Synthesis of discrete mass poly(butylene glutarate) oligomers

Article abstract of DOI:10.1021/ma021056b

A series of discrete mass oligomers of the perfectly alternating copolymer poly(butylene glutarate) containing 2, 4, 8, 16, 32, and 64 structural units have been synthesized from glutaric anhydride and butanediol using an iterative divergent-convergent st

Full text of DOI:10.1021/ma021056b

3898
Macromolecules 2003, 36, 3898-3908
Synthesis of Discrete Mass Poly(butylene glutarate) Oligomers
J oh n B. Willia m s,‡ Toby M. Ch a p m a n ,*,‡ a n d Da vid M. Her cu les†
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, and
Department of Chemistry, Vanderbilt University, Nashville, Tennesseee 37235
Received J uly 5, 2002; Revised Manuscript Received February 19, 2003
ABSTRACT: A series of discrete mass oligomers of the perfectly alternating copolymer poly(butylene
glutarate) containing 2, 4, 8, 16, 32, and 64 structural units have been synthesized from glutaric anhydride
and butanediol using an iterative divergent-convergent strategy. These materials were designed to serve
as models for more complex polymer distributions. Orthogonal protection of difunctional starting material
using 9-fluorenylmethoxycarbonyl chloride and p-methoxybenyl alcohol allowed control of chain growth
during coupling with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and (N,N-dimethyl-
amino)pyridine. Condensation products were monofunctionalized by removal of one protecting group using
mild acidic or basic conditions that preserved the orthogonal protecting group. The fully unprotected
target products were isolated in highly pure form and, with the exception of the 64-mer, in high yield
(>70%). The synthetic oligomers were characterized using 1H NMR, HPLC, GPC, EI-MS, CI-MS, LSI-
MS, and MALDI-TOF-MS to confirm structure, molecular weight, and purity.
In tr od u ction
introduced by Merrifield,16 to covalently anchor growing
chains during synthesis. These supports allow addition
of large excesses of monomer and coupling reagents to
drive the desired process to near completion, thus
increasing reaction efficiencies and providing higher
yields. Excess reactants and byproducts can be con-
veniently removed by simple filtration and washing with
appropriate solvents between steps. The product is
isolated by selected cleavage of the support-polymer
bond.
Synthetic polymers of precisely defined degree of
polymerization and structure may be utilized as models
for their higher molecular weight, less well-defined
polymeric homologues and have revealed important
information related to the physical,1 electronic,2 and
optical properties3 of these materials. Although synthe-
sis of uniform polymeric materials has been a target for
over 35 years, the major synthetic obstacle is the
isolation of the product in a pure form. Earlier efforts
have focused on fractionation of oligomers produced by
standard polymerization reactions with shortened reac-
tion times and lower reaction temperatures to decrease
molecular weight. Alternatively, discrete oligomers have
been generated by degradation of polymers with higher
degrees of polymerization. However, the yields were
often very low and the preparative fractionations were
inadequate for the isolation of pure products.4
Recent synthetic strategies have been focused on
stepwise approaches. Most simply, a monofunctional
monomer is added to a growing chain of the monomer,
the product is purified, and the chain end refunction-
alized for the addition of the next unit. An analogous
approach is the addition of an oligomeric segment of a
known degree of polymerization followed by purification
and refunctionalization as above. Again, purification of
the product in the presence of polymeric homologues can
be problematic. Stepwise synthesis has been applied to
the production of pure oligopeptides5 and has yielded
compounds containing up to 175 chain atoms.6 Pure
oligomers of polyurethanes,7-10 poly(ethylene glycol),11-13
and biodegradable oligo(ester amides)14 have also been
prepared in a similar manner. Linear oligomers of poly-
(hydroxy butyrate) (P(3-HB)) containing up to 96 3-HB
units have been produced using an exponential seg-
ment-coupling strategy.15
Similar synthesis can be performed on soluble sup-
ports such a poly(ethylene glycol) (PEG).17,18 The utili-
zation of homogeneous solution phase chemistry ensures
accessibility of reactants to activated sites. Linear PEG
distributions with Mn g 5000 amu have favorable
physicochemical properties that allow separation of
supported products from compounds not covalently
bound to active chain ends. Soluble supports have been
applied to the assembly of dendrimers of uniform
purity.19 However, improvements in reaction efficiencies
and yields using supports, whether soluble or insoluble,
are offset in long synthetic sequences by a decrease in
the purity of the final product(s). These impurities stem
from incomplete reactions, resulting in deletion of chain
segments and formation of structurally similar com-
pounds that are difficult to separate from the target
product.
An increasingly important approach to providing
control of macromolecular architecture is to utilize
biological systems for the preparation of high-perfor-
mance polymers.20 The design, synthesis, and expres-
sion of an artificial gene encoding a poly(R,L-glutamic
acid) (PLGA) derivative has been shown to produce
materials having very low polydispersity indexes.21
Biosynthesis of monodispersed derivatives of poly(γ-
benzyl R,L-glutamate) has provided products that dem-
onstrate smectic ordering in solutions and in films. The
results of this study suggest that methods of preparing
monodispersed polymers having these types of struc-
tures may provide access to new smectic phases having
layer spacing that may be precisely controlled on the
scale of tens of nanometers.22
The above synthesis technique can be enhanced by
using insoluble polymeric supports, similar to those
‡ University of Pittsburgh.
† Vanderbilt University.
* Corresponding author.
10.1021/ma021056b CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/29/2003

Macromolecules, Vol. 36, No. 11, 2003
Poly(butylene glutarate) Oligomers 3899
Sch em e 1. Iter a tive Diver gen t-Con ver gen t Syn th esis of Bu tylen e Glu ta r a te Oligom er sa
a
Pa and Pb refer to the protecting groups on A and B, respectively.
A practicable approach, based on an iterative diver-
gent-convergent strategy, has been applied to the
synthesis of long-chain linear aliphatic hydrocar-
bons.23,24 Using this approach, the starting material,
monomer M, with nonfunctional end groups X and Y,
is divided into two portions. In one portion, the end
group X is activated to form X′, and similarly, in the
second fraction, Y is converted to activated Y′. The two
functionalized fractions are then covalently linked to
form XMMY with a loss of X′Y′. After purification of
XMMY, the process can be repeated, resulting in “mo-
lecular doubling” of the X[M]nY chain. Purification is
simplified since remaining reactant molecules are half
the size of the product chains.
differing degrees of polymerization and/or other reaction
byproducts.
Synthetic control of the degree of polymerization was
accomplished through monoprotection of the difunc-
tional starting materials, glutaric anhydride (A) and
butanediol (B), using protecting groups that are non-
labile under reaction conditions required for esterifica-
tion or removal of an orthogonal protecting group.
p-Methoxybenzyl ester33 (Pa), which is labile under
mildly acidic conditions but stable in basic solutions,
was chosen for protection of the carboxylic acid moiety.
Protection of the alcohol functionality was achieved
using 9-fluorenylmethoxycarbonyl34 (FMOC) (Pb), which
is selectively removed in the presence of tertiary amines
but is relatively inert in acidic solutions.
Condensation reagents and conditions were investi-
gated to identify reactions that optimized yield, mini-
mized byproducts, and preserved orthogonal protection.
Dicyclohexylcarbodiimide (DCC) with catalytic (N,N-
dimethylamino)pyridine (DMAP) was initially chosen,
but this system produced progressively increasing
amounts of the acylureas of the acid-functionalized
starting materials with increase in reactant chain
length, thus reducing both the reaction yields and the
capability to adequately purify the oligomeric products.
This problem was most likely the result of a decreasing
probability of reactant chain-end encounters with in-
creasing chain length, thus lowering the relative rates
of reaction for ester vs acylurea formation. A complex
of phenyl dichlorophosphate (PDP) with N,N-dimethyl-
formamide (DMF) was successfully applied for conden-
sation of butylene glutarate dimers but produced lower
yields when coupling larger copolymer chains.
