 00 Q0 0. Q0 00 Q0 00
0 0
m
0+0 0 0
O
c O 0 0
. . O
Iv mm Nuov —. m
I. 00.0-0.0 0 0
20> o
.0. 000.00 0 .000 000 0.00
1. 00.01000 1. _ 2
IF mm.m-ww.v 00 mm 0030.50.50h
.Eaa. 015. 000 20:03.00.“—
..... ...00 00.5000 000.5500 00..0> 505000...

 

89

 

20.2 .5000... 82.000.902.50.025.000.00.000000.00.00.28 .0 52.0000 ”:22 0.. .00.... 0.00.".

.500...
0. 00 00 00 00 00 00 00 00 00. 0.. 00. 00. 0... 00. 00. 00. 00. 00. 000

— h! P \h{ b D — L F P — b — b F P — b L n —r b — b! _ LI .- —

 

 

 

0.00.00. 0
o. wmuodm : O
0.00-0.00 o 0
0.00-0.00 0
m.mm-m.wm O
ohm-mic
ncédm
onumdo
0.00-0.00 0
Won-0mm Coo EwZom
O..O®uOQN Om. mawflvaz
ode-0.8. 0.. mm 0.3.0.0080...
AEQB 0:5. mm. 35:00..”—
...._.0 000.5000 0005.500 00005 505000...

 

 

 

9O

 

20.20200. .00._00>_0_.00..0.0._0>..0..0._0.0000.0.000.000.0500 .0 52.0000 0.22 I. ...0.< 0.50.0

 

 

 

 

 

 

 

 

 

 

A803 0. .
md o._. 0. ON m0 o.m Om oé m... Qm Om 0.0 00 ON ms ow m6 0.0 Do
4 .. -
0
0+9
: O

. - . 0
IV gm 3.. 0_Ooo «cg—om
IN mm 0.8 m 0 0:0 0:
1. 00.100... 1. _ z
I. 00.0-00.0 0.. 00 05.0.0050.

E03 01.2 oom 20:03—09.”—
..:_ Esw .00....050 com-.5800 :m_.m> 0:00:35...

 

91

 

20.2500. 00.850.05.20.050000.000... 0000.00.00.58 .0 52.0000 «:22 0.. .00.... 050.0

.500...
0 0. 00 00 00 00 00 00 00 00 00. 0.. 00. 00. 0... 00. 00. 00. 00. 00. 000

_ F p p h 0 p L _ u _ . — p _ p P

—
-

\— P h F b P r b! L — b.

 

 

 

 

 

 

 

O

0.00-0.00 0 0
000.000 0 0
nae-mam. ,
0..-00-0mm . o o 0.000 .:0>_om
0.00-QR . 00. 030.032
mks-mg... 00 mm 0.30.0053.

€50. NIS. m0 22.0302".

...00 0.0.5000 0005.500 00:05 5052.0...

 

92

REFERENCES

93

(1)

(2)

(3)

(4)
(5)

(6)

(7)
(8)
(9)

(10)

(11)
(12)

(13)
(14)

(15)

(16)

Auras, R. A.; Singh, S. P.; Singh, J. J. Packaging Technology and Science 2005, 18,
207-216.

Vink, E. T. H.; Rabago, K. R.; Glassner, D. A.; Gruber, P. R. Polymer Degradation
and Stability 2003, 80, 403-419.

Sinclair, R. G. Journal of Macromolecular Science-Pure and Applied Chemistry
1996, A33, 585-597.

Simmons, T. L.; Baker, G. L. Biomacromolecules 2001, 2, 658-663.

Dechy—Cabaret, 0.; Martin-Vaca, B.; Bourissou, D. Chemical Reviews 2004, 104,
6147-6176.

Drumright, R. E.; Gruber, P. R.; Henton, D. E. Advanced Materials 2000, 12, 1841-
1846.

Purchasing 2009, 138, 46-47.
Vert, M. Biomacromolecules 2005, 6, 538-546.
Bogaert, J. C.; Coszach, P. Macromolecular Symposia 2000, 153, 287-303.

John, R. P.; Nampoothiri, K. M.; Pandey, A. Applied Microbiology and
Biotechnology 2007, 74, 524-534.

Fukushima, K.; Hirata, M.; Kimura, Y. Macromolecules 2007, 40, 3049-3055.

du Boullay, O. T.; Marchal, 13.; Mafiin-Vaca, B.; Cossio, F. P.; Bourissou, D.

