m-Phenylene Ethynylene Sequences Joined by Imine Linkages: Dynamic Covalent Oligomers

Article abstract of DOI:10.1021/jo035007o

Imine metathesis between m-phenylene ethynylene oligomers of various lengths was performed in acetonitrile, a solvent in which oligomers containing eight or more repeat units adopt a compact helical conformation. The equilibrium constants and corresponding free energy change for the imine metathesis reactions were estimated. The results showed that the magnitude of equilibrium shifting measured by the free energy change for the formation of imine-containing oligomers increases linearly below a critical product chain length and grows asymptotically above it. The linear region is ascribed to the constant increase in contact area between monomer units of adjacent helical turns as the product chain grows to the 12-mer. Once the ligation product is 12 units in length, full contact is made between adjacent helical turns. On the other hand, for imine metathesis between oligomers leading to products having more than 12 units, the driving force is the difference between the folding energy of products and that of reactants. The additional stabilizing energy is roughly constant, regardless of the chain length, since the contact area between adjacent helical turns is unchanged. Consistent with the notion that the imine bond only minimally destabilizes the helical conformation, the position of the imine bond in the ligation product has been observed to have no significant effect on the folding stability. The magnitudes of equilibrium shifting are similar for ligation products of the same length but having the imine at various positions along the sequence. This suggests that the imine bond is compatible with the m-phenylene ethynylene backbone, regardless of the position in the sequence. Imine metathesis of m-phenylene ethynylene oligomers could allow a quick access to an unbiased, dynamic library of oligomer sequences joined by imine linkages.

Full text of DOI:10.1021/jo035007o

m -P h en ylen e Eth yn ylen e Sequ en ces J oin ed by Im in e Lin k a ges:
Dyn a m ic Cova len t Oligom er s
Keunchan Oh, Kyu-Sung J eong,† and J effrey S. Moore*
Departments of Chemistry and Material Science & Engineering,
University of Illinois, Urbana, Illinois 61801
moore@scs.uiuc.edu
Received J uly 12, 2003
Imine metathesis between m-phenylene ethynylene oligomers of various lengths was performed in
acetonitrile, a solvent in which oligomers containing eight or more repeat units adopt a compact
helical conformation. The equilibrium constants and corresponding free energy change for the imine
metathesis reactions were estimated. The results showed that the magnitude of equilibrium shifting
measured by the free energy change for the formation of imine-containing oligomers increases
linearly below a critical product chain length and grows asymptotically above it. The linear region
is ascribed to the constant increase in contact area between monomer units of adjacent helical
turns as the product chain grows to the 12-mer. Once the ligation product is 12 units in length,
full contact is made between adjacent helical turns. On the other hand, for imine metathesis between
oligomers leading to products having more than 12 units, the driving force is the difference between
the folding energy of products and that of reactants. The additional stabilizing energy is roughly
constant, regardless of the chain length, since the contact area between adjacent helical turns is
unchanged. Consistent with the notion that the imine bond only minimally destabilizes the helical
conformation, the position of the imine bond in the ligation product has been observed to have no
significant effect on the folding stability. The magnitudes of equilibrium shifting are similar for
ligation products of the same length but having the imine at various positions along the sequence.
This suggests that the imine bond is compatible with the m-phenylene ethynylene backbone,
regardless of the position in the sequence. Imine metathesis of m-phenylene ethynylene oligomers
could allow a quick access to an unbiased, dynamic library of oligomer sequences joined by imine
linkages.