The above strategy has been applied to the synthesis
of phenyl-alkyne oligomers25-27 and oligo(thiophene-
ethynylene)2,27,28smaterials that may serve as molec-
ular-scale electronic devices or molecular wires. The
approach has also been used to isolate single linear
oligomers of nylon-6, which were subsequently studied
using time-of-flight secondary ion (TOF-SIMS),29 elec-
trospray ionization (ESI), matrix-assisted laser de-
sorption/ionization time-of-flight (MALDI-TOF),30 and
MALDI collision-induced dissociation (CID) mass spec-
trometry.31
The purpose of this work was the synthesis of discrete
mass oligomers of the perfectly alternating copolymer
poly(butylene glutarate) using an iterative divergent-
convergent synthetic strategy. These oligomers have
application as standard reference materials for the mass
calibration of analytical techniques such as mass spec-
trometry and gel permeation chromatography (GPC),
which are commonly utilized to determine molecular
weight averages of polymers. These materials may also
serve as models of more complex distributions, thus
simplifying the study of ion production, transmission,
and detection efficiencies as well as fragmentation
processes in mass spectrometry. Model oligomers of
accurately known molecular weight provide the ability
to study possible reasons for discrepancies32 in polymer
molecular weights averages obtained using various
techniques.
Consistent condensation results were achieved using
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydro-
chloride35 (EDCI) catalyzed by (N,N-dimethylamino)-
pyridine. This approach rendered reaction yields of 70-
80% of chromatographically purified product for reactant
chain lengths of 32 or fewer structural units, with little
or no formation of adducts or oligomeric byproducts,
thus facilitating simpler product purification.
Resu lts a n d Discu ssion
Syn th etic Str a tegy. The target products of this
synthesis were discrete mass oligomers containing 2, 4,
8, 16, 32, and 64 structural units of the perfectly
alternating copolymer poly(butylene glutarate). The
X-mer denotation used in this report is defined as the
combined number of glutaric acid and 1,4-butanediol
residues within the given polymer chains having uni-
form structures. The applicability of these materials to
the study of analytical phenomenon mandated that
the final products be isolated in a highly pure form,
i.e., free of significant amounts of oligomers having
The iterative divergent-convergent synthetic ap-
proach applied to the controlled synthesis of discrete
mass butylene glutarate copolymer oligomers is il-
lustrated in Scheme 1. Difunctional monomers A and
B were monoprotected using orthogonal protecting
groups Pa and Pb, which can each be selectively removed
without perturbation of the other, yielding APa and BPb.
Coupling of the orthogonally protected copolymer mono-
mers using condensation reagents yielded the fully
protected tetramer Pa[AB]2Pb, which was then divided
into two molar equivalents. Protecting groups Pa and

3900 Williams et al.
Macromolecules, Vol. 36, No. 11, 2003
Sch em e 2. Syn th esis of th e Bu tylen e Glu ta r a te Dim er a
a
Conditions: (a) 70° C, 4 h; (b) pyridine, 0 °C f RT, 18 h; (c) phenyl dichlorophosphate/N,N-dimethylformamide, 0 °C, 0.5
h/RT, 18 h; (d) 5.0% TEA/CH2Cl2, RT, 4 h.
Pb were then selectively removed to form monofunc-
tionalized Pa[AB]2 and [AB]2Pb. Molecular doubling
followed by selective or complete deprotection of prod-
ucts yielded a series of the discrete unprotected target
oligomers [AB]n where n ) 1, 2, 4, 8, 16, and 32.
phosphate-N,N-dimethylformamide complex, to pro-
duce the p-methoxybenzyl-protected butylene glutarate
dimer (7B). Product 7A was subsequently fully depro-
tected by mixing with 5% TEA in CH2Cl2 for 4 h to yield
the fully deprotected dimer (7C).
Dim er Syn th esis. Synthesis of the poly(butylene
glutarate) (PBG) dimer is presented in Scheme 2.
Glutaric acid mono-p-methoxybenzyl ester (3) was pre-
pared by melt mixing (70 °C) of 1 equiv of 4-methoxy-
benzyl alcohol (1) with 2 equiv of glutaric anhydride (2).
The mono-FMOC-protected butanediol (6) was synthe-
sized by reaction of 9-fluorenylmethyl chloroformate (4)
with 20 equiv of butanediol (5) using pyridine as a
catalyst. Purified product (6) was subsequently melt
mixed (70 °C) with 2 equiv of glutaric anhydride (2) to
form the FMOC-protected butylene glutarate dimer
(7A). Purified product (3) was then condensed with
excess butanediol (5) (10 equiv), using a phenyl dichloro-
Molecu la r Dou blin g. The synthesis of PBG oligo-
mers having higher degrees of polymerization is sche-
matically outlined in Scheme 3. Orthogonally mono-
protected dimers (7A and 7B) were coupled using EDCI/
DMAP to produce the fully protected PBG tetramer (8).
Product 8 was then refunctionalized by dividing this
product into 2 equimolar fractions followed by selective
removal of one protection group. The p-methoxybenzyl
group was removed by stirring product 8 in 5% tri-
fluoroacetic acid (TFA) in CH2Cl2 for 2 h yielding (8A).
The FMOC group was removed by stirring 8 in 5%
triethylamine (TEA) in CH2Cl2 for 4 h, forming tetramer
(8B). EDCI/DMAP coupling of 8A and 8B yielded the

Macromolecules, Vol. 36, No. 11, 2003
Poly(butylene glutarate) Oligomers 3901
Sch em e 3. Molecu la r Dou blin g of Un ifor m Bu tylen e Glu ta r a te Oligom er sa
a
Conditions: (a) EDCI/DMAP, 0 °C, 2 h/RT, 18 h; (b) 5% TFA/CH2Cl2/RT, 2 h; (c) 5% TEA/CH2Cl2/RT, 4 h.

3902 Williams et al.
Macromolecules, Vol. 36, No. 11, 2003
Ta ble 1. P h ysica l P r op er ties, Syn th etic, a n d An a lytica l Resu lts fr om Discr ete Ma ss P oly(bu tylen e glu ta r a te)
In ter m ed ia tes a n d Oligom er s
entry
compounda no.
repeat units
molecular formula
mol wtb
mass spec
NMR ratioc
HPLC (min)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3
6
1
1
2
2
2
4
4
4
4
8
8
8
8
16
16
16
16
32
32
32
32
64
64
64
64
C
C
C
C
13H16O5
19H20O4
24H26O7
17H24O6
252.10
312.14
426.17
324.16
204.10
732.31
612.26
510.25
390.19
252d
1:1
1:1
1:1
1:1
1:1
3:1
3:1
3:1
3:1
5:1
5:1
6:1
5:1
11:1
12:1
11:1
11:1
23:1
24:1
23:1
23:1
47:1
48:1
45:1
46:1
2.60
3.05
2.99
2.73
3.18
2.91
2.77
2.84
3.12
3.04
2.78
3.06
3.60
3.23
2.97
2.72
3.59
3.36
3.34
3.06
3.59
4.11
3.97
3.84
4.07
98.7
84.8
93.2
77.1
88.1
74.5
90.1
88.3
86.9
80.1
75.1
79.1
85.3
80.0
88.6
89.1
75.2
70.9
87.1
88.2
82.2
23.1
82.5
83.3
79.1
312d
7A
7B
7C
8
8A
8B
8C
9
9A
9B
9C
10
10A
10B
10C
11
11A
11B
11C
12
12A
12B
12C
426d
324d
C9H16O5
205e
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
41H48O12
33H40O11
26H38O10
18H30O9
59H76O20
51H68O19
44H66O18
36H58O17
95H132O36
87H124O35
80H122O34
72H114O33
167H244O68
159H236O67
152H234O66
144H226O65
311H468O132
303H460O131
296H458O130
288H460O129
732d
612d
510d
413f-h
1127h
1007h
905h
1104.49
984.44
882.42
762.37
785g,h
1872h
1752h
1650h
1530g,h
3361h
3241h
3139h
3018g,h
6340h,i
6221h,i
6120h,i
5999h,i
1848.85
1728.79
1626.78
1506.72
3337.56
3217.51
3115.51
2995.44
6314.99
6194.93
6092.93
5972.87
a
b
d
From Schemes 2 and 3. Nominal. c 1H NMR ratio of main chain methylene to chain end or protecting group methylene. EI-MS
(M)+. e CI-MS (M + H)+. f LSI-MS (M + Na)+. ESI-MS (M + Na)+. MALDI-TOF-MS (M + Na)+. Apex of isotopic envelope.
