Foldamers as reactive sieves: Reactivity as a probe of conformational flexibility

Article abstract of DOI:10.1021/ja067670a

A series of m-phenyleneethynylene (mPE) oligomers modified with a dimethylaminopyridine (DMAP) unit were treated with methyl sulfonates of varying sizes and shapes, and the relative reactivities were measured by UV spectrophotometry. Using a small-molecule DMAP analogue as a reference, each of the methyl sulfonates was shown to react at nearly identical rate. In great contrast, oligomers that are long enough to fold, and hence capable of binding the methyl sulfonate, experience rate enhancements of 18-1600-fold relative to that of the small-molecule analogue, depending on the type of alkyl chain attached to the guest. Three different oligomer lengths were studied, with the longest oligomers exhibiting the fastest rate and greatest substrate specificity. Even large, bulky guests show slightly enhanced methylation rates compared to that with the reference DMAP, which suggests a dynamic nature to the oligomer's binding cavity. Several mechanistic models to describe this behavior are discussed.

Full text of DOI:10.1021/ja067670a

Published on Web 04/10/2007
Foldamers as Reactive Sieves: Reactivity as a Probe of
Conformational Flexibility
Ronald A. Smaldone and Jeffrey S. Moore*
Contribution from the Departments of Chemistry, Materials Science and Engineering and
The Beckman Institute for AdVanced Science and Technology, UniVersity of Illinois,
Urbana, Illinois 61801
Received October 26, 2006; E-mail: moore@scs.uiuc.edu
Abstract: A series of m-phenyleneethynylene (mPE) oligomers modified with a dimethylaminopyridine
(DMAP) unit were treated with methyl sulfonates of varying sizes and shapes, and the relative reactivities
were measured by UV spectrophotometry. Using a small-molecule DMAP analogue as a reference, each
of the methyl sulfonates was shown to react at nearly identical rate. In great contrast, oligomers that are
long enough to fold, and hence capable of binding the methyl sulfonate, experience rate enhancements of
18-1600-fold relative to that of the small-molecule analogue, depending on the type of alkyl chain attached
to the guest. Three different oligomer lengths were studied, with the longest oligomers exhibiting the fastest
rate and greatest substrate specificity. Even large, bulky guests show slightly enhanced methylation rates
compared to that with the reference DMAP, which suggests a dynamic nature to the oligomer’s binding
cavity. Several mechanistic models to describe this behavior are discussed.
Introduction
guest systems have been developed that are capable of reacting
catalytically, but these systems typically perform transformations
The development of synthetic catalysts has resulted in the
ability to perform a wide range of reactions under mild
conditions with impressive levels of selectivity. The most
successful of these have high substrate generality, allowing for
widespread application in synthesis.1-4 While substrate general-
ity is usually desired, a limitation to this approach may be the
inability to “choose” a particular reactive site in a polyfunctional
substrate, or a specific substrate based on molecular structure
distant from the reactive site. This type of selectivity is well-
known in biological systems that combine substrate recognition
with efficient, catalytic reactivity. Enzymes are able to locate a
specific substrate from a myriad of nearly isosteric molecules
with very low rates of error (e.g., DNA polymerases, RNA
synthetases).5 Catalytic systems designed to possess recognition-
based reactivity are less well developed and have not found
widespread use in synthetic applications.6,7
that can be carried out with greater efficiency using small-
molecule catalysts (e.g., hydrolysis, Diels-Alder reactions).8,10
Synthetic systems with a well-defined secondary structure
capable of combining molecular recognition along with the
ability to perform useful conversions are rare in the literature.9,11
Rarer still are modular constructs that allow systems to be
designed and easily modified to specifically recognize different
substrates.9 Foldamers possess such a modular construction and
are candidates for catalysts that combine recognition with
reactivity. Our laboratory and others have been interested in
pursuing foldamer-based reactivity.9,15-17 Compared with other
supramolecular catalysts or reactors, m-phenyleneethynylene
(mPE) oligomers are unique in that they combine conformational
flexibility in the helical state, along with a modular structure
amenable to site-specific functionalization via sequence design.