In tr od u ction
identified. From a library of random nucleic acids 100
monomers in length, it is found that approximately 1 in
1010 sequences bind to a target ligand with minimum
affinity of 105-106 M-1. Interestingly, a library of random
peptides containing 80 amino acid units have been found
to display functional activity (defined as ATP binding
affinity with Kd ) 100 nM value) with similar frequency.4
The lack of a general amplification methodology re-
quires that alternative approaches be found to identify
macromolecular sequences from nonnatural building
blocks. Our approach to tyligomers involves dynamic
covalent oligomerssthe joining of bisfunctionalized, fold-
able segments through reversible covalent linkages.5
Introduction of reversible covalent linkages into poly-
meric chains may offer a dynamic combinatorial ap-
proach6 to identify masterpiece sequences2 in a reason-
Polymerizations are potentially a powerful way to
introduce structural and functional diversity into a
chemical system, since a range of structures is possible
by manipulating the monomer composition, sequence,
and chain length. Polymers having well-defined folded
structures (tyligomers)1 can potentially create 3D binding
cavities for targets of interest. However, the search for
nonnatural, copolymer sequences that are capable of
binding or performing catalytic functions is challenged
by the magnitude of diversity available to such system.2
This point is apparent from recent aptamer studies. In
vitro selection and amplification have been used to isolate
nucleic acids with desired binding and catalytic proper-
ties from a large number of random sequences.3 Succes-
sive rounds of selection and amplification allow a small
subset of sequences that have the desired property to be
(3) (a) J oyce, G. F. Curr. Opin. Struct. Biol. 1994, 4, 331-336. (b)
Chapman, K. B.; Szostak, J . W. Curr. Opin. Struct. Biol. 1994, 4, 618-
622. (c) Wilson, D. S.; Szostak, J . K. Annu. Rev. Biochem. 1999, 68,
611-647.
(4) Keefe, A. D.; Szostak, J . W. Nature 2001, 410, 715-718.
(5) Oh, K.; J eong K.-S.; Moore, J . S. Nature 2001, 414, 889-893.
(6) For reviews, see: (a) Rowan, S. J .; Cantrill, S. J .; Cousins, G. R.
L.; Sanders, J . K. M.; Stoddart, J . F. Angew. Chem., Int. Ed. 2002, 41,
898-952. (b) Lehn, J .-M. Chem. Eur. J . 1999, 5, 2455-2463. (c) Lehn,
J .-M.; Eliseev, A. V. Science 2001, 291, 2331-2332. (d) Ganesan, A.
Angew. Chem., Int. Ed. 1998, 37, 2828-2831. (e) Klekota, B.; Miller,
B. L. Trends Biotechnol. 1999, 17, 205-209.
† Current address: Department of Chemistry, Yonsei University,
Seoul 120-749, Korea.
(1) Hill, D. J .; Mio, M. J .; Prince, R. B.; Hughes, T. S.; Moore, J . S.
Chem. Rev. 2001, 101, 3893-4012.
(2) (a) Lorsch, J . R.; Szostak, J . W. Acc. Chem. Res. 1996, 29, 103-
110. (b) Moore, J . S.; Zimmerman, N. W. Org. Lett. 2000, 2, 915-918.
(c) Orgel, L. E. Acc. Chem. Res. 1995, 28, 109-118. (d) Cheeseman, J .
D.; Corbett, A. D.; Shu, R.; Croteau, J .; Gleason, J . L.; Kazlauskas, R.
J . J . Am. Chem. Soc. 2002, 124, 5692-5701.
10.1021/jo035007o CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003
J . Org. Chem. 2003, 68, 8397-8403
8397

Oh et al.
solvent denaturation studies.5 The main limitation of
imine metathesis is hydrolysis of the imine bond by
residual water, which can compete with metathesis under
aqueous conditions.
In addition to the ligation reaction, the design of
reactive oligomeric segments is an important factor to
consider in the search for new tyligomers. For hetero-
polymers that are both soluble and globular, the compo-
sition and distribution of solvophobic/solvophilic residues
must be optimized.9 Copolymers with too many solvo-
philic residues will lead to soluble macromolecules that
adopt random coil conformations, while copolymers with
too many solvophobic residues will form aggregates or
precipitates.9a,e,f Consequently, oligomeric segments must
be designed to avoid “deep thermodynamic traps”, such
as insoluble or cyclic products that could easily result
from reversible chemistry. Thus, as building blocks for
tyligomer synthesis, we see the need for a set of starter
sequencessshort sequences consisting of irreversibly
joined monomers that terminate in labile ends. These
starter sequences are chosen to avoid the extremes of
monomer composition that lead to deep traps. The starter
sequences approach is expected to allow for a closed
reaction polymerization, where there is no need to remove
any side products in order to drive high polymer forma-
tion.10
F IGURE 1. (a) The parital chemical structures of oligomers
showing the overlap between imine linkage and meta-
connected phenylene ethynylene repeat units. (b) A computer-
minimized space-filling model of unsubstituted imine 12-mer
in a helical conformation. The imine linkage is displayed as
stick type for clarity.