g
h
i
fully protected PBG octamer (9). As shown in Scheme
3, orthogonal deprotection of fully protected oligomers
(9, 10, 11, 12) yielded the FMOC-protected (9A, 10A,
11A, 12A) and the 4-methoxybenzyl-protected (9B, 10B,
11B, 12B) oligomers. Subsequent molecular doubling
using EDCI/DMAP coupling of copolymers of the same
degree of polymerization yielded orthogonally protected
products (10, 11, 12). Removal of FMOC with 5% TEA
from fractions of the protected acids (8A, 9A, 10A, 11A,
12A) produced the unprotected synthetic target copoly-
mers (8C, 9C, 10C, 11C, and 12C) with 4, 8, 16, 32,
and 64 structural units, respectively.
The synthesis of the fully protected 64-mer resulted
in a low reaction yield (23.1%). The lower yield may have
resulted from the reduced probability due to increased
chain length of the hydroxyl-functionalized oligomers
encountering an activated carboxyl terminus. In addi-
tion, ions from oligomeric byproducts, in the ca. 3000
Da range, were detected in the MALDI spectra of
impure 64-mer reaction products, indicating the pres-
ence of competing reactions that further lowered product
yield and inhibited efficient purification.
An a lysis of P BG Oligom er s. Progressive growth
and purity of the products were monitored using thin-
layer chromatography (TLC), high-performance liquid
chromatography (HPLC), gel permeation chromatogra-
phy (GPC), proton nuclear magnetic resonance spec-
troscopy (1H NMR), electron impact ionization (EI),
chemical ionization (CI), liquid secondary ion (LSI),
electrospray ionization (ESI), and matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry
(MALDI-TOF-MS) (Table 1). GPC traces and MALDI
spectra of these discrete mass oligomers are included
within a report detailing the analytical applications of
these synthetic materials [Anal. Chem., in press].
P u r ifica t ion of P BA Oligom er s. Products of the
above coupling reactions and mono-deprotection steps
were purified by gradient low-pressure liquid chroma-
tography (LPLC) using silica gel as the stationary phase
and hexanes or methylene chloride/ethyl acetate as the
mobile phase. Column fractions of synthetic intermedi-
ates contaminated with components not resolved by
LPLC were repurified using higher resolution flash
liquid chromatography (FLC).36 The fully functionalized
oligomers were isolated by rotary evaporation to remove
reaction solvents and TEA and then dried in a vacuum.
The crude products were redissolved and then filtered,
followed by recovery of the soluble materials using
rotary evaporation. The waxy products were isolated in
pure form by precipitation from a CH2CH2 solution
using hexanes or diethyl ether. The 64-mer was recrys-
tallized from hot ethanol.
Figure 1 presents the 1H NMR spectra of the fully
protected PBG 32-mer. The ratios of main chain meth-
ylene (-[(OdC)CH2CH2CH2(CdO)]-) (m) (2H) (1.95
ppm) to protecting group methylene (p-methoxybenzyl
(s) (2H) (5.04 ppm) or FMOC methylene (d) (2H) (4.45
ppm)) of all protected products are included in Table 1.
1
These ratios were calculated using peak areas from H
Rea ction Yield s. The reaction yields from the syn-
thesis of PBG oligomers and their intermediates, along
with analytical results, are given in Table 1. It is seen
that coupling reactions using PDP/DMF or EDCI/DMAP
gave reaction yields of ca. 70-80% for starting materials
having structural units e32. Reaction yields from
deprotection steps were generally in the 80-90% range.
High reaction yields were essential due to the number
of synthetic steps (up to 25) required to obtain higher
molecular weight products.
NMR spectra and were utilized to monitor progressive
chain growth of fully and monoprotected intermediates.
1
Figure 2 displays a series of H NMR spectra of the
fully functionalized PBG oligomer products (compounds
7C-12C of Table 1). NMR spectra support the absence
of nonoligomeric impurities and illustrate the increase
in the number of repeat units by monitoring the inten-
sity ratio, calculated by integration of peak areas, of a
repeat unit methylene (central methylene of the glutaric

Macromolecules, Vol. 36, No. 11, 2003
Poly(butylene glutarate) Oligomers 3903
F igu r e 1. Proton nuclear magnetic resonance (1H NMR) spectrum of the orthogonally protected butylene glutarate 32-mer. The
proton peak assignments are shown in the inset.
acid comonomer) (-[(OdC)CH2CH2CH2(CdO)]-) (m)
(2H) (1.95 ppm) to the terminal group methylene
(-CH2OH) (t) (2H) (3.65 ppm).
indicated the presence of the PBG octamer (m/z ) 785)
having an intensity, relative to that of the product peak,
of 10%. The presence of the PBG octamer was also
observed (8%) in the ESI-MS spectra of this material.
1
In general, H NMR ratios from poly(butylene glu-
tarate) spectra tended to overestimate the relative
number of main chain to end group methylene groups
for copolymers with a degree of polymerization higher
than 2. For example, the expected ratio for compound
11C, composed of 16 glutaric acid monomer units,
should be 16:1 as opposed to the measured value of 23:
1. This discrepancy is probably due to loss of lower
intensity end-group signals in spectral background
noise. Thus, the application of these NMR ratios for
molecular weight determination would result in errone-
ously high results.
Mass spectrometric analysis was successfully per-
formed on all products listed in Table 1. EI-MS and CI-
MS analysis of products having structural units g8
provided peaks from intact products M+ and (M + H)+,
respectively, and indicated an absence of oligomeric
impurities in these materials. CI-MS analysis of the
unprotected dimer exhibited the (M + H)+ peak at m/z
) 205. LSI-MS analysis of the unprotected tetramer
(8C) produced the (M + Na)+ peak at m/z ) 413. The
MALDI-TOF-MS spectrum of the tetramer (8C) also
provided the (M + Na)+ peak (m/z ) 413) but also
MALDI-TOF-MS was utilized extensively for the
evaluation of the purity of both protected and function-
alized PBG oligomers having degrees of polymerizations
g8. The MALDI spectrum of the fully functionalized
PBG 64-mer (12C) is presented in Figure 3. The highest
intensity peak seen in the MALDI spectrum results
from the sodium cationized molecular ion (M + Na)+
(5999 Da), which appears 23 amu higher than the
predicted molecular weight of the oligomer. Additional
weaker peaks (ca. 25% relative to the (M + Na)+
intensity) are seen at 16 and 22 Da above the (M + Na)+
peak and are identified as the potassium cationized
molecular ion (M + K)+ and the sodium cationized
sodium salt of the carboxylic acid of the oligomer (M +
2Na - H)+. The appearance of the latter ion probably
results from the addition of NaCl to sample/matrix
mixture during the preparation of MALDI sample
targets. MALDI analysis of the fully deprotected 8-, 16-,
and 32-mer also provided base peaks representative of
the sodium cationized molecular ions at m/z ) 785,
1530, and 3019 (9C-11C), respectively, as well as lower

3904 Williams et al.
Macromolecules, Vol. 36, No. 11, 2003
levels of oligomeric impurities were also observed in the
MALDI spectra of the fully functionalized PBG oligomer
products 9C-11C. The MALDI spectrum of the PBG
octamer (9C) indicated the presence of the 16-mer (m/z
) 1530) (3%). However, this impurity was not detected
during ESI-MS analysis of this compound. MALDI
analysis of the 16-mer (10C) produced peaks contributed
to the loss by the product of one butylene glutarate unit
(m/z ) 1344) (3%), the loss of one glutaric acid unit (m/z
) 1416) (1%), and the presence of the fully functional-
ized 8-mer (m/z ) 785) (3%). The presence of the 8-mer
(3%) was also observed in the ESI-MS spectra of the
product 16-mer. MALDI spectra of the 32-mer (11C)
provided peaks from impurities identified as the PBG
16-mer (m/z ) 1530) (3%), 30-mer (m/z ) 2832) (4%),
31-mer (m/z ) 2904) (2%), and 34-mer (m/z ) 3204)
(2%).