Recent developments in the solid-phase synthesis of these
molecules allow for rapid synthesis as well and facile modifica-
tion of the cavity interior.18 In moving toward the development
of foldamers that operate via covalent catalysis mechanisms,
we wanted to understand how reactivity of functionalized mPEs
There have been many attempts toward artificial “enzymes”
that combine molecular recognition properties with catalytic
reactivity.8-14 Over the past several decades numerous host-
(1) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(2) Denmark, S. E.; Heemstra, J. R. J.; Beutner, G. L. Angew. Chem., Int. Ed.
2005, 44, 4682-4698.
(12) Vriezema, D. M.; Aragones, M. C.; Elemans, J. A. A. W.; Cornelissen, J.
J. L. M.; Rowan, A. E.; Nolte, R. J. M. Chem. ReV. 2005, 104, 1445-
1490.
(3) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017.
(4) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442-4489.
(13) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Adhya, M. J. Org. Chem. 1989,
54, 5302-5308.
(5) Fersht, A. Enzyme Structure and Mechanism; W. H. Freeman and Company
Limited: Reading and San Francisco, 1977.
(14) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Manimaran, T. L. J. Org. Chem.
1983, 48, 3619-3620.
(6) Hilvert, D.; Hill, K. W.; Nared, K. D.; Auditor, M. T. M. J. Am. Chem.
Soc. 1989, 111, 9261-9262.
(15) Peelen, T. J.; Yonggui, C.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127,
11598-11599.
(7) Schultz, P. G.; Lerner, R. A. Science 1995, 269, 1835-1842.
(8) Kang, J.; Hilmersson, G.; Santamaria, J.; Rebek, J., Jr. J. Am. Chem. Soc.
1998, 120, 3650-3656.
(16) Dolain, C.; Zhan, C.; Leger, J.-M.; Daniels, L.; Huc, I. J. Am. Chem. Soc.
2005, 127, 2400-2401.
(9) Miller, S. J. Acc. Chem. Res. 2004, 37, 601-610.
(10) Richeter, S.; Rebek, J., Jr. J. Am. Chem. Soc. 2004, 126, 16280-16281.
(11) Yang, J.; Breslow, R. Angew. Chem., Int. Ed. 2000, 39, 2692-2694.
(17) Heemstra, J. M.; Moore, J. S. J. Am. Chem. Soc. 2004, 126, 1648-1649.
(18) Elliott, E. L.; Ray, C. R.; Kraft, S.; Atkins, J. R.; Moore, J. S. J. Org.
Chem. 2006, 71, 5282-5290.
9
5444
J. AM. CHEM. SOC. 2007, 129, 5444-5450
10.1021/ja067670a CCC: $37.00 © 2007 American Chemical Society

Foldamers as Reactive Sieves
A R T I C L E S
Scheme 1. Methylation of a DMAP-Modified mPE Oligomer
depended on substrate scope. Described herein is a modular
oligomeric system with a helical secondary structure that,
although exhibiting only simple reactivity, is able to differentiate
substrates on the basis of subtle differences in size and shape
remote to the reactive group.
ations for different sized methylating reagents and different
length oligomers is used here to provide useful, albeit qualitative,
information about the range of conformations accessible to the
foldamer.
To quantify the reactivity of these oligomers and the various
substrates, we employ the general kinetic model shown in eq
1. This model proposes two separate pathways through which
an oligomer can be methylated.
Previous studies have demonstrated the ability of mPE
oligomers to adopt a solvophobically driven helical conformation
that exhibits molecular recognition capabilities.19-21 When
properly functionalized, oligomers of sufficient length display
rate enhancements of methylation with iodomethane (Scheme
1).17 Competitive inhibition studies supported the idea that the
methylation reaction occurs within the hydrophobic, helical
cavity.22 This discovery led to the possibility that the oligomer
cavity could act as a “reactive sieve”, capable of selectively
transforming substrates of a certain size or shape. A similar
mechanistic concept has been suggested in biological systems
where certain synthetase enzymes employ multiple, increasingly
selective filters to ensure that the correct amino acid substrate
is bound to the active site.23,24 Here we describe studies aimed
at testing the concept of reactive sieving in mPE oligomers.