able time scale. It is expected that the distribution of
dynamic copolymer sequences should be sensitive to the
environmental conditions and target ligands that are
present during the equilibration process. For optimal
results, a uniform distribution of all possible sequences
is desirable, prior to the addition of the target ligand.6b
This unbiased sequence library demands that the chem-
istry used to join segments be selected carefully. As a
reversible ligation to join bisfunctionalized segments,
metathesis reactions ensure that bond energies are the
same on both sides of the equilibrium. Since the bond
energy changes do not bias the reaction equilibrium, the
product distribution is dependent solely on the thermo-
dynamic stability of each component or complex with the
target ligand. The reversible reaction should proceed
rapidly at low temperature so that binding and folding
are not disfavored during equilibration and so that
sequence space can be explored in a reasonable time
scale. Another desirable feature of the reversible reaction
is that it be easily quenched so that sequence redistribu-
tion does not take place during analysis.
Imine metathesis was selected as a ligation reaction
because the reaction meets the criteria mentioned above.
Under appropriate conditions, imine metathesis is a fast,
reversible process.5,7 It is quenched by the addition of
proton scavenger. The equilibrium constant of imine
metathesis is close to unity, allowing for an unbiased
reaction mixture in the absence of the external stimuli.
In addition to reactivity, the geometry of the imine bond
was postulated to be commensurate with the compact
helical conformation of the m-phenylene ethynylene
backbone previously studied in our laboratory.8 This was
supported by molecular modeling (Figure 1) and estima-
tions of folding stability experimentally determined from
m-Phenylene ethynylene oligomers have been selected
to test the above ideas, since these oligomers undergo a
reversible conformational transition between a random
and helical state, depending upon chain length and the
solvent composition.8 Previous studies on m-phenylene
ethynylene sequences joined by imine linkages have
shown that the dynamic pool of imine oligomers formed
from imine metathesis can be shifted by folding to favor
the conformationally ordered sequences.5 Similar ap-
proaches were used to enhance the proportion of se-
quences with the highest affinity to a particular ligand.11
We have also shown that the reversible polymerization
of bisfunctionalized imine oligomers can be driven toward
high polymer by folding.12 These results suggest that
ligand binding could be exploited to amplify the optimal
sequences for dynamic covalent oligomers.
As a prerequisite step, it is essential to examine the
thermodynamic landscape of ligation products to see
whether there is an overriding preference for certain
segments or isoenergetic unbiased mixture of sequences.6b
Here we examine the chain length dependence of a
specific system, and the effect of the position of the
dynamic linkage within the oligomeric products using
monofunctional imine oligomers.
(9) (a) Dill, K. A. Biochemistry 1985, 24, 1501-1509. (b) White, S.
H. Annu. Rev. Biophys. Biomol. Struct. 1994, 23, 407-439. (c) Gates,
R. E.; Fisher, H. F. Proc. Nat. Acad. Sci. U.S.A. 1971, 68, 2928-2931.
(d) Fisher, H. F. Proc. Nat. Acad. Sci. U.S.A. 1964, 51, 1285-1291. (e)
Yamaguchi, A.; Yomo, T.; Tanaka, F.; Prijambada, I. D.; Ohhashi, S.;
Yamamoto, K.; Ogasahara, K.; Yutani, K.; Kataoka, M.; Urabe, I. FEBS
Lett. 1998, 421, 147-151. (f) Prijambada, I. D.; Yomo, T.; Tanaka, F.;
Kawama, T.; Yamamoto, K.; Hasegawa, A.; Shima, Y.; Negoro, S.;
Urabe, I. FEBS Lett. 1996, 382, 21-25.