The MALDI experiment was very sensitive to the
presence of oligomeric impurities. Spectra of pure
preparative column fractions of protected products
indicated little or no contamination from materials
differing from the product only in the degree of poly-
merization. However, spectra of the impure LPLC
fractions of the products from the condensation and
deprotection reactions revealed that larger amounts of
impurities corresponding to product n ( 0.5, 1, 2 were
formed during synthesis.
The purity of the fully functionalized target products
was also evaluated using GPC. The GPC experiment is
also sensitive to the presence of nontargeted oligomers
having significantly differing degrees of polymerization
from that of the product. The results support the mass
spectrometric determination that the inclusion of sig-
nificant quantities of these impurities in the products
was not evident. The molecular weight averages and
polydispersity estimates from GPC analysis of fully
functionalized products, calibrated using poly(ethylene
glycol) (PEG) standards, are presented in Table 2. While
the molecular weight averages determined from these
GPC traces generally agree with the calculated values
and those measured by mass spectrometric methods,
F igu r e 2. Progressive growth of butylene glutarate oligomers
monitored by proton nuclear magnetic resonance (1H NMR)
spectroscopy. The peaks from the carboxyl repeat units (-(Cd
O)CH2CH2CH2(CdO)-) and the hydroxyl termini (-CH2OH)
are identified.
intensity ions corresponding to (M + K)+ and (M + 2Na
- H)+.
As seen in Figure 3, the MALDI mass spectrum of
the 64-mer (12C) also indicated the presence of oligo-
meric impurities corresponding to addition (66-mer) (m/z
) 6185) (4%) or subtraction (62-mer) (m/z ) 5813) (5%)
of one butylene glutarate unit, as well as peaks at m/z
) 5885 (63-mer) (4%), corresponding to the subtraction
of one glutaric acid unit ((CdO)-(CH2)3-(CdO)-O). Low
F igu r e 3. MALDI-TOF mass spectrum of the fully functionalized butylene glutarate 64-mer using trans-3-indole acrylic acid as
the matrix. The molecular ions (M + Na)+ of the product and oligomeric impurities are identified.

Macromolecules, Vol. 36, No. 11, 2003
Poly(butylene glutarate) Oligomers 3905
Ta ble 2. GP C Molecu la r Weigh t Aver a ges of Discr ete
Ma ss P BG Oligom er s
a vacuum providing a solid (mp ) 66-68 °C) [yield: 54.7 g
1
(98.7%)]. EI-MS: 252, 137, 121 m/z. H NMR (CDCl3) δ: 7.29
(d, 2H), 6.90 (d, 2H), 5.04 (s, 2H), 3.82 (s, 3H), 2.41 (t, 4H),
1.98 (m, 2H) (ratio 1:1) (theoretical ratio 1:1). HPLC (aceto-
nitrile): 2.60 min; TLC Rf ) 0.67 (80% CH2Cl2:ethyl acetate).
Mon o-F MOC-P r otected Bu ta n ed iol Mon om er (6). In a
round-bottom flask, 49.0 g of butanediol (5) (540 mmol) was
dissolved in 100 mL of THF and cooled to 0 °C. With stirring,
6.4 g of pyridine (81 mmol) was added followed by the dropwise
addition (over 10 min) of 7.0 g of 9-fluorenylmethyl chloro-
formate (4) (27.1 mmol) in 50 mL of THF. The ice bath was
removed, and the reaction was stirred for 18 h. The solvent
was removed, and resulting mixture was placed in 250 mL of
CH2Cl2 and extracted with 3 × 250 mL of water. The organic
layer was evaporated and dried, and the crude product was
purified using gradient LPLC with CH2Cl2:ethyl acetate
(1:0-1:1) as the eluent [yield: 7.15 g (84.8%)]; oil. EI-MS: 312,
178, 165 m/z. 1H NMR (d6-acetone) δ: 7.78 (d, 2H), 7.63 (d,
2H), 7.44 (t, 2H), 7.33 (t, 2H), 4.46 (d, 2H), 4.29 (t, 1H), 4.23
(t, 2H), 3.69 (t, 2H), 1.82 (m, 2H), 1.68 (m, 2H) (ratio 1:1)
(theoretical ratio 1:1). HPLC (acetonitrile) 3.05 min; TLC Rf
) 0.41 (80% CH2Cl2:ethyl acetate).
compda repeat
no.
c
entry
units mol wtb
Mn
Mw Mw/Mn Mp
1
2
3
4
5
6
7C
8C
2
4
204.10
390.19
762.37
1506.72 1710 1940
2995.44 3460 3860
5972.87 5840 6180
190
300
860
200
400
870
1.04
1.33
1.01
1.14
1.12
1.06
200
355
890
1990
3550
5910
9C
8
10C
11C
12C
16
32
64
From Schemes 2 and 3. Nominal. c From peak apex.
a
b
some overestimation of molecular weight of products is
observed. This probably results from relative differences
in the hydrodynamic volume of the polyester analytes
and PEG standards at similar masses.
Con clu sion s
The synthesis of a series of structurally uniform
oligomers of the perfectly alternating copolymer of
glutaric acid and butanediol has been made possible by
orthogonal monoprotection of the respective difunctional
monomers followed by effective coupling of monofunc-
tional comonomers using EDCI/DMAP. An iterative
divergent-convergent strategy consisting of orthogonal
deprotection of equimolar fractions of fully protected
PBA oligomers, followed by EDCI coupling, has pro-
duced poly(butylene glutarate) oligomers of high purity
with 2, 4, 8, 16, 32, and 64 structural units. These
materials have immediate application as models for
development of analytical methodology for polymers,
examination of disparities in molecular weight deter-
minations of polymers using different methods, study
of mass spectrometric processes, and utilization as
calibration standards for relative methods of determi-
nation of polymer molecular weight averages.
F MOC-P r otected Bu tylen e Glu ta r a te Dim er (7A). In
a round-bottom flask equipped with a condenser, 7.15 g (22.4
mmol) of mono-FMOC-butanediol (6) was dissolved in 50 mL
of CH2Cl2 followed by the addition of 5.2 g (46 mmol) of glutaric
anhydride (2) with stirring. The reaction mixture was stirred
at 70 °C for 4 h, then cooled and dissolved in 250 mL of diethyl
ether, and extracted with 6 × 250 mL of H2O. The organic
phase was dried, and the product was purified using gradient
LPLC on a column of silica gel with CH2Cl2:ethyl acetate (1:
0-1:2) as the eluent [yield: 9.10 g (93.2%)]; oil. EI-MS: 426,
1
178, 165 m/z. H NMR (CDCl3) δ: 7.78 (d, 2H), 7.63 (d, 2H),
7.44 (t, 2H), 7.32 (t, 2H), 4.41 (d, 2H), 4.30 (t, 1H), 4.20 (t,
2H), 4.13 (t, 2H), 2.43 (t, 3H), 2.41 (t, 3H), 1.95 (t, 2H), 1.76
(m, 5H) (ratio 1:1) (theoretical ratio 1:1). HPLC (acetonitrile)
2.99 min; TLC Rf ) 0.56 (80% CH2Cl2:ethyl acetate).
p-Meth oxyben zyl Bu tylen e Glu ta r a te Dim er (7B). Into
a dry round-bottom flask containing 7.0 g of N,N-dimethyl-
formamide (96 mmol) at 0 °C, 12.7 g of phenyl dichlorophos-
phate (60 mmol) was added with mechanical stirring. The
resulting complex was allowed to stand under dry N2 at 0 °C
for 10 min followed by mixing with 0 °C anhydrous THF. To
the resulting suspension, 10.0 g (39.7 mmol) of glutaric acid
mono-p-methoxybenzyl ester (3) was added and stirred until
the solution was homogeneous (10 min), followed by 35.7 g (397
mmol) of butanediol (5). After 10 min, 12.6 g of pyridine (160
mmol) was added, and the reaction mixture was stirred at RT
for 18 h. The solvent was removed, the mixture was placed in
200 mL of CH2Cl2 and extracted with 3 × 250 mL of water.
