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This is to certify that the

thesis entitled

Determining Stereochemical Relationships:
Synthesis of Poly(lactide) Hexads

presented by

Erin E. Paske

has been accepted towards fulfillment
of the requirements for

M. S. degree in Chemi Stry

 

Major professor

Date May 8, 2002

 

0-7639 MS U is an Affirmative Action/Equal Opportunity Institution

 

 

 

 

 

 

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6/01 cJClRC/DaleDuepGErp. 15

DETERMINING STEREOCHEMICAL RELATIONSHIPS: SYNTHESIS OF
POLY(LACTIDE) HEXADS
BY

Erin E. Paske

A Thesis
Submitted to
Michigan State University
In partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE
Department of Chemistry

2002

ABSTRACT
DETERMINING STEREOCHEMICAL RELATIONSHIPS: SYNTHESIS OF
POLY(LACTIDE) HEXADS
By

Erin E. Paske

The polylactides are environmentally benign polymers with applications as
biodegradable and bioresorbable materials. The physical properties of
polylactides depend on the crystallinity of the polymer, which in turn are
determined by the regularity of the distribution of stereocenters in the backbone
of the polylactide chain. A powerful tool for determining the regularity of
polymers is the use of Nuclear Magnetic Resonance (NMR) in conjunction with
well-defined model compounds and modeling. To date, interpretations of the
NMFI spectrum of polylactide have often been contradictory.

Poly(lactide) hexads of known stereochemistry were synthesized using an
iterative procedure and characterized by NMFI to firmly establish the NMR
assignments. Comparisons of the 130 NMR spectra of various hexads and
Shorter oligomers allowed assignment of the methine region of the spectra. A
simple additivity model that considers the effects of neighboring and next-nearest
neighboring stereocenters provides reasonable agreement with the experimental

results.

ACKNOWLEDGMENTS

Several people have made my time at Michigan State University a
pleasant experience. I would like to thank Dr. Baker for his guidance and support
through grad school. Without the NMR help of Kermit Johnson, Long Lee, and
Art Bates, much of this work would have not been possible.

Current and former Baker group members have made being a grad
student a fun experience. My gratitude goes out to Cory, Micah, J. B., Tianqi,
Chun, Tara, Kirk, Mao, Gao, Bao, Ping, Ying, quei, Fung, Leslie, Nate, and Gia.
Lunches were made even better by Leslie, Nate, and Kirk.

I would also like to thank my family and other friends who supported me

through grad school. Thanks for listening and being there when I needed you.

TABLE OF CONTENTS

LIST OF TABLES ......................................................................... v
LIST OF FIGURES ...................................................................... vii
LIST OF SCHEMES ..................................................................... ix
ABBREVIATIONS ........................................................................ x

1. Introduction ............................................................................ 1
1.1 Propagation Mechanisms and Models ............................... 3

1.2 Microstructure of Polymers .............................................. 6

1.3 Empirical Chemical Shift Rules ......................................... 8

1.4 Microstructure of Polypropylene ...................................... 1 O

1.5 Microstructure of Poly(propylene oxide) ............................ 14

1.6 Microstructure of Polylactide .......................................... 14

1.7 References ................................................................. 31

2. Discussion ........................................................................... 33
2.1 References ...................................................................... 60

3. Experimental ......................................................................... 61

iv

Table 1.1.

Table 1.2.
Table 1.3.
Table 2.1.
Table 2.2.
Table 2.3.
Table 2.4.
Table 2.5.
Table 2.6.
Table 3.1.
Table 3.2.
Table 3.3.
Table 3.4.
Table 3.5.
Table 3.6.
Table 3.7.
Table 3.8.
Table 3.9.
Table 3.10.
Table 3.11.

LIST OF TABLES

Parameters for Calculating the 130 NMR Chemical Shifts
of Alkanes Using Empirical Additivity Relationships ........... 9

Influence of Chiral Centers on the Chemical Shift Tensor... 26

Next-nearest Neighbor Effects ...................................... 28
The 32 Possible Hexads ............................................. 35
Hexads Synthesized ................................................... 42
Summary of Hexad Methine Shifts ................................. 50
Corrective Factors ...................................................... 51
Calculated Methine 13C Chemical Shifts .......................... 52

Deviations in Calculation of Chemical the Shifts of Hexads. 53
Yield and 1H-NMR Data for Hydroxy-terminated Diad ......... 66
Yields and 1H-NMR Data for Hydroxy-terminated Triads..... 66
Yields and 1H-NMR Data for Hydroxy-tenninated Tetrads... 67
Yields and 1H-NMR Data for Hydroxy-terminated Pentads.. 68
Yields and 1H-NMR Data for Hydroxy-terminated Hexads... 7O
Yields and 1H-NMR Data for Benzyl-terrninated Diads ....... 73
Yields and 1H-NMR Data for Benzyl-terminated Triads ...... 73
Yields and 1H-NMR Data for Benzyl-terminated Tetrads ..... 74
Yields and 1H-NMR Data for Benzyl-terminated Pentads.... 75
Yields and 1H-NMR Data for Benzyl-terminated Hexads ..... 77

Yield and 13C-NMR Data for (S)-Acetoxypropanoic Acid
Methyl Ester ............................................................. 80

Table 3.12.

Table 3.13.

Table 3.14.

Table 3.15.

Table 3.1 6.

Yields and ‘H- and 13C-NMR Data for Acetoxy-terminated
Diads ......................................................................

Yield and 1H- and 13C-NMR Data for the Acetoxy-
terrninated Triad ........................................................

Yields and 1H- and 13C-NMR Data for Acetoxy-terminated
Tetrads ....................................................................

Yields and 1H- and 13C-NMR Data for Acetoxy—terminated
Pentads ...................................................................

Yields and 1H- and 13C-NMR Data for Acetoxy-tenninated
Hexads ....................................................................

vi

79

79

8O

81

83

Figure 1.1.
Figure 1.2.
Figure 1.3.
Figure 1.4.

Figure 1.5.

Figure 1.6.

Figure 1.7.

Figure 1.8.

Figure 1.9.

Figure 1.10.

Figure 1.11.

Figure 1.12.

LIST OF FIGURES

Stereochemical configuration of polymers ........................ 3
Bemoullian addition .................................................... 4
First order Markov addition ........................................... 5

An illustration of (a) head to tail junctions and (b) tail-to-tail
(T-T) and head-to-head (H-H) junctions in polypropylene... 7

Geometrical isomerism in polybutadiene. 1,4-enchainment
can be either (a) cis (Z) or (b) trans (E). 1,2-enchainment
can occur in an (0) isotactic or (d) syndiotactic sequence...

Comparison of the 25 MHz 130 NMR of (a) isotactic; (b)
atactic; and (c) syndiotactic polypropylene ....................... 12

Comparison of the 100 MHz 1SC NMR spectrum of
regioirregular polypropylene with the chemical shifts
calculated for a variety of microstructures ........................ 13

Methyl resonances from the 100 MHz 1H NMR spectra of
polymer from 60% L-lactide with 40% rao-lactide; polymer
from 28% L-Iactide with 72% rac-lactide .......................... 15

Methine resonances from the 100 MHz 1H-NMR spectra of
poly(L-lactide); (b) polymer from 28% L-lactide and 72%
rao-Iactide ................................................................ 17

1H NMR (homodecoupled C-H signal) of co-poly(D,L-

lactide)s prepared from mesa D,L-lactide and L-lactide with
SM") octoate: (a) poly(Dso. L50); (b) PO'YID40.L60);

pOIY(Dzo,L30); (d) poly(L-lactide) .................................... 20

13C NMR (CH group) of co-poly(D,L-Lactide)s prepared
from rao-lactide with Sn(l|) octoate (a) poly(Dso, L50); (b)
poly(D4o, L60); (c) poly(Dzo, L80) ..................................... 21

Methine resonances in the 130 NMR spectra of

poly(lactide) samples (a) poly(lactide) from 3% L-Iactide,

3% D-lactide, 94% meso-lactide;(b) poly(lactide) from

51.5% L-lactide, 1.5% D-lactide, 47% meso-Iactide; (c)
poly(lactide) from 70.9% L-Iactide, 0.99% D-lactide, 47%
meso-lactide ............................................................. 22

vii

Figure 1.13.

Figure 1.14.
Figure 1.15.

Figure 1.16.
Figure 1.17.

Figure 2.1.

Figure 2.2.
Figure 2.3.
Figure 2.4.

Figure 2.5.
Figure 2.6.

Figure 2.7.
Figure 2.8.
Figure 2.9.

Figure 2.10.
Figure 2.11.

Methine resonances in the homonuclear decoupled 1H
NMR spectra of poly(lactide) samples (a) poly(Dso, L50-
lactide); poly(Dso, L40-lactide); and (c) pOIY(D7o, Lgo-Iactide).

HETCOR spectrum of poly(meso-lactide) ......................

Tetrad assignments for poly(rao-lactide) and poly(meso-
lactide) based on the HETCOR spectra as proposed by
Chisholm ..................................................................

isii and isis pentads ....................................................
HETCOR spectrum of atactic poly(lactide) .......................

An example of synthetic methodology used to synthesize
hexads .....................................................................

Comparison of methine regions of is and iis n-ads ............

hexads .....................................................................
Comparison of the isiii, isisi, isiss hexad methine regions...

Comparison of the methine regions of ssiii, sssii, sssss
hexads .....................................................................

isiii hexad ..................................................................
HMBC of iissi hexad ...................................................
Expansion of iissi hexad HMBC ....................................
HMQC of iissi hexad ...................................................

Expansion of iissi HMQC .............................................

viii

23

24

25

26
30

4O

43
45

46

47

48
49
56
57
58
59

Scheme 1.1.

Scheme 1.2.