(10) Odian, G. Principles of Polymerization, 3rd ed.; J ohn Wiley &
Sons: New York, 1991; Chapter 2.
(11) Nishinaga, T.; Tanatani, A.; Oh, K.; Moore, J . S. J . Am. Chem.
Soc. 2002, 124, 5934-5935.
(12) (a) Zhao, D.; Moore, J . S. J . Am. Chem. Soc. 2002, 124, 9996-
9997. (b) Zhao, D.; Moore, J . S. Macromolecules 2003, 36, 2712-2720.
(7) To´th, G.; Pinte´r, I.; Messmer, A. Tetrahedron Lett. 1974, 15, 735-
738.
(8) (a) Nelson, J . C.; Saven, J . G.; Moore, J . S.; Wolynes, P. G. Science
1997, 277, 1793-1796. (b) Prince, R. B.; Saven, J . G.; Wolynes, P. G.;
Moore, J . S. J . Am. Chem. Soc. 1999, 121, 3114-3121.
8398 J . Org. Chem., Vol. 68, No. 22, 2003

Dynamic Covalent Oligomers
SCHEME 1
Resu lts a n d Discu ssion
proton NMR resonances for oligomers longer than the
8-mer are poorly resolved and buried in the aromatic
region. Direct monitoring of the reaction mixture was not
feasible. To circumvent this problem, the metathesis
reactions were performed in dry acetonitrile in the
presence of oxalic acid catalyst, quenched, concentrated,
and redissolved in CDCl3, where the imine CH proton
resonance for one of the reactants is resolved from the
overlapped product imine CH proton resonances. The
reactions were quenched by adding the resin-supported
amine propylaminomethylpoly(styrene-co-divinylben-
zene). The beads were conveniently removed by filtration
prior to concentrating the solution.
The synthesis of imine oligomers with various lengths
is shown in Scheme 1. Oligomer segments 8-16 were
synthesized by repetitive Sonogashira coupling of ap-
propriate aryl halide and terminal acetylene precursors.8b,13
C-terminal and N-terminal imine groups (18-22 and 24-
27) were added by condensation of the corresponding
aldehydes and amines.
For all of the metathesis experiments, equimolar
quantities of C- and N-terminal imine oligomers were
dissolved in dry acetonitrile. Oxalic acid was added to
this solution and the reaction mixture was stirred at room
temperature (Scheme 2). The equilibrium product dis-
tribution resulting from imine metathesis was deter-
mined by NMR spectroscopy. Under the reaction condi-
tions in polar solvents such as acetonitrile, the imine CH
To ensure that no redistribution took place following
quenching, model metathesis reactions using simple
monofunctional imines were conducted (see Scheme 3 and
the Supporting Information). C-terminal imine monomer
36 was dissolved in dry acetonitrile, and oxalic acid was
added to this solution. There was no change in NMR over
(13) Zhang, J .; Pesak, D. J .; Ludwick, J . L.; Moore, J . S. J . Am.
Chem. Soc. 1994, 116, 4227-4239.
J . Org. Chem, Vol. 68, No. 22, 2003 8399

Oh et al.
SCHEME 2
SCHEME 3
metathesis between short oligomers when the ligation
product is shorter than a critical chain length, which is
a hexamer. When the chain length of ligation products
increases from the 8-mer to the 12-mer, the magnitude
of equilibrium shifting linearly increases. When both
reactants and products are capable of folding, the mag-
nitude of equilibrium shifting increases asymptotically
above the 12-mer.