Journal of the American Chemical Society 2006, 128, 16442-16443.

Baker, G. L.; Vogel, E. B.; Smith, M. R. Polymer Reviews 2008, 48, 64-84.

Ryner, M.; Stn'dsberg, K.; Albertsson, A. C.; von Schenck, H.; Svensson, M.
Macromolecules 2001, 34, 3877-3881.

Trimaille, T.; Moller, M.; Gumy, R. Journal of Polymer Science Part a-Polymer
Chemistry 2004, 42, 4379-4391.

Kowalski, A.; Duda, A.; Penczek, S. Macromolecular Rapid Communications
1998, 19, 567-572.

94

(17) Kricheldorf, H. R.; Kreiser-Saunders, 1.; Stricker, A. Macromolecules 2000, 33,
702-709.

(18) Nederberg, F .; Connor, E. F .; Moller, M.; Glauser, T.; Hedrick, J. L. Angewandte
Chemie-International Edition 2001, 40, 2712-2715.

(19) Bonduelle, C.; Martin-Vaca, B.; Cossio, F. P.; Bourissou, D. Chemistry-a European
Journal 2008, 14, 5304-5312.

(20) Fried, J. R. 2003, 2nd Ed, 155-156.
(21) Yin, M.; Baker, G. L. Macromolecules 1999, 32, 7711-7718.
(22) J ing, F .; Smith, M. R.; Baker, G. L. Macromolecules 2007, 40, 9304-9312.

(23) Joziasse, C. A. P.; Veenstra, H.; Grijpma, D. W.; Pennings, A. J. Macromolecular
Chemistry and Physics 1996, 197, 2219-2229.

(24) Zhang, L.; Nederberg, F.; Messman, J. M.; Pratt, R. C.; Hedrick, J. L.; Wade, C. G.
Journal of the American Chemical Society 2007, 129, 12610-+.

(25) Ovitt, T. M.; Coates, G. W. Journal of the American Chemical Society 1999, 121,
4072-4073.

(26) Cheng, M.; Attygalle, A. B.; Lobkovsky, E. B.; Coates, G. W. Journal of the
American Chemical Society 1999, 121 , 11583-11584.

(27) Gupta, B.; Revagade, N.; Anjum, N.; Atthoff, B.; Hilbom, J. Journal of Applied
Polymer Science 2006, 100, 1239-1246.

(28) Urayama, H.; Moon, S. I.; Kimura, Y. Macromolecular Materials and Engineering
2003, 288, 137-143.

(29) Odelius, K.; Finne, A.; Albertsson, A. C. Journal of Polymer Science Part a-
Polymer Chemistry 2006, 44, 596-605.

(30) Karikari, A. S.; Edwards, W. F.; Mecham, J. 8.; Long, T. E. Biomacromolecules
2005, 6, 2866-2874.

(31) Tasaka, F.; Ohya, Y.; Ouchi, T. Macromolecular Rapid Communications 2001, 22,
820-824.

(32) Ouchi, T.; Ichimura, S.; Ohya, Y. Polymer 2006, 47, 429-434.

(33) Breitenbach, A.; Kissel, T. Polymer 1998, 39, 3261-3271.

95

(34) Ouchi, T.; Kontani, T.; Ohya, Y. Journal of Polymer Science Part a-Polymer
Chemistry 2003, 41 , 2462-2468.

(35) Ouchi, T.; Kontani, T.; Ohya, Y. Polymer 2003, 44, 3927-3933.
(36) Fox, T. G. Bulletin of the American Physical Society 1956, 1, 123.
(37) Kumar, R.; Gao, W.; Gross, R. A. Macromolecules 2002, 35, 6835-6844.

(38) Benabdillah, K. M.; Coudane, J .; Boustta, M.; Engel, R.; Vert, M. Macromolecules
1999, 32, 8774-8780.

(39) Lee, R. S.; Yang, J. M. Journal of Polymer Science Part a—Polymer Chemistry
2001, 39, 724-731.

(40) Chen, X. H.; Gross, R. A. Macromolecules 1999, 32, 308-314.

(41) Trimaille, T.; Gurny, R.; Moller, M. Journal of Biomedical Materials Research
Part A 2007, 80A, 55-65.