The organic fraction was dried and the product was purified
by gradient LPLC with hexane:ethyl acetate (5:1-1:3) as the
eluent [yield: 9.92 g, (77.1%)]; oil. EI-MS: 324, 137, 121 m/z.
1H NMR (CDCl3) δ: 7.29 (d, 2H), 6.90 (d, 2H), 5.04 (s, 2H),
4.10 (t, 2H), 3.80 (s, 3H), 3.65 (t, 2H), 2.40 (t, 2H), 2.36 (t, 2H),
1.93 (t, 2H), 1.71 (t, 2H), 1.66 (t, 2H) (ratio 1:1) (theoretical
ratio 1:1). HPLC (acetonitrile) 2.73 min; TLC Rf ) 0.31 (80%
CH2Cl2:ethyl acetate).
Exp er im en ta l Section
Syn t h esis. Butanediol, glutaric anhydride, 4-(N,N-di-
methylamino)pyridine, p-methoxybenzyl alcohol, 9-fluorenyl-
methyl chloroformate, N,N-dimethylformamide, phenyl dichlo-
rophosphate, pyridine, and 1-ethyl-3-[3-(dimethylamino)propyl]-
carbodiimide hydrochloride (EDCI) were purchased from
Aldrich Chemical Co. and dried prior to use. Triethylamine
(TEA) and trifluoroacetic acid (TFA) were purchased from
Avocado Research Chemical Limited. Methylene chloride, N,N-
dimethylformamide, and tetrahydrofuran, employed for cou-
pling reactions, were distilled and stored over molecular sieves
until needed. All glassware was oven-dried and purged with
dried nitrogen prior to use. All coupling reactions subsequently
described were carried out under dry nitrogen. Solvents were
removed using a water aspirated rotary evaporator heated
with a water bath.
Low-pressure liquid chromatography (LPLC) was performed
on a column of silica gel (Baker (60-200 mesh)) (weight silica
gel:weight sample ≈ 30-100:1) using the cosolvents ethyl
acetate and methylene chloride or hexanes as the mobile
phase. Flash liquid chromatography (FLC) was performed on
a column of silica gel (Merck, 230-400 mesh, 60 Å, Aldrich)
with the cosolvents ethyl acetate and methylene chloride as
the mobile phase. Thin-layer chromatography (TLC) was
performed on Whitman 250 µM silica gel plates.
Glu ta r ic Acid Mon o-p-m eth oxyben zyl Ester Mon om er
(3). Glutaric anhydride (50.0 g, 440 mmol) was dissolved in
50 mL of CH2Cl2 and mixed with p-methoxybenzyl alcohol
(30.4 g, 220 mmol) in a two-neck round-bottom flask with a
condenser. The reaction mixture was stirred at 70 °C for 4 h
and at RT overnight. This mixture was dissolved in 200 mL
of diethyl ether and extracted with 6 × 200 mL of H2O. The
organic phase was rotary-evaporated and dried overnight in
Bu tylen e Glu ta r a te Dim er (7C). In an 50 mL Erlenmeyer
flask, 100 mg (0.23 mmol) of FMOC-protected butylene glu-
tarate (7A) was stirred with 1.2 g (11.7 mmol, 50 equiv) of
TEA in 30 mL of CH2Cl2 for 4 h. After removal of the solvent
and TEA by rotary evaporation and vacuum-drying, the
product was isolated by filtration of a CH2Cl2 solution followed
by washing with hexanes [yield: 42.2 mg (88.1%)]; oil. CI-
1
MS: 205, 115. ESI-MS: 227, 150, 102 m/z. H NMR (CDCl3)
δ: 4.13 (t, 2H), 3.69 (t, 2H), 2.38 (p, 4H), 1.95 (m, 2H), 1.76 (t,
2H), 1.70 (t, 2H) (ratio 1:1) (theoretical ratio 1:1). HPLC
(acetonitrile) 3.18 min.
Or th ogon a lly P r otected Bu tylen e Glu ta r a te Tetr a m er
(8). In a round-bottom flask at 0 °C, 3.2 g (9.9 mmol) of
p-methoxybenzyl butylene glutarate (7B), 4.2 g (9.9 mmol) of
FMOC-butylene glutarate (7A), and 0.25 g of DMAP (2.0
mmol) were mixed with stirring in 75 mL of CH2Cl2. EDCI
(1.6 g) (10.9 mmol) was added, and the mixture was stirred at

3906 Williams et al.
Macromolecules, Vol. 36, No. 11, 2003
0 °C for 2 h and at RT for 18 h. After concentration, the product
was purified by gradient LPLC with CH2Cl2:ethyl acetate (1:
0-1:1) as the eluent [yield: 5.40 g, (74.5%)]; oil. EI-MS: 732,
17H), 1.94 (m, 10H), 1.75 (m, 13H) (ratio 5:1) (theoretical ratio
4:1). HPLC (acetonitrile) 2.78 min; TLC Rf ) 0.48 (60% CH2Cl2:
ethyl acetate).
1
554, 510, 178, 121 m/z. H NMR (CDCl3) δ: 7.78 (d, 2H), 7.63
p-Meth oxyben zyl-P r otected Bu tylen e Glu ta r a te Oc-
ta m er (9B). In a round-bottom flask, 3.15 g (2.93 mmol) of
orthogonally protected butylene glutarate octamer37 (9) was
stirred in a solution of 5.0% TEA in 50 mL of CH2Cl2 at RT
for 4 h. The volatile components were removed by rotary
evaporation and dried overnight. The crude product was
redissolved in CH2Cl2, filtered, and then purified by gradient
LPLC with CH2Cl2:ethyl acetate (9:1-0:1) as the eluent.
Impure LPLC column fractions were repurified using FLC
(80% CH2Cl2:ethyl acetate) [yield: 2.04 g (79.1%)]; oil. MALDI-
TOF-MS: 921, 905 m/z. 1H NMR (CDCl3) δ: 7.28 (d, 2H), 6.88
(d, 2H), 5.04 (s, 2H), 4.10 (t, 16H), 3.80 (s, 3H), 2.37 (m, 18H),
1.94 (t, 12H), 1.68 (m, 15H) (ratio 6:1) (theoretical ratio 4:1).
HPLC (acetonitrile) 3.06 min; TLC Rf ) 0.46 (60% CH2Cl2:
ethyl acetate).
(d, 2H), 7.44 (t, 2H), 7.33 (t, 2H), 7.29 (d, 2H), 6.90 (d, 2H),
5.05 (s, 2H), 4.41 (t, 2H), 4.29 (t, 1H), 4.23 (t, 2H), 4.10 (t, 4H),
3.80 (s, 3H), 2.39 (m, 9H), 1.91 (m, 5H), 1.78 (t, 5H), 1.70 (t,
5H) (ratio 2.5:1) (theoretical ratio 2:1). HPLC (acetonitrile) 2.91
min; TLC Rf ) 0.78 (80% CH2Cl2:ethyl acetate).