Scheme 1.3

Scheme 2.1.
Scheme 2.2.
Scheme 2.3.

LIST OF SCHEMES

Lacfides .................................................................. 2
Polypropylene and poly(propylene oxide) ....................... 6
Poly(propylene oxide) and poly(lactide) ........................ 27
Synthetic route to poly(lactide) hexads ........................... 34
Methanolysis of L-lactide ............................................. 36
Protecting groups tried ................................................ 37

ix

COSY
DCC
DCU
DEPT
DMAP

EDC

HETCOR
HMBC
HMQC

INADEQUATE

NOE
NOESY
TBDMS
TMS
TMSCI

TrCl

ABBREVIATIONS
Correlated Spectroscopy
Dicyclohexylcarbodiimide
Dicyclohexyl Urea
Distortionless Enhancement by Polarization Transfer
N, N-dimethylaminopyridine

1-(3-DimethylaminopropyI)-3-ethylcarbodiimide
hydrochloride

Heteronuclear Chemical Shift Correlation
Heteronuclear Multiple Bond Correlation
Heteronuclear Multiple-Quantum Coherence

Incredible Natural Abundance Double Quantum Transfer
Experiment

Nuclear Overhauser Effect

Nuclear Overhauser Effect Spectroscopy
Tetrabutyldimethylsilyl

Trimethylsilyl

Trimethylsilyl Chloride

Tritylchloride

1 . Introduction

Recent advances in the fermentation of glucose and improvements in
synthesis and processing have positioned polylactide as a “green” altemative to
petroleum-based plastics. In addition to having good mechanical properties and
the processability needed for applications such as fibers and packaging
materials, polylactides offer two important advantages over materials derived
from petroleum. The monomer is derived from the fermentation of starch, a
renewable material, and the polymer degrades to lactic acid, an environmentally
benign product. Cost is the main constraint for widespread use of biodegradable

materials in packaging. Petroleum-based polymers, such as polyethylene, cost

about $0.16/pound,1 whereas polylactide is projected to be priced between $0.50
and $0.75/pound.

Historically, polylactide was produced for use in medical applications to
take advantage of its biocompatibility. Polylactide is non-toxic and degrades in
vivo to benign products. Polylactide and other biodegradable polymers have
been used since the 19605 as resorbable synthetic sutures because they can be
processed to give strong filaments that degrade rapidly. Degradable polymers
also have important time-release applications in medicine as well as in the
veterinary and agrochemical fields. Active ingredients ranging from pesticides to
contraceptives can be delivered by sustained release from polylactide followed
by the ultimate biodegradation of the carrier medium.

Lactic acid has one chiral center, and thus there are three different cyclic

dimers of lactic acid. Tenned Iactides, L-lactide and D-lactide are enantiomers

and contain lactic acid residues with 8,8 and R,R stereochemistry respectively,
while D,L-lactide, often termed meso-Iactide, has R,S stereochemistry (Scheme

1.1). A 1:1 mixture of L-and D-lactide is termed racemic or rac-lactide.

O O O
OJK‘_.~“ OJJY Ck
\\"'|\n/O \“‘.‘\n/0 N0
O O

O
L-Lactide meso-Lactide D-Lactide
Scheme 1.1. Lactides

In polymers, the stereochemical configuration refers to the relative
handedness of successive monomer units. Taticity in polymers refers only to the
relative configurations of the stereocenters (e.g. R or S) along the polymer chain
and are not related to the physical (up or down) orientations of the groups with
respect to the polymer chain (Figure 1.1). Atactic polymers have a completely
random sequence of stereocenters, syndiotactic polymers have perfectly
alternating stereocenters, and isotactic polymers have identical stereocenters. A
configurational sequence of two chiral centers is termed a diad, three chiral
centers a triad, four centers a tetrad, and so on.

The regularity of the arrangement of the stereocenters in the polylactide
chain strongly influences the properties of polymers. A random arrangement of
stereocenters results in amorphous polylactide with a T9 near 60 °C, while
crystalline polylactides are obtained when the stereocenters are arranged in a
regular pattern, as is found in chains where the stereocenters are identical

(isotactic), or alternate (syndiotatic). Stereoregular polylactide has a Tm near 180

°C, but incorporation of rac-lactide in crystalline polylactide inhibits crystallization

. . . 2
and leads to a rapid decrease In tenSIIe strength and degradation rate.
Therefore, full characterization of a polymer requires an analytical method for

determining its microstructure.

iiiiifi ‘TZLZEI‘ iii—i

isotactic syndiotactic atactic

Figure 1.1. Stereochemical configuration of polymers.

1.1 Propagation Mechanisms and Models

The microstructure of polymer chains depends on the mechanism that
governs the growth of the polymer. If the propagation mechanism is known, then
a partial assignment of the resonances may be obtained by comparing the
observed NMR intensities with those calculated from propagation models.
Conversely, the propagation mechanism can be extracted by assigning the
resonances and comparing the peak intensities with those predicted by

propagation models.

There are several simple models for the propagation of polymer chains,3 with
each differing in how the existing microstructure of a growing chain influences the
addition of the next monomer unit to the chain. The Bemoulli, or zero-order
Markov model, assumes that each monomer addition is a random occurrence,

and is insensitive to previous monomer addition reactions (Figure 1.2).

l Pl I

I —’ ll

%_Ps. i.?.I
' l'l'd

For a stereosequence of length n, Bemoullian addition leads to 2

+Ii<

 

Figure 1.2. Bemoullian addition.

V”) possible

combinations of pairwise relationships that can be observed in NMR spectra. For
example there are 22:4 possible combinations for triads, 23:8 possible
combinations for tetrads and so on. Stereosensitivity to triads, tetrads, and
pentads should give rise to 4, 8, and 16 components in the NMR spectra,
respectively, for the case of Bemoullian addition of monomers to a growing chain
end. In polylactide, where each monomer contains two stereocenters,
Bemoullian pair-wise addition leads to patterns with 3, 5, and 7 lines,
respectively.

Higher order Markov models assume that the end of a growing chain
influences the addition of the monomer unit. In the first order Markov model, only
the last monomer added influences addition of the next monomer unit, while the
second-order Markov model considers the relative configuration of the last three

psuedoasymmetric centers of the growing polymer chain (Figure 1.3).3

:0

——O

—{>

ti<ii

ii ..
i<a£t

Figure 1.3. First order Markov addition.

 

I
Q: :0
‘IO :0 :0
o— —4> o—

Experimentally, it has been found that most propagating species that deviate
from Bemoullian statistics have a “block-like” configuration to varying degrees.
This behavior is especially common in ionic polymerizations. Coleman and Fox
proposed that “block” configurations are generated in ionic polymerizations
because the propagating chain end may exist in two (or possibly more) states,
corresponding to chelation by the counter ion and interruption of this chelation by

solvation. The Coleman-Fox model disregards any influence of the chain-end

stereochemistry on the mode of addition of the next monomer unit.3

A polymer can be shown to be consistent or inconsistent with a given model

at a given level of sequence discnmination. From dyad Information alone, any
mechanism can be fitted but none can be tested. Using triad information, a
Bernoulli model can be tested and Markov models of any order can be fitted.

First-order Markov models can be tested using tetrad information, and higher

orders fitted. These statements can be extended to longer sequences. There
are some limitations to the testing process. Various propagation models often
predict approximately equal amounts of two or more stereosequences and often
the models cannot be distinguished on the basis of intensity alone. In addition,
the intensities of some of the peaks can be very small and difficult to observe in
spectra. Therefore, a complete and unambiguous assignment of resonances

cannot be done by this method alone.

1.2 Microstructure of Polymers
The microstructure of a polymer refers to those features of polymer chains
which are fixed by their covalent structure, and is generally understood to include

regioisomerism, stereochemical configuration, geometrical isomerism, branching

. . 3
and cross-linking. In the NMR spectra of polymers, peaks that correspond to the
different microstructures can be resolved, providing a detailed and quantitative
characterization of chain microstructure. Polymers such as polypropylene or

poly(propylene oxide) (Scheme 1.2) exhibit NMR resonances

W View

Polypropylene Poly(propylene oxide)
Scheme 1.2. Polypropylene and poly(propylene oxide)
due to regioisomerism, as well as stereochemical configuration. In these
polymers, the incoming monomer unit can add to the growing polymer chain in a

head-to-tail, head-to-head, or tail-to-tail orientation as shown in Figure 1.4. The

additional resonances due to regioisomerism greatly complicate the 1H NMR
spectrum. 13C NMR generally offers the potential for greater spectroscopic

resolution and is better suited for the analysis of polymer microstructure.

(a)

 

 

 

 

 

 

A A A A A
----———CH2——CH2——CH2——CH2 CH2—----
B B B B B
a» .12: as;
A A A A A
- - - - CH2 CH2CH2 I I CH2 CH2 - - - -
B B B B B
W—J
Inverted Unit

Figure 1.4. An illustration of (a) head to tail junctions and (b) tail-to-tail (T-T)
and head-to-head (H-H) junctions in polypropylene.

The polymerization of diene monomers can produce structures having
combinations of geometrical and stereochemical isomerism. 1,4-enchainment of
polybutadiene can be either cis (Z) or trans (E) as shown in Figure 1.5. The 1,2-
structures occur in isotactic or syndiotactic sequences.

Assigning the microstructures of polymers can be challenging. Comparing
polymer spectra with those of model compounds or model polymers was one of
the first methods used to establish NMR assignments. This approach has been
very effective, but requires the precise synthesis and isolation of many

compounds. Empirical chemical shift rules have been devised to identify peaks

based on the correlation between the expected chemical shift and peak

intensities.
H H H CH2
CH2 :CH2 CH2 H n
n
(a) (b)
CHg’Cf—CHZICI—‘CHz CHZIC—CHZIQ—CHZ

l ’l l ’H l "I, I 9
CH H 9H n H ’"CH CH H n

CH2 CH2 CH2 CH2
(c) (9)

Figure 1.5. Geometrical isomerism in polybutadiene. 1,4-enchainment can be either
(a) cis (Z) or (b) trans (E). 1,2-enchainment can occur in an (c) isotactic or (d)
syndiotactic sequence.