Previously8b we showed that the helical conformation
of phenylene ethynylene oligomers is stable at room
temperature in acetonitrile above a critical length and
that there is a linear correlation between folding stability
and chain length. From solvent denaturation studies, the
difference in the free energy between the helical and
random conformations can be estimated for the m-
phenylene ethynylene oligomers. Each additional repeat
unit contributes approximately 0.7 kcal/mol of stability
to the helical conformation. This has been ascribed to the
fact that the folding stability is proportional to the contact
area between adjacent turns in a compact helical con-
formation. The imine oligomers containing six or fewer
repeat units are too short to fold, so there is no stable
helical conformation in the reactants. The driving force
for equilibrium shifting in metathesis between short
oligomers is, thus, the stabilizing energy only from folding
of ligation products. The intramolecular contact between
monomer units of adjacent turns along the backbone is
possible only after the ligation product is longer than the
critical length and it increases linearly up to the point
at which full contact is made between adjacent helical
turns (i.e., two full turns, Figure 4a,c).
20 min. The acid catalyst was then quenched with the
resin-supported amine and an equimolar quantity of
N-terminal imine monomer 35 was added. No metathesis
was observed over 16 h. On the other hand, the metath-
esis of N- and C-terminal imine monomers 35 and 36
reached equilibrium within 40 min in the presence of acid
catalyst. This observation supports the notion that the
quenching method is effective to stop metathesis and that
the imine metathesis occurs negligibly in neutral organic
solvents.
The magnitudes of equilibrium shifting in imine me-
tathesis between short oligomers were obtained through
NMR measurements. The data are reported as the free
energy difference relative to dimer formation. For the
calculation of the equilibrium constants, the imine CH
proton peaks of both reactants and products were inte-
grated to estimate the molar concentration of each species
in the reaction mixture (Figure 2 and Table 1).14 As seen
in Figure 3, there is no equilibrium shifting in imine
Reactant oligomers containing eight or more repeat
units form a stable helix even before they undergo
ligation. The driving force for ligation of prefolded oligo-
mers is, therefore, the difference between the folding
energy of products and that of reactants, which would
be the additional contact between adjacent helical turns
around the newly formed imine linkage in the ligation
product. The additional stabilizing energy from aromatic
stacking interactions is estimated to be constant, regard-
(14) The concentrations of the two reactants are identical, since the
reaction starts from an equimolar mixture. For the same reason, the
two products are also of equal concentration. Thus, the square of the
peak intensity ratio of the product to the reactant at equilibrium
corresponds to the equilibrium constant. Once equilibrium is estab-
lished, one peak from the reactant and two overlapped peaks from two
products are integrated after baseline correction. Integration of the
reactant peak and half the value of the overlapped product peaks were
used to calculate the equilibrium constants.
8400 J . Org. Chem., Vol. 68, No. 22, 2003

Dynamic Covalent Oligomers
1
F IGURE 2. Partial H NMR spectra (500 MHz, CDCl3, 294 K) showing the imine CHdN region for the reactants and products
of the imine metathesis reaction. Signals from the reaction of C-terminal 8-mer 20 and N-terminal 8-mer 25 at 0 d (a), 1 d (b),
2 d (c), and 5 d (d). The equilibration was performed in acetonitrile with 5 mol % of oxalic acid relative to total imine at 294 K and
an initial concentration of 5 mM for both 20 and 25. The reaction was quenched with the resin-supported amine at a given time
and the reaction mixture was dissolved in CDCl3 for NMR analysis.
TABLE 1. Equ ilibr iu m Con sta n ts for Va r iou s Im in e Meta th esis Rea ction s
reactants
K
eq (294 K)
1.1b
entry
C-terminal
N-terminal
ligation product
2 d
5 d
-∆∆G (kcal mol-1
)
1a
2a
3a
4a
5a
6
7
8
9
10
11
1-mer
1-mer
6-mer
6-mer
6-mer
4-mer 18
6-mer 19
8-mer 20
8-mer 20
10-mer 21
12-mer 22
1-mer
4-mer
2-mer
4-mer
6-mer
12-mer 27
10-mer 26
8-mer 25
12-mer 27
10-mer 26
12-mer 27
2-mer
5-mer
8-mer
10-mer
12-mer
16-mer 28
16-mer 29
16-mer 30
20-mer 31
20-mer 32
24-mer 33
0.00
0.00
0.50
1.66
2.35
2.9 ( 0.4
3.1 ( 0.1
3.3 ( 0.3
3.3 ( 0.1
3.6 ( 0.2
3.8 ( 0.1
1.1 ( 0.1b
2.6 ( 0.1b
19 ( 1b
62 ( 2b
70
250
170
400
220
340
800
260
170
340
550
580
a
b
See ref 5. Equilibrium is attained after about 1 h.