F MOC-P r otected Bu tylen e Glu ta r a te Tetr a m er (8A).
In a round-bottom flask, 5.2 g (7.10 mmol) of orthogonally
protected butylene glutarate tetramer37 (8) was stirred in a
200 mL solution of 5% TFA in CH2Cl2 for 2 h. The reaction
mixture was extracted 3 × 200 mL of water, and the organic
fraction was rotary evaporated and dried overnight. The crude
product was purified by gradient LPLC with CH2Cl2:ethyl
acetate (1:0-0:1) as the eluent [yield: 3.92 g, (90.1%)]; oil. EI-
MS: 612, 178, 165 m/z. 1H NMR (CDCl3) δ: 7.78 (d, 2H), 7.63
(d, 2H), 7.44 (t, 2H), 7.33 (t, 2H), 4.41 (t, 2H), 4.28 (t, 1H),
4.23 (t, 2H), 4.10 (t, 6H), 2.39 (m, 9H), 1.93 (m, 6H), 1.78 (t,
5H), 1.70 (t, 6H) ppm (ratio 3:1) (theoretical ratio 2:1). HPLC
(acetonitrile) 2.77 min; TLC Rf ) 0.26 (80% CH2Cl2:ethyl
acetate).
p-Meth oxyben zyl-P r otected Bu tylen e Glu ta r a te Tet-
r a m er (8B). In a round-bottom flask, 4.30 g (5.90 mmol) of
orthogonally protected butylene glutarate tetramer37 (8) was
stirred in a 100 mL 5% w/w solution of TEA in CH2Cl2 at RT
for 4 h. The volatile components were removed using rotary
evaporation, and the crude product was dried overnight, then
dissolved in CH2Cl2, and filtered, followed by purification by
gradient LPLC with CH2Cl2:ethyl acetate (1:0-0:1) as the
eluent [yield: 2.65 g (88.3%)]; oil. EI-MS: 510, 373, 121 m/z.
1H NMR (CDCl3) δ: 7.29 (d, 2H), 6.90 (d, 2H), 5.06 (s, 2H),
4.13 (t, 5H), 3.82 (s, 3H), 3.69 (t, 2H), 2.39 (m, 9H), 1.96 (m,
5H), 1.69 (t, 11H) (ratio 2.5:1) (theoretical ratio 2:1). HPLC
(acetonitrile) 2.84; TLC Rf ) 0.18 (80% CH2Cl2:ethyl acetate).
Bu tylen e Glu ta r a te Tetr a m er (8C). In an 50 mL Erlen-
meyer flask, 50 mg (0.082 mmol) of FMOC-protected butylene
glutarate tetramer (8A) was stirred with 410 mg (4.1 mmol,
50 equiv) of TEA in 30 mL of CH2Cl2 for 4 h. The solvent and
TEA were removed by rotary evaporation followed by vacuum-
drying, and the pure product was isolated by filtration of a
CH2Cl2 solution and washing with hexanes [yield: 27.7 mg
(86.9%)]; oil. CI-MS 391. ESI-MS, LSI-MS, and MALDI-TOF-
MS 413 m/z. 1H NMR (CDCl3) δ: 4.13 (t, 6H), 3.69 (t, 2H),
2.38 (m, 8H), 1.95 (m, 6H), 1.70 (s, 11H) (ratio 3:1) (theoretical
ratio 2:1). HPLC (acetonitrile) 3.12 min.
Bu tylen e Glu ta r a te Octa m er (9C). In an 50 mL Erlen-
meyer flask, 75 mg (0.085 mmol) of FMOC-protected butylene
glutarate octamer (9A) was stirred with 30 mL of 5% TEA in
CH2Cl2 at RT for 4 h and then extracted with 3 × 30 mL of
H2O. The organic solvent was removed by rotary evaporation,
and the crude product was then vacuum-dried (48 h) and
isolated by filtration of a CH2Cl2 solution followed by precipi-
tation with hexanes [yield: 55.3 mg (85.3%)]; waxy solid.
1
MALDI-TOF-MS 807, 785 m/z. H NMR (CDCl3) δ: 4.13 (t,
16H), 3.69 (t, 2H), 2.38 (m, 17H), 1.95 (m, 10H), 1.70 (s, 17H)
(ratio 5:1) (theoretical ratio 4:1); HPLC (acetonitrile) 3.60 min.
Or t h ogon a lly P r ot ect ed Bu t ylen e Glu t a r a t e 16-m er
(10). In a round-bottom flask, 2.27 g (2.31 mmol) of FMOC-
protected butylene glutarate octamer (9A), 2.04 g (2.31 mmol)
of p-methoxybenzyl-protected butylene glutarate octamer (9B),
and 0.06 g (0.47 mmol) of DMAP were mixed in 100 mL of
CH2Cl2 at 0 °C. EDCI (0.45 g) (2.55 mmol) was added, and
the reaction mixture was stirred at 0 °C for 2 h and at RT for
18 h. The mixture was then reduced to 10 mL, and the crude
product was purified by gradient LPLC with CH2Cl2:ethyl
acetate (8:1-5:1) as the eluent. Impure fractions were re-
purified by FLC with CH2Cl2:ethyl acetate (7.5:1) as the eluent
[yield: 3.42 g (80.0%)]; oil. MALDI-TOF-MS: 1888, 1872 m/z.
1H NMR (CDCl3) δ: 7.77 (d, 2H), 7.61 (d, 2H), 7.39 (t, 2H),
7.33 (t, 2H), 7.28 (d,2H), 6.88 (d, 2H), 5.04 (s, 2H), 4.34 (d,
2H), 4.23 (t,1H), 4.18 (t, 2H), 4.09 (t, 38H), 3.78 (s, 3H), 2.35
(m,40H), 1.91 (t, 22H), 1.76 (s, 6H), 1.66 (s, 30H) (ratio 11:1)
(theoretical ratio 8:1). HPLC (acetonitrile) 3.23 min; TLC Rf
) 0.73 (60% CH2Cl2:ethyl acetate).
Or th ogon a lly P r otected Bu tylen e Glu ta r a te Octa m er
(9). In a round-bottom flask, 3.20 g (5.20 mmol) of FMOC-
protected butylene glutarate tetramer (8A), 2.65 g (5.20 mmol)
of p-methoxybenzyl-protected butylene glutarate tetramer
(8B), and 0.13 g (1.0 mmol) of DMAP were stirred at 0 °C.
1.10 g of EDCI (5.72 mmol) was added, and the reaction
mixture was stirred at 0 °C for 2 h and at RT for 18 h. The
solvent was reduced, and the crude product was purified by
gradient LPLC using CH2Cl2:ethyl acetate (1:0-1:1) [yield:
4.60 g (80.1%)]; oil. MALDI-TOF-MS: 1143, 1127 m/z. 1H
NMR (CDCl3) δ: 7.78 (d, 2H), 7.61 (d, 2H), 7.40 (t, 2H), 7.33
(d, 2H), 7.29 (d, 2H), 6.88 (d, 2H), 5.04 (s, 2H), 4.40 (t, 2H),
4.23 (t, 1H), 4.17 (t,2H), 4.11 (t, 11H), 3.79 (s, 3H), 2.36 (m,
17H), 1.93 (t, 10H), 1.78 (t, 8H), 1.67 (t, 7H) (ratio 5:1)
(theoretical ratio 4:1). HPLC (acetonitrile) 3.04 min; TLC Rf
) 0.54 (80% CH2Cl2:ethyl acetate).