1.3 Empirical Chemical Shift Rules

The chemical shifts of carbon nuclei are sensitive to their neighboring
substituents. Carbon substituents on and B to an observed carbon nucleus
produce comparable deshielding (~9 ppm), relative to an unsubstituted carbon.4
The y substituents shield the carbon nucleus with a magnitude that depends on
the distance between the observed carbon and the y substituent. Unlike the a
and B effects, the y-effect is a shielding effect and dependant on molecular
confonnation.5 The determination of polymer microstructure has been facilitated
by comparing the calculated chemical shifts to those of the polymer.

For those structures in which large differences in chemical shift are

expected, it is possible to compare the observed chemical shifts with those

calculated on the basis of empirical rules established in small molecules. An

example of such a model was developed by Breitmaier for the calculation of
chemical shifts in saturated hydrocarbons.6 The chemical shift, 5c, is given by:
5C=B+2Alm+£ S, (1 )

where B is the chemical shift of methane (-2.3 ppm), n, is the number of carbons
at position [away from the carbon of interest, A, is the additive shift due to carbon
1, and S, is a term included to account for branching. The shift parameters A, are
given in Table 1.1 for the a to e carbons. It is interesting to note that although the
7 carbon is far from the carbon of interest, it still has an effect on the chemical

shift. Application of this method can be illustrated by calculating the carbon

chemical shift for the third carbon in 2-methyl hexane.‘S

TABLE 1.1. Parameters For Calculating the 13C(SNMR Chemical Shifts of
Alkanes Using Empirical Additivity Relationships

 

 

Carbon Position A. (i010 ppm)
or 9.1
B 9.4
y -2.5
6 0.3
e 0.1

 

 

 

 

CH3—CH—CH2—CH2—CH2—CH3

CH3
2-Methylhexane
This carbon has two a, three [3, and one y neighbor, and is a 2° carbon next to a
3° carbon (which contributes a corrective factor of .—2.5), so the chemical shift
calculated from Table 1.1 is:
66 = B+ 2A0, + 3A3 + A, + S[2°(3°)]
=-2.3 + 18.2 + 28.2 - 2.5 —2.5
=39.1,
which may be compared with the observed value of 39.45 ppm. The idea of using

a mathematical model to predict chemical shifts will be very useful in predicting

the chemical shifts of polylactide.

1 .4 Microstructure of Polypropylene

The aforementioned methods have been used to establish the regioisomer

assignments in polypropylene.3 Since polypropylene’s chemical structure is
analogous to polylactide, techniques used to determine the microstructure of
polypropylene can be extended to polylactide. Polypropylene is a commercially
important material, and its synthesis by some synthetic routes is known to
produce polymers that contain regiodefects. Since the properties of the polymer
depend on the distribution and nature of the defects, it is important to know how

those defects may arise. Assigning the 13C NMR resonances in polypropylene is

10

hampered by the overlap of many signals in the methine and methylene region
as well as the possibility of stereochemical isomerism and regioisomerism.

A simple way to assign the resonances in the NMR of atactic
polypropylene is to compare the NMR spectra of regioregular polypropylene to
that of regioirregular polypropylene (Figure 1.6). A sample of isotactic
polypropylene has a relatively simple 13C NMR, with only three resonances, one
for each type of carbon. Syndiotactic polypropylene has a slightly more
complicated spectrum. The spectrum of atactic polypropylene can be compared
to those from the isotactic and syndiotactic samples, and resonances in the
atactic sample can be assigned accordingly. However, this method is limited
because only a small number of resonances can be assigned. Several other
methods were used to assign the remaining resonances.

In an early example, Zambelli et al. used heptamethyl heptadecane model

compounds labeled at the 9 position to assign the resonances in the

7
polypropylene Spectrum. Based on empirical observations, a mathematical
model like the one developed by Breitmaier was devised to assign the
resonances in polypropylene. This model incorporated calculations for a variety

of microstructures. Figure 1.7 shows the complete assignment of the

resonances in the 100 MHz ‘30 spectrum.8

Because of the complexity of the one-dimensional spectrum, two-
dimensional NMR has been used to further identify the resonances of
polypropylene. Several two-dimensional experiments are particularly useful for

defining polymer structure. A COSY spectrum (a two dimensional spectrum that

11

correlates hydrogens on adjacently bonded carbons) proved insufficient for
making a complete assignment of the polypropylene spectrum because the
resonances were too close together to provide meaningful data. However, the

130 NMR spectrum was less complicated.

 

.
CH2 i CH3

I CH
——CH—CH2— CH 3

 

 

(a) lsotactic

 

 

(b) Atactic

(c) Syndiotactic

_ _ 4L LL.

1 I l
40 30 20

pmm vs. TMS

Figure 1.6. Comparison of the 25-MHz 13C NMR of (a) isotactic; (b) atactic;
(c) syndiotactic polypropylene. Reprinted with permission. 9

 

 

 

 

 

 

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A two-dimensional INADEQUATE experiment (correlates directly bonded
carbon atoms) was used to make the final assignments. The sensitivity of the
INADEQUATE spectrum is greatly reduced because the odds of having two 13C
atoms adjacent to each other is about 10,000 times less than for protons. In
spite of these difficulties, it was possible to trace the chain connectivities and

assign the resonances in polypropylene.

1.5 Microstructure of Poly(propylene oxide)

Poly(propylene oxide) is another polymer that has been extensively
analyzed by ”C NMR, in terms of both its stereochemistry9 and its

regioisomerism.1O Poly(propylene oxide) is a better analog to polylactide than
polypropylene since poly(propylene oxide) has an oxygen in the main chain. The

assignments for poly(propylene oxide) have been made primarily on the basis of

chemical shift calculations and DEPT NMR spectra.10

1.6 Microstructure of Poly(lactide)
The microstructure of polylactide has been studied intensively in recent

years. In 1975, Lillie and Schulz proposed that the 1H and 13C NMR spectra of

. . . . 11 ,
polylactide were senSItIve up to the triad level. Various copolymers were
prepared by varying the feed ratios of L- and rac-lactide in bulk polymerizations
catalyzed by zinc dust. Lillie and Schulz observed that the relative intensities of

NMR resonances decreased or increased depending on the feed ratio of L- and

14

rac-lactide (Figures 1.8 and 1.9). Due to significant overlap of the peaks, they

were unable to conclusively assign the resonances.

Following Lillie and Schultz’s report, Schindler and Harper12 concluded
that the 1H NMR spectra of polymers obtained from rac-lactide and tin initiators
such as SnCl4, ShCIz, stannous octoate, or tetraphenyl tin could be interpreted by
applying Bemoullian polymerization statistics, and did not reflect the feed ratio of
L-Iactide to rac-lactide. They further proposed that frequency of
transesterification reactions during polymerization was too low for NMR to detect
the additional stereosequences that would be produced by transesterification. In
contrast, Chabot and co-workers reported that transesterification was significant

when they used zinc dust to polymerize various mixtures of L- and rac-lactide in

bulk.13 They found that the best fit of the experimental and calculated intensities
of the carbonyl peaks in the 13C NMR was obtained by assuming pentad
sensitivity instead of triad sensitivity as proposed by Lillie and Schultz. The
polymerization of rao-lactide should result in only seven unique pentads, and
thus the carbonyl region of the 13C NMR could show up to seven resonances.
Through the use of resonance enhancement techniques, they observed more
than seven lines in the carbonyl region, consistent with Significant
transesterification. Chabot and co-workers were unable to confirm the
mechanism of the transesterification events, but proposed that the attack at the
ester bonds in the polymer chain by active chain ends might contribute to the

configurational rearrangements.

15

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

l l l

1.621.59 1.551.52
8 in ppm

Figure 1.8. Methyl resonances from the 100 MHz 1H NMR spectra
of (a) polymer from 60% L-lactide with 40% rac-lactide; (b) polymer
from 28% L-lactide with 72% rac-lactide. Reprinted with

permission.11

16

 

 

 

 

l

I I J
5.20 5.13 5.06 4.99
5 in ppm
Figure 1.9. Methine resonances from the 100 MHz 1H-NMR spectra of (a)

poly(L-lactide); (b) polymer from 28% L-lactide and 72% rac-lactide. Reprinted
with permission 2.

17

In a systematic study, Kricheldorf and co-workers improved upon the
previous sequence assignments by comparing polymers obtained from the

polymerization of rac- and meso-lactide with two tin initiators under identical

reaction conditions.14 Tributyltin methoxide (BugsnOMe) was known to catalyze

transesterification during the polymerization of L-Iactide and various lactones at

moderate temperatures.14 However, Sn(ll) octoate gave high molecular weight
polylactides without racemization. They also evaluated the influence of the
reaction time and temperature on the stereochemical course of the
polymerizations.

Kricheldorf and co-workers considered more information when proposing
their assignments of the NMR spectra.14 They compared poly(D,L-lactide)s
9 prepared from reo- and meso-lactide in the absence of transesterification and
racemization of monomers or monomeric units. Polymerization at high
temperatures (eg. 180 °C) provided perfectly random stereosequences due to
rapid transesterification. Copolylactides prepared by copolymerization of L-
lactide with rac-Iactide also were studied. They found that both the 1H and 130
NMR methine signals of various mixtures of poly(D,L-Iactides) displayed five

peaks, indicating at least tetrad level sensitivity for both signals (Figures 1.10 and

i4 . . . . .
1.11). Bemoullian statistics were used to aSSIgn the possrble stereosequences,
disregarding transesterification.