(42) Glans, J. H.; Turner, D. T. Polymer 1981, 22, 1540-1543.

(43) Sasaki, T.; Uchida, T.; Sakurai, K. Journal of Polymer Science Part B-Polymer
Physics 2006, 44, 1958-1966.

(44) Du, F. S.; Ye, W. P.; Gu, Z. W.; Yang, J. Y. Journal of Applied Polymer Science
1997, 63, 643-650.

(45) F eng, Y.; Klee, D.; Hooker, H. Macromolecular Bioscience 2004, 4, 587-590.

(46) Feng, Y.; Klee, D.; Hocker, H. Macromolecular Chemistry and Physics 2002, 203,
819-824.

(47) J iang, X. W.; Smith, M. R.; Baker, G. L. Macromolecules 2008, 41, 318-324.

(48) Karbowiak, T.; Debeaufort, F.; Voilley, A. Critical Reviews in Food Science and
Nutrition 2006, 46, 391-407.

(49) Young, T. Philosophical Transactions of the Royal Society 1805, 95, 65-67.
(50) Vogler, E. A. Advances in Colloid and Interface Science 1998, 74, 69-117.

(51) Pepin, X.; Blanchon, S.; Couarraze, G. Pharmaceutical Science & Technology
Today 1999, 2,111-118.

96

(52) Paragkumar, N. T.; Dellacherie, E.; Six, J. L. Applied Surface Science 2006, 253,
2758-2764.

(53) Yang, J. Y.; Yu, J.; Li, M.; Pan, H. Z.; Gu, Z. W.; Cao, W. X.; Feng, X. D. Acta
Chimica Sinica 2001, 59, 1809-1812.

(54) Gandini, A.; Belgacem, M. N. Progress in Polymer Science 1997, 22, 1203-1379.

(55) Theander, 0.; Nelson, D. A. Advances in Carbohydrate Chemistry and
Biochemistry 1988, 46, 273-326.

(56) Win, D. T. Assumption University Journal of Technology 2005, 8, 185-90.

(57) Roquemalherbe, R.; Deonatemartinez, J .; Navarro, B. Journal of Materials Science
Letters 1993, 12, 1037-1038.

(58) Galego, N.; Gandini, A. Revista Cenic 1975, 6, 163.
(59) Galego, N.; Gandini, A. Revista Cenic 1984, 15, 143.

(60) Zaldivar, D.; Peniche, C.; Bulay, A.; Roman, J. S. Journal of Polymer Science Part
a-Polymer Chemistry 1993, 31, 625-631.

(61) Amri, H.; Belgacem, M. N.; Gandini, A. Polymer 1996, 37, 4815-4821.

(62) Fox, T. G.; Flory, P. J. Journal of Applied Physics 1950, 21, 581-591.

(63) Mealares, C.; Hui, Z.; Gandini, A. Polymer 1996, 37, 2273-2279.

(64) Moreau, C.; Belgacem, M. N.; Gandini, A. Topics in Catalysis 2004, 27, 11-30.
(65) Mitiakoudis, A.; Gandini, A. Macromolecules 1991, 24, 830-835.

(66) Degering, E. F.; Boatright, L. G. Journal of the American Chemical Society 1950,
72, 5137-5139.

(67) Normant, H. Comptes Rendus Hebdomadaires Des Seances De L Academie Des
Sciences 1947, 225, 580-581.

(68) Farmahini-Farahani, M.; Jafari, S. H.; Khonakdar, H. A.; Yavari, A.; Bakhshi, R.;
Tarameshlou, M. Macromolecular Materials and Engineering 2007, 292, 1103-
1 110.

(69) Lucht, B. L.; Collum, D. B. Accounts of Chemical Research 1999, 32, 1035-1042.

97

(70) Purkarthofer, T.; Pabst, T.; van den Broek, C.; Gn'engl, H.; Maurer, 0.; Skranc, W.
Organic Process Research & Development 2006, 10, 618-621.

(71) Raucher, S.; Lui, A. S. T.; Macdonald, J. B. Journal of Organic Chemistry 1979,
44, 1885-1887.

(72) Felfer, U.; Strauss, U. T.; Kroutil, W.; Fabian, W. M. F .; Faber, K. Journal of
Molecular Catalysis B-Enzymatic 2001, 15, 213-222.

98

R

 

"71111111117111lefillifli‘gilluixfiu :11“