F MOC-P r otected Bu tylen e Glu ta r a te Octa m er (9A). In
a round-bottom flask, 4.05 g (3.75 mmol) of orthogonally
protected butylene glutarate octamer37 (9) was stirred for 2 h
in 100 mL of 5% w/w TFA in CH2Cl2. The reaction mixture
was extracted with 3 × 100 mL of water and the organic
fraction rotary-evaporated and vacuum-dried. The crude prod-
uct was purified by gradient LPLC with CH2Cl2:ethyl acetate
(1:0-0:1) as the eluent. Impure LPLC column fractions were
repurified using FLC (80% CH2Cl2:ethyl acetate) [yield: 2.72
g (75.1%)]; oil. MALDI-TOF-MS: 1023, 1007 m/z. 1H NMR
(CDCl3) δ: 7.76 (d, 2H), 7.61 (d, 2H), 7.46 (t, 2H), 7.32 (t, 2H),
4.40 (d, 2H), 4.28 (t, 1H), 4.22 (t, 2H), 4.09 (t, 14H), 2.37 (p,
F MOC-P r otected Bu tylen e Glu ta r a te 16-m er (10A). In
a round-bottom flask, 1.50 g (0.811 mmol) of orthogonally
protected butylene glutarate 16-mer (10) was stirred with 50
mL of 5% w/w TFA in CH2Cl2 at RT for 2 h. The reaction
mixture was extracted 3 × 50 mL of water and the organic
fraction was dried prior to purification of the crude product
by gradient LPLC with CH2Cl2:ethyl acetate (7:1-0:1) as the
eluent [yield: 1.24 g (88.6%)]; oil. MALDI-TOF-MS: 1768,
1
1752 m/z. H NMR (CDCl3) δ: 7.78 (d, 2H), 7.62 (d, 2H), 7.40
(t, 2H), 7.33 (t, 2H), 4.40 (d, 2H), 4.23 (t, 1H), 4.19(t), 4.10 (t,
38H), 2.35 (m, 42H), 1.92 (m, 24H), 1.78 (t, 7H), 1.73 (t, 29H)
(ratio 12:1) (theoretical ratio 8:1). HPLC (acetonitrile) 2.97 min;
TLC Rf ) 0.42 (60% CH2Cl2:ethyl acetate).
p-Meth oxyben zyl-P r otected Bu tylen e Glu ta r a te 16-
m er (10B). In a round-bottom flask, 1.45 g (0.785 mmol) of
orthogonally protected butylene glutarate 16-mer37 (10) was
stirred with 4.0 g of TEA (50 equiv) in 50 mL of CH2Cl2 at RT
for 4 h. The reaction mixture was rotary-evaporated and dried
overnight to remove volatile components. The crude product
was dissolved in CH2Cl2, filtered, and then purified by gradient
LPLC with CH2Cl2:ethyl acetate (8:1-5:1) as the eluent.
Impure fractions were repurified by FLC with CH2Cl2 (6:1) as
the eluent [yield: 1.14 g 89.1%)]; oil. MALDI-TOF-MS: 1666,
1
1650 m/z. H NMR (CDCl3) δ: 7.28 (d, 2H), 6.87 (d, 2H), 5.04
(s, 2H), 4.09 (t, 39H), 3.79 (s, 3H), 3.65 (t, 2H), 2.35 (m, 42H),
1.92 (m, 22H), 1.64 (s, 36H) (ratio 11:1) (theoretical ratio 8:1);
HPLC (acetonitrile) 2.72 min; TLC Rf ) 0.48 (60% CH2Cl2:
ethyl acetate).

Macromolecules, Vol. 36, No. 11, 2003
Poly(butylene glutarate) Oligomers 3907
Bu tylen e Glu ta r a te 16-m er (10C). In an 50 mL Erlen-
meyer flask, 50 mg (0.029 mmol) of FMOC-protected butylene
glutarate octamer (10B) was stirred with 146 mg (1.5 mmol,
50 equiv) of TEA in 30 mL of CH2Cl2 for 4 h. The solvent and
TEA were removed by rotary evaporation and vacuum-drying
overnight. The product was isolated by filtration of a CH2Cl2
solution followed by precipitation with hexanes [yield: 32.8
precipitation product mixture was removed from the frit using
acetone, then dried and recrystallized three times from 50 mL
of hot ethanol, filtered, washed with ethanol, removed from
the frit using acetone, and dried after each recrystallization.
The recrystallized product was purified by gradient FLC with
CH2Cl2:ethyl acetate (7:3-1:1) as the eluent. Product fractions
were combined and recrystallized five times from 50 mL of
ethanol, washed, and dried [yield: 14.0 mg (23.1%)]; waxy
1
mg (75.2%)]; waxy solid. MALDI-TOF-MS 1552, 1530 m/z. H
1
NMR (CDCl3) δ: 4.13 (t, 37H), 3.69 (t, 2H), 2.38 (m, 40H), 1.95
(m, 22H), 1.70 (s, 36H) (ratio 11:1) (theoretical ratio 8:1); HPLC
(acetonitrile) 3.59 min.
solid. MALDI-TOF-MS: 6356, 6340 m/z. H NMR (CDCl3) δ:
7.78 (d, 2H), 7.63 (d, 2H), 7.44 (t, 2H), 7.31 (t, 2H),7.29 (d,
1H), 6.90 (d, 2H), 5.04 (s, 2H), 4.40 (d, 2H), 4.09 (s, 160H),
3.80 (s, 2H), 2.37 (s, 176H), 1.92 (t, 94H), 1.69 (s,164H) (ratio
47:1) (theoretical ratio 32:1). HPLC (acetonitrile) 4.11 min;
TLC Rf ) 0.42 (60% CH2Cl2:ethyl acetate).
Or t h ogon a lly P r ot ect ed Bu t ylen e Glu t a r a t e 32-m er
(11). In a round-bottom flask 0.89 g (0.515 mmol) of FMOC-
protected butylene glutarate 16-mer (10A), 0.84 g (0.515 mmol)
of p-methoxybenzyl-protected butylene glutarate 16-mer (10B),
and 13 mg of DMAP (0.10 mmol) were stirred at 0 °C in 50
mL of CH2Cl2. EDCI (0.11 g) (0.567 mmol) was added, and
the reaction mixture was stirred at 0 °C for 2 h and at RT for
20 h. The mixture was concentrated to 10 mL, and the crude
product was purified by LPLC with CH2Cl2 (3:2) as the eluent
[yield: 1.22 g (70.9%)]; waxy solid. MALDI-TOF-MS: 3377,
F MOC-P r otected Bu tylen e Glu ta r a te 64-m er (12A). In
an 25 mL Erlenmeyer flask, 12.0 mg (2.0 µmol) of fully
protected butylene glutarate 64-mer (12) was stirred in a 5%
TFA in 15 mL of CH2Cl2 for 2 h. The reaction mixture was
extracted 3 × 25 mL of H2O, and the organic phase was dried
by rotary evaporation and vacuum-drying overnight. The pure
product was isolated by precipitation with 50 mL of ether from
2 mL of CH2Cl2 and recrystallization using 50 mL of ethanol
[yield: 9.8 mg (82.5%)]; waxy solid. MALDI-TOF-MS: 6237,
1
3361 m/z. H NMR (CDCl3) δ: 7.78 (d, 2H), 7.63 (d, 2H), 7.44
(t, 2H), 7.31 (t, 2H),7.29 (d, 2H), 6.90 (d, 2H), 5.04 (s, 2H), 4.40
(d, 2H), 4.28 (t, 1H), 4.22 (t, 2H), 4.09 (t, 94H), 3.80 (s, 3H),
2.37 (m, 104H), 1.92 (t, 50H), 1.69 (s, 96H) (ratio 23:1)
(theoretical ratio 16:1). HPLC (acetonitrile) 3.36 min; TLC Rf
) 0.53 (60% CH2Cl2:ethyl acetate).
1
6221 m/z. H NMR (CDCl3) δ: 7.78 (d, 2H), 7.62 (d, 2H), 7.41
(t, 2H), 7.32 (t, 2H), 4.41 (d, 2H), 4.10 (s, 166H), 2.38 (s, 171H),
1.96 (t, 96H), 1.70 (s, 153H) (ratio 48:1) (theoretical ratio 32:
1). HPLC (acetonitrile) 3.97 min; TLC Rf ) 0.31 (50% CH2Cl2:
ethyl acetate).