The assignments made by Kricheldorf were accepted as the correct

assignments until Thakur and co-workers disclosed15 that the‘aC and 1H NMR

spectra of polylactide were sensitive to the hexad level. Assignments at the

18

hexad level were made using homonuculear decoupling and high resolution NMR

spectroscopy techniques15 (Figures 1.12 and 1.13), in conjunction with the trends
seen in the spectra with changes in the feed composition.

A debate concerning the NMR assignments arose when Chisholm and co-

workers16 contradicted the assignments proposed by Kricheldorf. Chisholm and
co-workers used HETCOR to correlate the homodecoupled methine protons with
the methine carbons of homodecoupled poly(rao-lactide) and poly(meso-lactide).
Their HETCOR spectrum (Figure 1.14) of poly(meso—Iactide) showed that a
resonance previously assigned to the isi tetrad in either the 1H- or 13C--NMR
spectrum clearly correlates with two resonances in the spectrum of the other
nucleus. They proposed an alternative assignment of the ‘30 and 1H NMR
spectra (Figure 1.15) even though their new assignments did not conform to

Bemoullian statistics.

19

ssi, iss

sss, ISI, ssi, iss

    

sis ssi/iss

    

 

 

 

 

T I T r I I j
5.25 5.20 5.15 5.25 5.20 5.15
III
525 5'20 5'15 _ 5725 5'20 5'15
5 (ppm)

Figure 1.10. 1H NMR (homodecoupled C-H signal) of ca-poly-(D,L-lactide)s
prepared from mesa D,L-lactide and L-lactide with Sn(ll) octoate: (a) poly(Dso;
L50); (b) poly(D4o,L50); (c) pOIY(Dzo,L30); (d) poly(L-lactide). Reprinted with
permission.1

20

a
sss _ b
SSI/ISS

  
 
 
   
 

iSi sis

iss/ssi

C III, IIs, Sii, sis

 

I I
70 69

Figure 1.11.130 NMR (CH group) of ca-poly(D,L-Lactide)s prepared from
rao-lactide with Sn(ll) octoate (a) poly(Dso, L50); (b) poly(D4o, L60); (c) poly(Dzo,
Leo)- Reprinted with permission.

21

isslssi sss isi isslssi sis

 

 

 

 

 

  

sssss

a

sisss/

sssis

isslssi sss isi isslssi
b

isslssi sss iSi isslssi
C

iissi/ :53?

issii

  

 

69.4 69.2 69.0
ppm

Figure 1.12. Methine resonances in the 13C NMR spectra of poly(lactide)
samples (a) poly(lactide) from 3% L-lactide, 3% D-lactide, 94% mesa-
lactide;(b) poly(lactide) from 51.5% L-lactide, 1.5% D-Iactide, 47% meso-
Iactide; (c) poly(lactide) from 70.9% L-Iactide, 0.99% D-Iactide, 47% mesa-
Iactide. Reprinted with permission.15

22

 

 

b . . . isi
ISISI

n iiisi/

isiii iiisi/

isiii

 

 

 

 

.4.

 

 

_5.250 ' 5.225 ' 5.200 ' 5.175 ' 5.150
ppm

Figure 1.13. Methine resonances in the homonuclear decoupled 1H NMR
spectra of poly(lactide) samples (a) poly(Dso, Lso-lactide); (b) poly(Dso, L40-
lactide); (c) poly(Dyo, Lao-lactide). Reprinted with permission. 6

23

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24

Iii, isi, iis/sii
sss

 

 

 

 

(a) (b) ssi/Iss
ISI
sii/"s. sis isi/SS, is Figure 1.15. Tetrad assignments for
1 HI poly(rac-lactide) and poly(mesa-lactide)
. t I . based on the HETCOR spectra as
59.5 59.0 595 ego proposed by Chisholm. Reprinted with
. . . permission.16
sss, ISI, SSI/Iss
(C) "' (d)

isi
iis/sii
sli/ Iis

sis H I
I r 7 r

5.10 5.05 5.00 5.10 5.05 5.00

sis, isslssi

 

 

 

Thakur and co-workers17 suggested that the influence of the chiral centers
adjoining the center unit of the pentad were different for 1H NMR and ”C NMR,
thus causing the discrepancy found in HETCOR as described by Chisholm.
Thakur proposed that the polylactide microstructure influences the 1H NMR and
”C NMR chemical shift tensors differently (Table 1.2). For example, in the
stereosequence —RRSSS- (Figure 1.16), represented by isii, the chirality of the
center unit is S. In 13C NMR the chemical Shift tensor of this stereocenter would
be affected by the two chiral centers to the left and one stereocenter to the right,
which leads to tetrad sii. However, in the 1H NMR, the same stereocenter would
be affected by one chiral center to the left and two chiral centers to the right
which leads to tetrad sis. Therefore, the sii resonance in the ”C NMR spectrum
should have a cross-peak with the sis resonance in the 1H NMR spectrum. The

isi tetrad is also found in the pentad isis (Figure 1.16). If the chemical shift

25

tensors for the central chiral center are rationalized as described above, there will
be a cross-peak between the sis tetrad and the isi tetrad. Therefore in the
HETCOR spectrum of poly(mesa-Iactide), the isi tetrad in the 1H NMR will have a

cross peak in the ”C NMR with both the sis and sii tetrads (Figure 1.14).

g o o 3 o o
a ofiOkOT/SLOJSO R Oil/'FiOJVfoil/S'Ok'fo
o 5 o i o n o 5 o o "

isli Isis

Figure 1.16. isii and isis pentads.

Table 1.2. Influence of Chiral Centers on the Chemical Shift Tensor

 

Influence of Tetrad Tetrad

Chiral Centers from isii from isis

 

 

1 Left .. .
2 Left . _ . .
1H NMR 1 Right ISI ISI

 

 

 

 

 

 

In questioning the validity of Thakur and co-workers assumption of chemical
shift tensors propagating in opposite directions,18 Chisholm noted that that this

phenomenon is rare and only was reported by Bovey and co-workers3 in their
study of atatic poly(propylene oxide). However, the structures of poly(propylene)

and poly(lactide) are indeed quite similar (Scheme 1.3), and drawing an analogy

26

between Bovey’s findings on poly(propylene oxide) and poly(lactide) case is

reasonable.

0 o
‘1’ r0 \I/Vn 1” O n
Poly(propylene oxide) Poly(lactide)

Scheme 1.3 Poly(propylene oxide) and poly(lactide)

Chisholm suggested an alternative explanation, that the observed spectral

evidence can be explained in terms of next nearest neighbor effects (Table

1.3).18 They proposed that the observed HETCOR spectra can be explained in
terms of triad and pentad sensitivity and not tetrad or hexad sensitivity. They
proposed that stereosequences ii and $3 would show unique triad resonances,
whereas heterotactic sequences is and si could be split by neighboring effects to
yield resonances that correlate with pentad sensitivity. Thus the is triad would
give rise to iisi, iiss, siss, and sisi pentads. The iisi and sisi pentads could come
from poly(raa-Iactide),while the siss and sisi pentads could arise from poly(meso-

lactide). Pentad iiss can only come from atactic polylactide.

27

Table 1.3. Next-Nearest Neighbor Effects

 

 

 

 

 

 

 

 

 

 

Possible Triads Pentad Origin
RRR Not affected rac-lactide
I 35 RSR Not affected mesa-Iactide
WW
is HRS iiss RRRSR ‘ atactic
siss RSSRS mesa-lactide
sisi RSSRR mesa- or rao-lactide
si R S S ssii RSRRR atactic
isis RRSSR rac-Iactide
isii RRSSS rac-lactide

 

 

 

 

 

 

 

The HETCOR spectra (Fig. 1.17) of atatic poly(lactide) should show all
possible pentad sequences and at least one should produce a new cross peak
due to the pentads (iiss and ssii) from atactic polylactide. Chisholm and co-
workers felt the appearance of a new peak in the HETCOR spectra (Figure 1.17)
supported their hypothesis and discredited the hypothesis of Thakur and co-
workers.

The application of the Bernoulli model to describe the propagation of the
polymer chain has been questioned by Kasperczyk, Thakur and others. In his
study of the lithium tert-butoxide initiated polymerization of raa-lactide, Kasperzyk

noted that the NMR intensities from the syndiotactic sequences were higher than

would be expected for Bemoullian addition.19 Thakur found that when Sn(ll)

28

octoate was used as the initiator, the stereospecificity of Iactide polymerization

changed over time.20

NMR study of polylactide model compounds may conclusively determine
the chemical shifts of the different microstructure of polylactide. Due to the
connectivity of Iactide, the polymer cannot have regio- or geometrical isomers,
and thus the NMR spectrum will only Show resonances due to stereoisomers.
Polylactide hexads with known stereochemistry were synthesized using an
iterative procedure. Each hexad had unique ”C and 1H NMR spectra, that were
assigned based on trends in the spectra as well as comparison to the spectra of
smaller oligomers. A method similar to the empirical chemical shift relationships
used to assign the chemical shifts of poly(propylene) and poly(propylene oxide),

was developed from analysis of the NMR spectra of poly(lactide) hexads.

29

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328368528
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30

References

1.

Bozell, J. J. Chemicals and Materials from Renewable Resources; American
Chemical Society: Washington DC.

Vert, M. Macromolecular Biamaterials, CRC Press:, 1986.

Bovey, F. A.; Mirau, P. A. NMR of Polymers; 2 ed.; Academic Press, Inc.: San

Diego, CA, 1996.

Stehling, F. C.; Knox, J. R. Macramalecules1975, 8, 595-603.
Grant, D. M.; Cheney, B. V. J. Am. Chem. Soc. 1967, 89, 5315.

Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy; 3 ed.; Weinheim:,
1987.

Zambelli, A.; Locatelli, P.; Bajo, G.; Bovey, F. A. Macromolecules 1975, 8,
687.

Asakura, T.; Nakayamma, N.; M.Demura; Asano, A. Macromolecules 1992,
25, 4876.

9. Tonelli, A.; Schilling, F. Acc. Chem. Res. 1981, 14, 233.

10.
11.
12.
13.
14.

15.

16.

17.

18.

Shilling, F. C.; Tonelli, A. E. Macromolecules 1986, 19, 1337.

Lillie, E.; Schulz, R. C. Die Makramlekulare Chemie1975, 176, 190-1906.
Schindler, A.; Harper, D. Polymer Letters 1976, 14, 729-734.

Chabot, F.; Vert, M.; Chapelle, S.; Granger, P. Palymer1983, 24, 53-59.

Kricheldorf, H. R.; Boettcher, C.; Tonnes, K.-U. Polymer 1992, 33, 2817-
2824.

Thakur, K. A. M.; Kean, R. T.; Hall, E. S.; Kolstad, J. J.; Lindgren, T. A.
Macromolecules 1997, 30, 2422-2428.

Chisholm, M. H.; lyer, S. S.; Matison, M. E.; McCollum, D. G.; Pagel, M.
Chemical Communications 1997, 1999-2000.

Thakur, K. A. M.; Kean, R. T.; Zell, M. T.; Padden, B. E.; Munson, E. J.
Chemical Communications 1998, 1 91 3-1 914.

Chisholm, M. H.; lyer, S. 8.; McCollum, D. G.; Pagel, M.; Wemer-Zwanziger,
U. Macromolecules 1999, 32, 963-973.

31

19. Bero, M.; Dobrzynski, P.; Kasperczyk, J. Journal of Polymer Science: Part A:
Polymer Chemistry 1999, 37, 4308-4042.

20. Thakur, K. A. M.; Kean, R. T.; Hall, E. S.; Kolstad, J. J.; Munson, E.
Macromolecules 1998, 31, 1487-1494.

32

2. Discussion

The notion of studying low molecular weight model compounds to better
understand the properties of polymers is a well-established strategy, especially
for clarifying the stereochemical relationships in polymers. Since Thakur and

Kricheldorf assigned the 1H and ”C NMR of poly(lactide) to the hexad level (six

repeating units),"2 compounds that contain six lactic acid residues should be
good model compounds for poly(lactide). Hexads were synthesized using an
iterative procedure so that the exact stereosequence of each hexad would be
known. Ideally, the 1H and ”C NMR spectra for each hexad would be identical to
the same hexad embedded in the poly(lactide) chain. However, the hexads are
short linear compounds, and thus the chain ends have a large effect on the
chemical shift of each carbon atom in the hexad. The magnitude of the “end
effect” on the chemical shift of each lactic acid residue in the hexad can be
estimated by comparing the chemical shifts of the all-isotactic hexad with the
spectrum of poly(L-lactide).

There are 32 possible hexads (Table 2.1), and since the isotactic and
syndiotactic relationships in polymers are based on the relative stereochemistry
of the chain, only one enantiomer of each hexad must be synthesized to
establish the stereochemical assignments. The synthesis of the hexads used an
iterative series of esterification reactions (Scheme 2.1) to grow the hexad from an
anchoring block. Initially, the commercially available and inexpensive S-
ethyllactate was evaluated as the anchoring block for each hexad. However, the

chemical shift of the methylene hydrogens of the ethyl ester group was similar to

33

that of the lactic acid methine proton, which could complicate the process of
making NMR assignments for the hexads. Since the spectrum of the methyl
ester of 8-Iactic acid shows less interference, the strategy was modified to use 8-
Iactic acid methyl ester as the anchor for each hexad. S-methyl lactate was
obtained in 93% yield from the HCI-catalyzed methanolysis of L-lactide (Scheme
2.2). Running the reaction in the absence of HCI gave the methyl ester of the 8,8
dimer in 96% yield, a particularly useful anchor block for the synthesis of hexads

that start with an 8.8 sequence.

 

POW/”OH HOj/iOM: '30ka /l\n/0Me DeprotectionI HOVKO/k'rOMe

Esterification

PO
D 1 t H
\HLOH POW/K0 ”fir 0:10,“ eproeCIon> oj/ILO Jfiro \l/lkOMe

Esterification T

Re eat
CH3C02H ° 0 °
3 A°°\'(u\o . Ooj/Iko , Haj/KO OMe
Esterification
O O 0

Scheme 2.1. Synthetic route to poly(lactide) hexads.

 

 

 

34

Table 2.1. The 32 possible Hexads

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tacticity Hexad Enantiomer Tacticity Hexad Enantiomer
issss SSRSRS RRSRSR ssiii SRSSSS RSRRRR
sisss SRRSRS RSSRSR iissi SSSRSS RRRSRR
ssiss SRSSRS RSRRSR isiss RRSSRS SSRRSR
sssis SRSRRS RSRSSR sisis RSSRRS SRRSSR
ssssi SRSRSS RSRSRR ’ ssisi RSRRSS SRSSRR
siiii RSSSSS SRRRRR I sisii SRRSS RSSRRR
isiii RRSSSS SSRRRR isisi SSRRSS RRSSRR
iisii RRRSSS SSSRRR iisis SSSRRS RRRSSR
iiiis RRRRRS SSSSSR sissi RSSRSS SRRSRR
sssii RSRSSS SRSRRR isssi RRSRSS SSRSRR
siiss RSSSRS SRRRSR A siisi SRRRSS RSSSRR
iisss RRRSRS SSSRSR isiis SSRRRS RRSSSR
ssiis RSRRRS SRSSSR siiis SRRRRS RSSSSR
iiiss SSSSRS RRRRSR sssss RSRSRS SRSRSR
issii SSRSSS RRSRRR iiiii SSSSSS RRRRRR

 

35

 

 

o
MeOH460°C * HO
O V $0Me

W =

o
0 MeOH, H+. 50°C> HOW/“\O/HPOMG
i o

 

Scheme 2.2. Methanolysis of L-lactide

To ensure that esterification took place in a predictable manner, each
lactic acid residue was added in the form of lactic acid with a protected hydroxyl
group and a free carboxylic acid. The ideal protecting group must be robust
enough to withstand the conditions of the esterification reaction, but be easily
removed. An added complication is that for purification reasons, esters were
used as substrates instead of acids, and the protecting group must also survive
the ester hydrolysis reaction. Several silane-based protecting groups were
evaluated (Scheme 2.3). Protection of the hydroxyl moiety with trimethylsilyl
chloride (TMSCI) was easily achieved, does not interfere with the coupling
chemistry, and is easily removed with tetrabutylammonium fluoride. However the
TMS group partially hydrolyzed under the basic conditions used to hydrolyze the
ethyl ester in a subsequent reaction. Similar results were obtained when the
protecting group was switched to the tetrabutyldimethylsilyl (TBDMS) group.

Benzyl bromide offer two potential advantages as a protecting group.
Removal of the benzyl group by hydrogenation would side-step the hydrolysis
problems encountered with the silanes, and the addition of the benzyl group

might induce crystallinity to the carboxylic acid and simplify purification of the

36

intermediates. As expected, the benzyl group was stable to hydrolysis, and both
(R)- and (S)-2-benzyloxylpropanoic acid were crystalline solids. Tritylchloride
(TrCl) was briefly considered, but the purification of the protected acid by vacuum

distillation was not successful, and resulted in oligomerization.

 

 

TMSCI A 0
97% TMSO i OCHzCH3
TBSCI, DMAP, O
3 TBSO
imidizole, CHCI2 \gkOCHzCH3
O 95% =

”(k/"momma

BnBr,A920, EIZO B o O
T T " , OCHZCH3

TrCl, DMAP, EtaN, 01-12012 0
"O , OCHZCHa

 

 

85%
Scheme 2.3. Protecting groups tried

Ether, THF, and CHzclz were considered as potential solvents for the
protection reaction. Running the reaction in dry CH20I2 at reflux allowed smooth
conversion to the benzyl ether, while using dry THF as the solvent led to an
inseparable mixture. Purification of ethyl (S)-2-benzyloxypropanoate and methyl
(R)-2-benzyloxypropanoate proved difficult. Vacuum distillation resulted in
oligomerization, while column chromatography using silica gel as the stationary
phase resulted in hydrolysis of the ester. Therefore the crude benzyl-protected

ester was hydrolyzed in a 1:1 mixture of 0.2M LiOH and THF to give after work

37

up, ~ 60% yield of (S)-2-benzyloxypropanoic acid and (R)-2-benzyloxypropanoic
acid as crystalline compounds with clean 1H NMR spectra.

Carbodiimides were used to couple the benzyl-protected acids to the
anchor block. Dicyclohexylcarbodiimide (DCC) gave the coupled product in high
yield, but 1H NMR showed that the dicyclohexyl urea (DCU) byproduct, which is
sparingly soluble in CH2CI2 , diethyl ether, and water could not be successfully
removed from the product. The urea byproduct of 1-(3-dimethylaminopropyI)-3-
ethylcarbodiimide hydrochloride (EDC), a water soluble analogue of DCC, is
water soluble and was removed completely with an aqueous workup. However,
the relatively low yield (~60%) of the reaction was a major drawback to using
EDC.

The use of a catalytic amount of N,N-dimethylaminopyridine (DMAP) was
necessary for the coupling reaction. When run for > 1 hour, ”C NMR spectra of
the coupled products showed signs of epimerization. The carboxylic acid acts as
an electron withdrawing group, and due to the relatively low pKa of the methine
proton in the protected hydroxy acids, DMAP was able to abstract the methine
proton from the protected acid. When run in the minimum amount of dry CH20I2
needed to dissolve EDC, no epimerization was observed for reaction times less
than a half hour. It was imperative for the reaction to be run in dry CHgCIz. In
wet solvent, the coupling reaction was too slow to compete with the reaction of
residual water with EDC. Thus, CH2Cl2 was dried over CaHz prior to use.