less of the chain length, since the contact area between
adjacent helical turns is presumably same (Figure 4b,d).
Therefore, the magnitude of the equilibrium shifting is
expected to be similar when the ligation products are
longer than the 12-mer. The linear relationship between
the magnitude of equilibrium shifting and chain length
does not hold once the reactant oligomers are in helical
conformation under the equilibration conditions. On the
basis of the solvent denaturation studies previously
mentioned, it is estimated that there is ca. 4.0 kcal/mol
of folding stabilizing energy from intramolecular contacts
between adjacent helical turns, assuming that there are
six units in one turn.15 This is in reasonable agreement
with the observed value (3.0-3.7 kcal/mol) for the
stabilizing energy measured from the imine metathesis,
where the ligation product has an additional stacking
interaction amounting to one helical turn compared to
the reactants.
Previously5 we showed that the imine metathesis in
chloroform did not exhibit significant equilibrium shift-
ing, regardless of the chain length. This observation has
(15) Matsuda, K.; Stone, M. T.; Moore, J . S. J . Am. Chem. Soc. 2002,
124, 11836-11837.
J . Org. Chem, Vol. 68, No. 22, 2003 8401

Oh et al.
those of the metathesis between oligomers of various
lengths in chloroform.
In previous studies,5,17 the imine bond was suggested
to be commensurate with the backbone of oligomers in a
compact helical conformation (Figure 1) and macrocycles
of the m-phenylene ethynylenes. To test the possibility
that the position of the imine bond along the backbone
might affect the stability of oligomers, imine metatheses
between oligomers of different length were also con-
ducted. Isomeric ligation products could thus be com-
pared. If the stability of product having an imine bond
off-center is decreased, the magnitude of the equilibrium
shifting is expected to be smaller than that for oligomers
with an imine bond in the center. The results are seen
in Table 1 and Figure 3 ([ points). The equilibrium
constant for imine metathesis between 8-mer 20 and 12-
mer 27 to produce a 20-mer ligation product was found
to be ca. 170 with a value of -∆∆G of at least 3.0 kcal
mol-1, which is in good agreement with that of the imine
metathesis between two 10-mers (3.0 kcal mol-1). The
position of the imine bond in the metathesis product,
therefore, does not affect the equilibrium shifting of the
metathesis reaction significantly. We also investigated
the case where the imine bond is located at the end of
the oligomer. Equilibrium constants of imine metathesis
were compared where the reactants are 4-mer and 12-
mer, 6-mer and 10-mer, and 8-mer and 8-mer to produce
16-mer ligation products in which the imine bond is at
various positions. The folding stabilities were found to
be ca. 2.9, 3.1, and 3.3 kcal/mol, respectively. The folding
stability is thus not significantly dependent upon the
position of the imine bond. The helical conformation is
not significantly reduced when an ethynylene bond is
replaced by an imine bond and the position does not
significantly change the shape of helical conformation
(Figure 1).
F IGURE 3. Plot of the free energy change for metathesis
reactions in Table 1 versus the chain length of the ligation
product with central imine bond (9) and with imine bond off-
center ([). The magnitude of the equilibrium shifting was
referenced to the free energy change for dimer formation. The
molar ratios were determined from the integration of the imine
1H NMR signals. Error estimates are based on the standard
deviation of -∆∆G values measured at 2 and 5 d.