F MOC-P r otected Bu tylen e Glu ta r a te 32-m er (11A). In
an 50 mL Erlenmeyer flask, 100.0 mg (0.030 mmol) of fully
protected butylene glutarate 32-mer (11) was stirred in a 5%
TFA in 25 mL of CH2Cl2 for 2 h. The reaction mixture was
extracted 3 × 25 mL of H2O, and the organic phase was dried
by rotary evaporation and vacuum-drying. The pure product
was isolated by precipitation with hexanes from CH2Cl2 [yield:
84.0 mg (87.1%)]; waxy solid. MALDI-TOF-MS: 3257, 3241
m/z. 1H NMR (CDCl3) δ: 7.78 (d, 2H), 7.62 (d, 2H), 7.41 (t,
2H), 7.32 (t, 2H), 4.41 (d, 2H), 4.28 (t, 1H), 4.10 (s, 91H), 2.38
(t, 92H), 1.96 (m, 48H), 1.70 (s, 99H) (ratio 24:1) (theoretical
ratio 16:1). HPLC (acetonitrile) 3.34 min; TLC Rf ) 0.44 (50%
CH2Cl2:ethyl acetate).
p-Meth oxyben zyl-P r otected Bu tylen e Glu ta r a te 64-
m er (12B). In a round-bottom flask, 3.0 mg (0.5 µmol) of
orthogonally protected butylene glutarate 64-mer (12) was
stirred with 50 mg of TEA in 5 mL of CH2Cl2 at RT for 4 h.
The reaction mixture was rotary-evaporated and dried over-
night to remove volatile components. The crude product was
dissolved in CH2Cl2 and filtered, then precipitated with 50 mL
of ether from 2 mL of CH2Cl2, filtered, and washed with ether.
The isolated precipitate was recrystallized using 50 mL of
ethanol, filtered, washed, and dried [yield: 2.5 mg (83.3%)];
1
wax. MALDI-TOF-MS: 6136, 6120 m/z. H NMR (CDCl3) δ:
7.28 (d, 1H), 6.87 (d, 2H), 5.04 (s, 2H), 4.09 (s, 158H), 3.79 (s,
3H), 3.65 (t, 2H), 2.35 (s, 182H), 1.92 (t, 90H), 1.64 (s, 161H)
(ratio 45:1) (theoretical ratio 32:1). HPLC (acetonitrile) 3.84
min.
p-Meth oxyben zyl-P r otected Bu tylen e Glu ta r a te 32-
m er (11B). In an 50 mL Erlenmeyer flask, 60 mg (18 µmol)
of fully protected butylene glutarate 32-mer (11) was stirred
with 75 mg (0.75 mmol, 50 equiv) of TEA in 30 mL of CH2Cl2
for 4 h. The solvent and TEA were removed by rotary
evaporation and vacuum-drying, and the product was isolated
by filtration of a CH2Cl2 solution and washing with hexanes
[yield: 49.4 mg (88.2%)]; waxy solid. MALDI-TOF-MS: 3155,
Bu tylen e Glu ta r a te 64-m er (12C). In an 50 mL Erlen-
meyer flask, 7.5 mg (1.0 µmol) of FMOC-protected butylene
glutarate 64-mer (12A) was stirred in 2 mL of 5% TEA:CH2Cl2
for 4 h. TEA and CH2Cl2 were then removed by rotary
evaporation followed by vacuum-drying for 48 h. The crude
product was redissolved in 2 mL of CH2Cl2, filtered, and
precipitated with 50 mL of ether and then filtered and washed.
The precipitate was recrystallized from hot ethanol, filtered,
washed with ethanol, captured with acetone, and dried [yield:
5.9 mg (79.1%)]; waxy solid. MALDI-TOF-MS: 6021, 6015,
5999 m/z. 1H NMR (CDCl3) δ: 4.12 (s, 179H), 3.69 (t, 2H), 2.39
(t, 187 H), 1.93 (t, 93H), 1.70 (s, 179H) (ratio 46:1) (theoretical
ratio 32:1). HPLC (acetonitrile) 4.07 min.
An a lysis. 1H nuclear magnetic resonance (NMR) spectra
were acquired using a Bruker Aspect-3000, AM-500 spectrom-
eter (500 MHz) without nuclear Overhauser enhancement
(NOE) using CDCl3 or d6-acetone as the solvent. Relative NMR
intensity values were obtained by integration to provide peak
areas. Electron impact (EI-MS), chemical ionization (CI-MS),
and liquid secondary ionization (LSI-MS) mass spectrometry
were performed on a VG Autospec 3 sector mass spectrometer
in the positive ion mode. MALDI-TOF-MS was performed on
a PE Biosystem Voyager System STR 4087 time-of-flight mass
spectrometer (Carnegie Mellon University) and a Voyager-DE
STR, PE Biosystems time-of-flight mass spectrometer (Vander-
bilt University) using trans-3-indoleacrylic acid (Aldrich) as
the matrix. Electrospray ionization mass spectrometry (ESI-
MS) was carried out using a Mariner (PE Biosystem) mass
spectrometer having a TOF analyzer. Relative peak intensities
from mass spectrometric techniques were estimated using
peak heights.
1
3139 m/z. H NMR (CDCl3) δ: 7.28 (d, 2H), 6.86 (d, 2H), 5.04
(s, 2H), 4.19 (s, 89H), 3.80 (s, 3H), 3.64 (t, 2H), 2.38 (t, 92H),
1.92 (m, 50H), 1.71 (s, 94H) (ratio 23:1) (theoretical ratio 16:
1). HPLC (acetonitrile) 3.06 min; TLC Rf ) 0.52 (50% CH2Cl2:
ethyl acetate).
Bu tylen e Glu ta r a te 32-m er (11C). In an 50 mL Erlen-
meyer flask, 50 mg (16 µmol) of FMOC-protected butylene
glutarate 32-mer (11B) was stirred with 78 mg (0.78 mmol,
50 equiv) of TEA in 30 mL of CH2Cl2 for 4 h. The solvent and
TEA were removed by rotary evaporation and vacuum-drying,
and the product was isolated by filtration of a CH2Cl2 solution
and washing with hexanes [yield: 39.5 mg (82.2%)]; waxy
1
solid. MALDI-TOF-MS: 3040, 3018 m/z. H NMR (CDCl3) δ:
4.12 (s, 81H), 3.69 (t, 2H), 2.39 (t, 90H), 1.93 (m, 46H), 1.70
(s, 89H) (ratio 23:1) (theoretical ratio 16:1). HPLC (acetonitrile)
3.59 min.
Or t h ogon a lly P r ot ect ed Bu t ylen e Glu t a r a t e 64-m er
(12). In a round-bottom flask 31.0 mg (1.0 µmol) of FMOC-
protected butylene glutarate 32-mer (11A), 30.0 mg (1.0 µmol)
of p-methoxybenzyl-protected butylene glutarate 32-mer (11B),
and 0.24 mg of DMAP (1.9 µmol) were stirred at 0 °C in 15
mL of CH2Cl2. EDI (2.03 mg) (10.6 µmol) was added, and the
reaction mixture was stirred at 0 °C for 4 h and at RT for 16
h. The mixture was extracted 4 × 30 mL of H2O, and the
organic fraction was evaporated and dried. The crude product
was dissolved in 5 mL of CH2Cl2 and precipitated using 50
mL of ether and then filtered and washed with ether. The

3908 Williams et al.
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Ack n ow led gm en t. This research was supported by
the Department of Chemistry, University of Pittsburgh,
and by NSF Grant CHE-9985864. The authors thank
Dr. Kasi Somayajula and Dr. Fu-Tyan Lin of the
University of Pittsburgh for their technical assistance
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the addition of supplemental material(s) produced in
separate but similar reaction.
a
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