After coupling the benzyl-protected a-hydroxy acid to the anchor, the

benzyl group was removed by hydrogenolysis. Typical conditions for such

38

reactions are 50 psi of H2 in the presence of a catalytic amount of 5% or 10%
palladium on carbon, often using a methanol/acetic acid solution as the solvent.
It is thought that the hydrogenation mechanism involves the abstraction of a
proton from the solvent, so a slightly protic solvent is needed. Under these
conditions, the benzyl group was removed but the ester linkages were also
hydrolyzed. Switching to CHzClz as the solvent gave no hydrogenolysis of the
benzyl ether even at 500 psi. The reaction proceeded slowly in diethyl ether at
55 psi H2, but was much faster at 500-600 psi. The time to completion of the
deprotection reaction varied widely, from as little as four hours to as much as one
week. This variability is likely due to poisoning of the catalyst, since reactions
run with Pd/C that had been stored on the bench top were slower than those that
used Pd/C that had been stored in the dry box. Batch to batch variation also
was observed for the Pd/C catalyst.

When the synthesis of the desired n-ad was completed, the benzylated n-
ad was deprotected and acetylated with acetic acid. The esterification was run
as before, except that acetic acid was used as the carboxylic acid. Careful
attention was needed, since the coupling reaction did not proceed in an excess
of acetic acid. The acetylation also required an additional equivalent of EDC,
presumably due to residual water in the acetic acid. The acetylation reaction was

complete in less than a half hour and gave a 60% yield of the product.

39

/AcOSSSSSSOMe
AcOSSSSSOMe

/ \AcORSSSSSOMe
M
AcOSSSSO 9\ /AcOSRSSSSOMe
AcORSSSSOMe
/ \ACORRSSSSOMe
AcOSSSOMe
/AcOSSRSSSOMe
AcOSRSSSOMe
/ . \ACORSRSSSOMe

AcORSSSOMe

/

/AcOSRRSSSOMe
ACORRSSSOMG\ACORRRSSSOM9

AcOSSSRSSOMe
AcOSSRSSOMe<
AcORSSRSSOMe

AcOSSOMe

\

AcOSRSSOMe

\ /AcOSRSRSSOMe
/ AcORSRSSOMe\_AcoRRSRSSOMe
AcORSSOMe /AcOSSRRSSOMe
/ACOSRRSSOM6\ACORSRRSSOM5
AcORRSSOMe

\ /AcOSRRRSSOMe

AcORRRSSOMe
\ACORRRRSSOMe

Figure 2.1. An example of synthetic methodology used to synthesize hexads.
The path to each hexad is shown in Figure 2.1. Seventeen of the 32
possible hexads were synthesized (Table 2.2), as well as smaller oligomers that
were acetylated and used to help make assignments of the ”C resonances.
Each hexad was a clear, colorless, viscous oil. For convenience, each hexad is
symbolically represented to reflect the stereochemistry of each lactic acid residue
with the end groups denoted by standard abbreviations. Thus, (2R)-2-{{(2’S)-2’-
{{(2”R)-2”-{{(2”’Sl-Z”’-{{(2’”’S)-2””{{(2’””Sl-Z’””-benzyloxypropanoylloxy}
propanoyl}oxy}propanoyl}oxy}propanoyl}oxy}propanoyl}oxy}propanoic acid
methyl ester is represented as BnORSRSSSOMe. Similarly, its acetylated

40

derivative is abbreviated as AcORSRSSSOMe. Each compound can also be
classified according to their stereochemical relationships. Recall that “5” refers to
a syndiotactic relationship (opposite configurations) between two adjoining
stereocenters and that “i’ refers to an isotactic relationship (same configuration)
between the two adjoining stereocenters. Thus, AcORSRSSSOMe can also be
represented as sssii, with the understanding that the hexad is always oriented
with the methyl ester to the right and the acetate to the left. Using this scheme,
there are two possible hexads for each sequence. For example, sssss refers to
two hexads, AcORSRSRSOMe and AcOSRSRSROMe. In this thesis, the
methine carbon atoms in each n-ad are numbered from left to right, with 1
corresponding to the methine next to the acetate ester.

Characterization of the methine region (68.0-69.5 ppm) of the ”C-NMR
spectra was emphasized since prior work on poly(lactide) focused on assigning
these resonances. Less useful was the methyl region, which often contains
overlapping peaks, and the carbonyl region, which could not be successfully
analyzed in each case due to low signal-to-noise ratios. Each hexad had six
methine resonances in the ”C-NMR. The corresponding methine region in the
1H-NMR was a complex multiplet from overlapping quartets, and could not be

successfully decoupled.

41

Table 2.2. Hexads Synthesized.

 

Tacticity Hexad Tacticity Hexad

 

sssis SRSRRS isiii RRSSSS

 

iiiis RRRRRS sssii RSRSSS

 

iisss RRRSRS ssiis RSRRRS

 

iiiss SSSSRS issii SSRSSS

 

ssiii SRSSSS iissi SSSRSS

 

isiss RRSSRS sisis RSSRRS

 

isisi SSRRSS issis RRSRRS

 

isssi RRSRSS sssss RSRSRS

 

iiiii SSSSSS

 

 

 

 

 

Each hexad has a characteristic ”C-NMR signature in terms of the placement of
the methine resonances. By considering the trends seen in the hexads as well
as data from shorter n-ads, each methine resonance was assigned as outlined
below. In the spectra of the is died and the structurally related iis triad (Figure
2.2), the most downfield and upfield peaks in each spectrum have similar
chemical shifts. The first and last methine in each n-ad are in similar chemical
environments, resulting in the methine assignments shown in Figure 2.2.
Analogous trends are observed for the iii, iiii, and iiiii n-ads (Figure 2.3), where a

comparison of the spectra Show that each resonance in the

42

.. It") 0 0 ;
ES O 5' S o/Y
; O 3 O

 

.l....‘....l...
69.40 69.20 69.00 68.80 68.60 68.40 68.20

I I I T ‘ Y ‘ Y I Y I

Figure 2.2. Comparison of methine regions of is and iis n-ads

shorter n-ad has a analogous resonance in the longer n-ad with a similar
chemical shift. The first three methines in each n—ad have similar chemical shifts
and hence similar chemical environments. The most downfield resonance in
each was assigned to the methine adjacent to the acetate, while the most upfield
resonance was assigned to the methine adjacent to the methyl ester because of
the similarity of the chemical shift to the most upfield resonance in most n-ads
that have an isotactic stereochemical relationship between the first two centers.
With the most upfield and downfield chemical shifts assigned, the peaks due to
methines 2 and 3 remain to be assigned in the iii tetrad. These resonances
correspond to methines 2 and 3, and were assigned on the basis of their

distance from the acetate and methyl ester.

43

The iiii pentad requires assignment of one additional resonance. A
comparison of the iii and iiii methine regions shows that the first three
resonances map onto one another. Assuming the assignment of these three
peaks are the same in each member of the series and assigning the most upfield
resonance as the methine nearest the methyl ester, the peak at 68.80 ppm was
assigned as methine 4. Following the same pattern, five out of the six peaks in
the ”C NMR of the iiiii hexad (Figure 2.3) were assigned, and the new peak was
identified as methine 5.

The methine regions of the remaining hexads were assigned using the
same approach, a comparison of the ”C NMR spectra with those of hexads that
share some of the same stereochemical sequences. For example, a comparison
of the methine region in the ”C NMR spectra of the iiiii and the iiiis hexads
(Figure 2.4) shows that they differ only in the position of the most upfield
resonance. Since the difference between the two hexads is stereochemistry of
the methine nearest the methyl ester, the peak at 68.49 ppm in the spectrum of
the iiiis hexad is methine 6.

Similar logic was used to assign the methine region of the isiii hexad
(Figure 2.5). Assignment of the isisi hexad follows from a comparison of the isisi
spectrum with that of the isiii hexad, which shows that resonances 4 and 5 of the
isisi hexad are shifted downfield relative to methines 4 and 5 of the isiii hexad.
The effect of the syndiotactic dyad can be more clearly seen if the spectra of isiss
and isisi are compared. The most downfield methine peak of the isiss hexad is

shifted quite drastically downfield compared to that of the isisi methine region.

iiiii °”3°°\/'\ 221/0 WN" Mom

 

I T I I I I V V V U I ‘ T I I ‘ Y ' T ‘ ‘ I 1 r I I I I

69.40 69 .20 69 .00 6880 68 '60 68 .40 68 20

45

IO 0 O S O S
""" CH3CO\'/'\ )S\1/0\3/'\ NOV/K /'6\1‘( 0M8
Illll ; s o 2 5 s 0 g s 0
: O = O «'- O

iiils

o o o - o s
enaco 1 ' R o 3 A R o 5 Mom
R O/2\n/ Ft O/\"/ R O
o o 0

 

l V j I V Y I Y

' I
68.40

‘ fT

.1....‘....‘. ml. .1.
69.40 69.20 69.00 68.80 68.60 68.20

Figure 2.4. Comparison of the methine regions of the iiiii and iiiis hexads.

The remaining peaks of the isiss methine region can be assigned by
comparison to the methine region of the isisi hexad; the most downfield peak was
assigned as methine 5 (Figure 2.5).