The simplistic notion of reactive sieving shown in Figure 1
raises two questions that this research attempts to clarify. First,
how significant must differences in the substrates be in order
for rate differences to be observed? Second, is the helix well
defined, or is conformational flexibility a factor, and if so, does
the cavity’s shape maintain sufficient fidelity to provide substrate
discrimination? Conformational flexibility and dynamics are
known to be factors in enzyme catalysis, and the extent of the
role played by these phenomena has been under intense
investigation and debate in recent literature.25-27 While molec-
ular recognition studies previously performed with mPE oligo-
mers provide insight into the equilibrium binding structure, little
information is available about chain dynamics.19,21 Theoretical
simulations have indicated that mPE foldamers are somewhat
flexible in the folded state, but no experimental verification of
this has been attempted.28 Monitoring the progress of methyl-
The background reaction is imagined as taking place through
an unfolded or partially folded conformation. On the basis of
previously reported data,17 the rate of the background reaction
is expected to be significantly smaller than the rate of reaction
for the oligomer-MeX complex. This expectation is generally
found to hold here. However, a sufficiently large or cumbersome
substrate may react slowly with the folded oligomer either
because of a low Ka, or because the progression of the complex
(19) Prince, R. B.; Barnes, S. A.; Moore, J. S. J. Am. Chem. Soc. 2000, 122,
2758-2762.
(20) Prince, R. B.; Saven, J. G.; Wolynes, P. G.; Moore, J. S. J. Am. Chem.
Soc. 1999, 121, 3114-3121.
(21) Tanatani, A.; Mio, M. J.; Moore, J. S. J. Am. Chem. Soc. 2001, 123, 1792-
1793.
(22) Heemstra, J. M.; Moore, J. S. J. Org. Chem. 2004, 69, 9234-9237.
(23) Fersht, A. R. Science 1998, 280, 541.
(24) Nureki, O.; Vassylyev, D. G.; Tateno, M.; Shimada, A.; Nakama, T.; Fukai,
S.; Konno, M.; Hendrickson, T. L.; Schimmel, P.; Yokoyama, S. Science
1998, 280, 578-582.
(25) Boehr, D. D.; McElheny, D.; Dyson, H. J.; Wright, P. E. Science 2006,
313, 1638-1642.
(26) Cannon, W. R.; Singleton, S. F.; Benkovic, S. J. Nat. Struct. Biol. 1996, 3,
821.
(27) Schnell, J. R.; Dyson, H. J.; Wright, P. E. Annu. ReV. Biophys. Biomol.
Figure 1. Cartoon illustration of “reactive sieving” along with an expected
rate profile for a reaction occurring at active site R*.
Struct. 2004, 33, 119.
(28) Lee, O.; Saven, J. G. J. Phys. Chem. B 2004, 108, 11988-11994.
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A R T I C L E S
Smaldone and Moore
Chart 1. DMAP-modified Trimer 2 and mPE Oligomers 3a-d
Used in This Study
Scheme 2. General Synthetic Method for DMAP-Modified mPE
Oligomers
sulfonates (5a-e) were chosen as methylating agents (5a is
synthesized as a racemic compound). The ability to systemati-
cally vary the alkyl group without affecting the chemical
reactivity as determined by reference to compound 2, along with
their UV transparency in the wavelength range monitored for
these kinetic studies (360 nm, 340 nm), made this class of
molecules ideal for this endeavor.
Chart 2. Methyl Sulfonate Esters Used in UV/Vis Kinetics
Experiments
Synthesis. A general synthetic scheme for preparing the
DMAP-modified mPE oligomers is shown in Scheme 2. The
synthesis of 6 and the oligomer fragments 7a and 7c have been
previously reported.17,22 The synthesis of fragments 7b and 7d
were carried out using an efficient, iterative solid-phase method
that we recently reported.18 Attachment of 7a-d to 6 was
accomplished by a Sonogashira cross-coupling reaction using
either Pd(PPh3)4 or a dimeric Pd(I) precatalyst previously
reported by this group.18 Oligomer fragments and DMAP
oligomers were purified by preparative gel permeation chro-
matography (GPC) and characterized by 1H NMR and MALDI
mass spectrometry. Full details are available in the Supporting
Information.
Several different pathways were utilized to prepare the various
methyl sulfonates.29-31 A synthetic scheme that shows these
methods and the experimental details describing preparations
of previously unreported methyl alkylsulfonates can be found
in the Supporting Information.
Results
The rate of reaction between methylating agents (4a-h, 5a-
e) and the oligomers (2, 3a-c) was measured by UV/vis
spectrophotometry (Figures 2 and 3).
The reactions were conducted in acetonitrile so as to employ
a solvent that is known to promote the helical conformation.