The equilibrium shifting for imine metathesis driven
by folding was observed in the polymerization of bisfunc-
tionalized imines as well.12 When bisfunctionalized imine
monomers having four repeat units were polymerized
under metathesis conditions, the monomers were con-
sumed to form dimers and sequential polymerization
occurred (Figure 5). The monomer itself is too short to
fold, whereas the dimer is longer than the critical chain
length. For dimerization, the driving force is the intra-
molecular aromatic stacking interactions in ligation
products of helical conformation. For subsequent steps
in the polymerization, the dimer is already in a helical
conformation. Thus, the driving force is aromatic stacking
between adjacent helical turns around the newly formed
imine bonds. This additional stabilization energy is
expected to drive the polymerization of imines once all
the monomer is consumed.
F IGURE 4. Schematic representation of imine metathesis of
m-phenylene ethynylene oligomers between short oligomers
(a) and between long oligomers (b). The equilibria for imine
metathesis and the folding are coupled. The additional stabi-
lizing energy is from the aromatic stacking of intramolecular
helical turn (c) or of intermolecular helices (d).
Con clu sion s
been ascribed to the fact that imine oligomers exist in
random conformational states in chloroform.16 When the
metathesis between C- and N-terminal imine 8-mers 20
and 25 was conducted in chloroform instead of aceto-
nitrile, an equilibrium constant of 1.6 was obtained. This
equilibrium constant is in reasonable agreement with
The effect of chain length on the magnitude of equi-
librium shifting in imine metathesis has been investi-
gated. The driving force for equilibrium shifting in
metathesis between short oligomers is the stabilizing
energy from folding of ligation products, since the reac-
(16) Hill, D. J .; Moore, J . S. Proc. Natl. Acad. Sci. U.S.A. 2002, 99,
5053-5057.
(17) Zhao, D.; Moore, J . S. J . Org. Chem. 2002, 67, 3548-3554.
8402 J . Org. Chem., Vol. 68, No. 22, 2003

Dynamic Covalent Oligomers
F IGURE 5. Schematic representation of reversible polymerization of bisfunctionalized m-phenylene ethynylene oligomers.12 Starter
sequences combine to form a product longer than the critial chain length, which is subsequently driven to high polymer.
tants are too short to fold. There is a linear correlation
between the magnitude of equilibrium shifting and chain
length below a critical length, since the contact area
increases linearly, as the product chain grows to 12-mer,
where the ligation product makes full contact between
adjacent helical turns. On the other hand, reactant
oligomers having eight or more repeat units are capable
of folding so that the driving force for metathesis is the
difference between the folding energy of products and
that of reactants. In the limit of long oligomer reactants,
this corresponds to the contact between adjacent helical
turns around the newly formed imine linkage in the
ligation product. The measured values are in reasonable
agreement with the difference in the free energy between
the helical and random conformations observed from
solvent denaturation studies of m-phenylene ethynylene
oligomers. Imine metatheses between oligomers of dif-
ferent length producing isomeric ligation products have
been conducted to explore the effect of imine position on
the equilibrium shifting. The position of the imine bond
in the ligation product has been observed to have no
significant effect on the folding stability and the magni-
tudes of equilibrium shifting. We therefore concluded that
imine metathesis between oligomers longer than a critical
length can be used to generate a dynamic, unbiased pool
with respect to chain length and the position of the
dynamic linkage, providing an ideal system to test ideas
for the generation of tyligomers and masterpiece se-
quences.
Ack n ow led gm en t. This material is based upon
work supported by the U. S. Department of Energy,
Division of Materials Sciences under Award No.
DEFG02-91ER45439, through the Frederick Seitz
Materials Research Laboratory at the University of
Illinois at UrbanasChampaign.
Su p p or tin g In for m a tion Ava ila ble: General methods,
quenching study of imine metathesis, decay time study, and
1
partial H NMR spectra showing the imine CH)N region for
the reactants and products of the imine metathesis reaction.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O035007O
J . Org. Chem, Vol. 68, No. 22, 2003 8403