The effect of syndiotactic dyads on the chemical shift of the methines can
be most clearly seen when one compares the methine regions of the ssiii, sssii,
and sssss spectra (Figure 2.6). As more adjoining syndiotactic dyads are added,
the resonances shift downfield. If we consider a polylactide chain in a planar
zigzag conformation, a syndiotactic relationship between two adjoining

stereocenters places the methyl groups on the same side of the plane defined by

46

9 o o o 8
ISI“ CHSCO 1 TR 0% Now/K New
R OW a S 0 g S O
o = o = o

isisi C”3‘”\/'\ o/'\,/° \lR/"\° /\/ °\/"\ CASE/m"

isiss 50.55% W 0% N o\l/ii\ No...

I l I l I § ‘ T V I I I I j I T f x 1 I U x 1 I I t t ‘

69.40 69.20 69.00 68. 80 68.60 68.40 68'20

Figure 2.5. Comparison of the isiii, isisi, isiss hexad methine regions.

47

o o o o
CHac'o ' R o\3/“\ S °\’>/'\ S We
SSIII 2 4 a
. o _ 0 . o
; 1S : s : S
: O 2 O 3 O

“3%N%N%N

 

9 o s o s o S
88355 \‘R/KO/IA‘K $0M YKO/GK'K
o o 0

124 5 6

 

I V I V l U r V V V I ‘ V I I ‘ f I I 7 U ‘ I 1 V T ‘ V V r U

6940 6920 69.00 68.80 68.60 68.40 68.20

Figure 2.6. Comparison of the methine regions of ssiii, sssii, sssss hexads.

48

the polymer backbone, deshielding the methine carbon and shifting the methine
resonance downfield relative to an isotactic dyad. Using the methods outlined
above, the methine region of the 13C NMR of each hexad was assigned. The
results are summarized in Table 2.3.

A simple model was devised to test for consistency in the assignment of
the chemical shifts. The approach is similar to the models developed for the
prediction of the chemical shifts in polypropylene and polypropylene oxide. For a
given resonance, the effects of adjacent stereocenters (a relationship), as well as
next nearest neighbors ([3 relationship) are considered. A 7 effect, similar to the 7
relationship in poly(propylene) and poly(propylene oxide) could also be included.
Using the iiiii hexad as the reference, the chemical shift of a methine in a given
stereosequence is calculated by adding corrective factors to the base chemical
shift for the methine of interest. For example, the chemical shift of methine 3 of
the isiii hexad (Figure 2.7) is calculated by adding corrective factors to the

methine chemical shift of the third methine from the iiiii hexad (Eq. 2.1).

(I? 0 ER * O S O
CHSCOWTR/‘KOWOgS/‘KONOYS/TKO/zflfwe
o = o =
T T T T T

B? a: 04' BF‘ 7%

Figure 2.7. isiii hexad.

Methine 3 chemical shift=iiiii base + (1L5 + a“. + BL. + 13“, + W. Eq. 2.1

49

Table 2.3. Summary of Hexad Methine Shifts.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sequence 1 2 3 4 5 6
iiiii 69.21 69.05 69.00 68.95 68.88 68.33
isiii 69.22 69.16 69.07 68.91 68.87 68.30

ISiSS 69.21 69.1 7 69.05 68.97 69.39 68.39
isisi 69.23 69.1 8 69.07 69.04 68.97 68.28
issis 69.23 69.1 0 69.42 69.05 68.89 68.52
issii 69.21 69.08 69.41 69.02 68.84 68.29
iiiis 69.1 9 69.03 68.98 68.97 68.88 68.49
iissi 69.1 9 69.05 68.93 69.37 69.03 68.30
iisss 69.19 69.04 69.01 69.39 69.18 68.39
isssi 69.22 69.07 69.40 69.28 69.1 8 68.38
iiiss 69.20 69.02 69.01 69.00 69.29 68.39
55555 69.39 69.32 69.28 69.27 69. 1 8 68.38
ssiis 69.36 69.27 69.01 68.91 68.82 68.44
ssiii 69.34 69.26 69.01 68.85 68.79 68.24
sssii 69.36 69.27 68.98 68.87 68.79 68.26
sisis 69.30 69.14 69.14 68.98 68.85 68.48
sssis 69.31 69.23 69.23 68.96 68.78 68.41

 

 

 

 

 

 

 

50

 

The corrective factors were estimated by using a broad range of values for
the corrective factors to calculate the chemical shifts of each methine in each
hexad. An Excel spreadsheet was used to compare the calculated and
experimentally measured values, and the sum of the squares of the deviations
(observed — calculated)2 was used to test for the quality of fit. The corrective
factors values that gave the minimum sum of the squares of the deviations are

summarized in Table 2.4. The calculated shifts are found in Table 2.5.

Table 2.4. Corrective factors

 

 

0.06 -0.12 0.19 0.02

BLi BLs BRi Rs

0.01 -0.03 0.00 -0.03
E

1?“: fl. 1h rs

0.07 0.05 0.00 0.06

 

 

 

 

 

 

 

 

In general, the calculated chemical shifts match the experimental values
reasonably well. However, hexads with 35 sequences often show substantial
deviation and either the assignments of these hexads are incorrect or
considering only adjacent and next nearest neighbor interactions is inadequate.

In principle, NMR experiments could be used to confirm the assignment of
the methine carbons. If the acetate or the methyl ester carbons could be

selectively excited, the transfer of excitation to the neighboring methine would

51

Table 2.5. Calculated Methine ‘30 Chemical Shifts

 

Methine Carbon in Hexad

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hexad 1 2 3 4 5 6
iiiil' 69.21 69.05 69.00 68.95 68.88 68.33
isiii 69.20 69.12 69.09 68.89 68.84 68.29

Isiss 69.20 69.18 69.12 69.03 69.19 68.43
isisi 69.20 69.1 8 69.06 69.06 69.02 68.25
issis 69.26 69.09 69.32 69.04 68.97 68.45
issii 69.26 69.09 69.26 69.07 68.80 68.27
iiiis 69.23 68.95 68.97 68.90 69.03 68.47
iissi 69.29 68.98 69.05 69.28 69.00 68.23
iisss 69.29 68.98 69.1 1 69.25 69.17 68.41
isssi 69.26 69.1 5 69.23 69.24 68.98 68.23
iiiss 69.23 69.01 68.94 69.07 69.21 68.43
55555 69.43 69.33 69.25 69.19 69.15 68.41
ssiis 69.37 69.30 69.1 1 68.84 69.01 68.47
ssiii 69.37 69.30 69.05 68.87 68.84 68.29
sssii 69.43 69.27 69.22 69.05 68.80 68.27
sisis 69.43 69.1 0 69.10 69.06 68.99 68.45
sssis 69.43 69.27 69.28 69.02 68.98 68.45

 

 

 

 

 

 

 

52

 

Table 2.6. Deviations in Calculation of Chemical Shift of Hexads.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Methine Carbon in Hexad
Hexad 1 2 3 4 5 6
iiiii 0.00 0.00 0.00 0.00 0.00 0.00
isiii 0.02 0.04 -0.03 0.02 0.03 0.02
isiss 0.01 -0.01 -0.07 -0.06 0.20 -0.03
isisi 0.03 0.00 0.00 -0.03 -0.06 0.04
issis -0.03 0.01 0.10 0.01 -0.08 0.07
issii -0.05 -0.01 0.14 -0.05 0.03 0.02
iiiis -0.04 0.08 0.01 0.07 -0.15 0.03
iissi -0.10 0.07 -0.13 0.09 0.03 0.08
iisss -0.10 0.06 -0.10 0.14 0.01 -0.02
isssi -0.04 -0.09 0.17 0.04 0.20 0.15
iiiss 0.03 -0.01 -0.06 0.07 -0.08 0.04
55553 0.04 0.01 -0.03 -0.08 -0.03 0.03
ssiis -0.01 -0.03 -0.1 1 0.07 -0.20 -0.02
ssiii -0.03 -0.04 -0.05 -0.02 -0.05 —0.05
sssii -0.07 0.00 -0.24 -0.18 -0.01 -0.01
sisis -0.13 0.04 0.03 -0.08 -0.14 0.03
sssis -0.12 -0.04 -0.05 -0.06 -0.20 -0.04
deviation 0. 03 0. 17 0. 10 0. 18

 

reveal the connectivity in the hexad. Repeating the process would allow

 

“sequencing” of the hexad. The HMBC (heteronuclear multiple bond correlation)

experiment is a two-dimensional experiment which reveals long range coupling

53

between carbons and hydrogens. It was hoped that the acetate methyl group
would correlate with the nearest methine carbon or hydrogen. However the
coupling was not strong enough to result in a cross peak (Figure 2.8, 2.9).

A NOE (Nuclear Overhauser Effect) experiment also was ineffective. It
was thought that through-space interactions may lead to a more conclusive
assignment of the methines. However the only correlation detected was between
the methyl and the methine hydrogens. A small NOE effect between the methyl
group of the ester and the acetate methyl group suggested a hairpin
conformation for the hexad. Preliminary molecular modeling showed that the
hairpin shape was plausible since it corresponded to one of the lowest energy
conformations of the hexad.

Several other two-dimensional experiments were tried. NOESY (Nuclear
Overhauser Effect Spectroscopy) is a two-dimensional experiment in which
direct, through space dipole-dipole interactions can been seen. This experiment
confirmed the one-dimensional NOE findings, but was not helpful in assigning the
resonances since there were no cross peaks were observed.

The cross-peaks in the 2D spectrum of an HMQC (Heteronuclear Multiple-
Quantum Coherence) experiment arise from the protons directly bonded to 13C
atoms. The HMQC (Figures 2.10 and 2.11) spectrum confirmed that the methyl
hydrogens were directly connected to the methyl carbons. it also confirmed that
the methine hydrogens were directly connected to the methine carbons. No long

range coupling between hydrogens and carbons was observed.

54

Several T1 experiments were also tried. It was thought that if the acetate
group could be selectively excited, the relaxation time for the nearest methine
carbon would be longer than that of a more distant methine carbon. However,
the T1 times of the methine carbons were too similar to be assigned
conclusively.

In conclusion, by comparing various polylactide hexads and smaller
oligomers, a mathematical relationship was devised to further understand the

stereochemical relationships in polylactide. The “discrepancy" found in the

HETCOR spectrum as described by Chisholm3 is probably due to chemical
tensor effects, since the chemical shift can be predicted to some degree of
certainty. Further progress in this area will likely require the use of isotopically
labeled hexads to enable a more conclusive assignment of the resonances.
Molecular modeling may also provide a better understanding of the
stereochemically dependent conformation of hexads and its impact, if any, on the
chemical shift of the methines. Since the conformation of a hexad in a “good”
solvent the hexad should be linear, but bent in a “bad” solvent, solvent effects
may affect the chemical shift of the methine carbons and play a role in the

outcome of the NOE experiments.

55

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59

2.1 References

1. Kricheldorf, H. FL; Boettcher, C.; Tonnes, K.-U. Polymer1992, 33, 2817-2824.

2. Thakur, K. A. M.; Kean, R. T.; Hall, E. S.; Kolstad, J. J.; Lindgren, T. A.
Macromolecules 1997, 30, 2422-2428.

3. Chisholm, M. H.; lyer, S. S.; Matison, M. E.; McCollum, D. G.; Pagel, M.
Chemical Communications 1997, 1999-2000.

60

3. Experimental

General. CHgClg was distilled over CaHg prior to use. Pd/C was stored in
a helium-filled dry box. L-lactide was obtained from Aldrich and D-Lactide from
Purac. Both lactides were purified by recrystalization from ethyl acetate. All
other chemicals and solvents were used as received. All hexad 13C NMR
spectra were obtained on a Varian 500 MHz spectrometer as 15 wt% solutions in
CDCI3.

Abbreviations for compounds. For convenience, each hexad is
symbolically represented to reflect the stereochemistry of each lactic acid residue
with the end groups denoted by standard abbreviations. Thus, (2R)-2-{{(2’S)-2’-
{{(2”R)-2”-{{(2"’S)-2"’-{{(2"”S)-2""{{(2””’S)—2’””-benzyloxypropanoyl}oxy}
propanoyl}oxy}propanoyl}oxy}propanoyl}oxy}propanoyl}oxy}propanoic acid
methyl ester is represented as BnORSRSSSOMe. Similarly, its acetylated
derivative is abbreviated as AcORSRSSSOMe rather than (R,S,R,S,S,S)—a-
acetyI-qi-(methoxy)hexakis[oxy(1-methyl-2-oxoethane-1,2-diyl)]. Compounds that
have a hydroxy terminus such as (28)-2-{{(2’S)-2’-{{(2"S)-2”-{{(2"’R)-2"’-{{(2””S-
2””-hydroxypropanoyl}oxy}propanoyl}oxy}propanoyl}oxy}propanoyl}oxy}
propanoic acid methyl ester are abbreviated as HOSSSRSOMe.

(S)-2-Benzyloxypropanoic acid, methyl ester. (S)-2-Hydroxypropanoic
acid ethyl ester (16.43 g, 9.08 mmol) and benzyl bromide (5.00 g, 4.59 mmol)
were added to a stirred solution of Ag(I)O (11.135 9, 4.59 mmol) in 25 mL of dry
CHzC|2_ After stirring at room temperature for 24 hours, the reaction mixture was

filtered and the solvent was removed via rotary evaporation. The crude product

61

was not purified further. ‘H NMR (300 MHz, CDCI3): 5 7.28 (m, 5H), 4.57 (d,
2H), 4.08 (q, 1H), 3.72 (s, 3H), 1.43 (d, 3H)

(R)—2-Benzyloxypropanoic acid, methyl ester. Prepared as described
above, except (R)-2-hydroxypropanoic acid methyl ester was used as the starting
material. 1H NMR (300 MHz, CDCI3): 57.28 (m, 5H), 4.57 (d, 2H), 4.08 (q, 1H),
3.72 (s, 3H), 1.43 (d, 3H)

(R)-2-Benzyloxypropanoic acid, isobutyl ester. Prepared as described
above, except (H)-2-hydroxypropanoic acid isobutyl ester was used as the
starting material. 1H NMR (300 MHz, coma): a 7.31 (m, 5H), 4.53 (dd, 2H), 4.08
(q, 1H), 3.97 (m, 2H), 1.95 (septuplet, 1H), 1.41 (d, 3H), 0.91 (d, 6H)

(S)-2-Benzyloxylpropanoic acid. (S)-2-Benzyloxylpropanoic acid methyl
ester 13.21 9 (0.0634 moles) was added to a mixture of 300 mL of 0.2 M
aqueous LiOH and 300 mL of THF. After stirring at room temperature for 5 days,
most of the THF was removed via rotary evaporation. The resulting aqueous
mixture was extracted with ether (3 x 100 mL), and then the combined organic
layers were washed with sat. NaHCO;; (3 x 75 mL). The aqueous layers were
combined and acidified. to pH 1 with cone. HCI, and were then extracted with
ether (3 x 100 mL). The organic layers were dried over MgSOa, filtered, and
concentrated by rotary evaporation to give 10.21 g (89%) of a white solid. 1H
NMR (300 MHz, CDCI3): 8 9.28 (br s, 1H), 7.31 (m, 5H), 4.80 (dd, 2H), 4.11 (q,
1H), 1.50 (d, 3H)

(R)—2-Benzyloxylpropanoic Acid. Prepared as described above except

(H)-2-hydroxypropanoic acid methyl ester was used as the starting material. 1H

62

NMR (300 MHz, CDCI3): 89.28 (br s, 1H), 7.31 (m, 5H), 4.80 (dd, 2H), 4.11 (q,
1H), 1.50 (d, 3H)

HOSOMe. A mixture of L-Lactide 5.50 9 (0.0382 moles) and 10 mL of
conc. HCI in 800 mL of methanol was heated to the reflux temperature for 24
hours. The solution was cooled, and all methanol was removed by rotary
evaporation to give 3.92 g of the ester (0.0400 mol, 49%) as a clear colorless oil.
NMR spectroscopy showed that the product was pure. 1H NMR (300 MHz,
CDCI3): 89.28 (s, 1H), 7.18 (m, 5H), 4.60 (dd, 2H), 4.09 (q, 1H), 1.51 (d, 3H)

HOROMe. Prepared as described above except 50.0 g (0.347 moles) D-
Lactide was used as the starting material. Yield: 63.15 g of the ester (0.61 mol,
88%) as a clear colorless oil. NMR spectroscopy showed that the product was
pure. ‘H NMR (300 MHz, 00013): 5 9.0 (s, 1H), 7.30 (m, 5H), 4.60 (dd, 2H), 4.11
(q, 1H), 1.45 (t, 3H)

HOSSOMe. L-Lactide 24.55 g (0. 170 moles) in 500 mL of methanol was
heated to the reflux temperature for 24 hours. The solution was cooled, and all
methanol was removed by rotary evaporation to give 27.22 g of the ester (0.15
moles, 91%) as a clear colorless oil. NMR spectroscopy showed that the product
was pure. ‘H NMR (300 MHz, CDCl3): 55.13 (m, 2H), 4.30 (q, 1H), 3.72 (s,
3H), 2.85 (5 br, 1H), 1.58 (d, 3H), 1.44 (m, 6H)

Hydrogenation. All hydrogenation reactions were carried out using the
same procedure. To a Parr bomb fitted with a glass sleeve and a stir bar, 5 mL of
diethyl ether was added to 0.0615 9 (0.1186 mmol) BnORRSRSOMe. 0.06 g of

10% Pd/C was added, the bomb was purged three times with N2, and then filled

63

with H; (1200 psi). The reaction was monitored by NMR. Upon completion of
the reaction, the heterogeneous mixture was gravity filtered to remove Pd/C, and
removal of the ether gave a clear, colorless liquid in 87% yield (0.050339). NMR
data for the hydroxy terminated compounds appear in Tables 3.1-3.5.

Coupling Procedure with (R)- or (S)-Benzyloxylpropanoic acid. (S)-2-
Benzyloxylpropanoic acid (0.0160 9, 0.0885 mmol), HORRRSOMe (0.0313 9,
0.0737 mmol), EDC (0.212 9, 0.1106 mmol), DMAP (0.0018 9, 0.0147 mmol),
and 2 mL of dry CH2CI2 were added to a round bottom flask at room temperature.
After stirring for a half hour, the solution was washed with 0.5 M HCI (3 x 5 mL),
followed by 5 mL of sat. NaHCOa. The organic layer was dried over M9804.
Following filtration, the solvent was removed via rotary evaporation to give
0.02999 (0.0510mmol, 69%) of a clear, colorless liquid. The product was
determined to be pure by NMR. NMR data for benzyl terminated compounds
appear in Tables 3.6-3.10.

Coupling Procedure with Acetic Acid. Acetic acid (0.282 9, 0.4694
mmol), HORSSSOMe (0.1000 9, 0.3139 mmol), EDC (0.0902 9, 0.4709 mmol),
DMAP (0.00779, 0.0630 mmol), and 2 mL of dry CHzclz were added to a round
bottom flask at room temperature. After stirring for a half hour, the solution was
washed with 0.5 M HCI (3 x 5 mL) followed by 5 mL of sat. NaHCOa. The
organic layer was dried over M9804. Following filtration, the solvent was
removed via rotary evaporation to yield 0.0736 9 (0.0204 mmol, 65%) of a clear,
colorless liquid. The product was determined to be pure by NMR. NMR data for

the benzyl terminated compounds appear in Tables 3.11-3.14.

64

 

 

 

 

 

 

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