Each methylating agent was used in large excess (5000 equiv)
in order to simplify the kinetic analysis. The second-order rate
coefficients (k2), obtained by dividing the pseudo-first-order rate
to product is inefficient (e.g., the methylating agent may only
bind in such a way that the reaction is unfavorable). Attempts
to “shut down” the reaction by making the oligomer’s cavity
congested are also described.
The structures of the oligomers studied are shown in Chart
1. Trimer 2 is a compound that provides a reference reaction
rate since it is incapable of adopting the helical conformation.
Oligomers 3a-c systematically increase in their length, whereas
3d has a large fraction of the helix cavity occupied by methyl
groups. Chart 2 shows the scope of substrates tested. In
particular, a series of linear (4a-h) and branched methyl
(29) Padmapryia, A. A.; Just, G.; Lewis, N. G. Synth. Commun. 1985, 15, 1057-
1062.
(30) Wilson, S. R.; Georgiadis, G. M. Org. Synth. 61, 74.
(31) Wilson, S. R.; Georgiadis, G. M.; Khatri, H. N.; Bartness, J. E. J. Am.
Chem. Soc. 1980, 102, 3577.
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5446 J. AM. CHEM. SOC. VOL. 129, NO. 17, 2007

Foldamers as Reactive Sieves
A R T I C L E S
Figure 2. UV spectra of unmethylated (blue curve) and methylated (red
curve) DMAP oligomers (2 top, 3a, bottom). UV spectra were taken in
acetonitrile at 25 °C in the concentration range of 3-4 µM for 3a and
15-25 µM for 2. The methylated products for both spectra have methyl
sulfonate counterions.
Figure 3. Representative plot of absorbance vs time (top) and (ln[Mo]/
[M])/[CH3X] vs time (bottom) for reaction of oligomer 3c with substrate
4e ([M0] ) initial oligomer concentration, [M] ) oligomer concentration).
Kinetic data were measured by monitoring the absorbance at 360 nm in
acetonitrile at 25 °C. Oligomer concentration was 4 µM with excess 4e
(5000 equiv). The second-order rate coefficient (k2) was obtained by dividing
the pseudo-first-order rate coefficient (k1 ) 0.00042 s-1) by the concentration
of methylating agent (5000 equiv, ∼0.02 M). Additional representative plots
are included in the Supporting Information.
by the concentration of methylating agent, are shown in Table
1, and plotted in Figure 4. As can be seen in Table 1, the rate
of the background reaction (kbackground), represented by reference
compound 2, is smaller than the experimental error for the rate
measurements of the longer oligomers and therefore not
significant in the analysis of 3a-c.
The data in Figure 4 indicate that the rate coefficients are
highly dependent on the substrate in remarkably subtle ways.
To illustrate that these rate differences are significant and that
they relate to the structure of the folded oligomer, rate
coefficients for each methylating agent were determined using
trimer 2 as a reference. These rate coefficients are essentially
constant for all substrates, as shown in Figure 5.
Table 1. Second-Order Rate Coefficients (k2) for Methylations of
3a-c
2 k2
×
3a k2
×
3b k2
×
3c k2
×
1
3
1
3
1
3
1
3
(M-1 s-
10-
)
(M-1 s-
10-
)
(M-1 s-
10-
)
(M-1 s-
10-
)
Linear Methyl Alkylsulfonate
methyl (4a)
ethyl (4b)
n-propyl (4c) 0.020 ( 0.002
n-butyl (4d) 0.022 ( 0.001
n-heptyl (4e) 0.023 ( 0.001
n-octyl (4f)
n-decyl (4g)
n-undecyl (4h) 0.025 ( 0.001 16.6 ( 0.5
0.028 ( 0.008
1.8 ( 0.3
2.4 ( 0.2
5.1 ( 0.3
3.4 ( 0.3
9.3 ( 0.7
2.4 ( 0.1
3.9 ( 0.2
3.6 ( 0.1
3.4 ( 0.3
9.8 ( 0.3
12.2 ( 0.4
18.9 ( 0.2
23.1 ( 0.8
3.3 ( 0.2
5.6 ( 0.2
6.0 ( 0.2
5.6 ( 0.7
21.2 ( 3
26.7 ( 7
26 ( 1
0.028 ( 0.003
Previous studies using methyl iodide as a methylating agent
showed that a DMAP-modified 13-mer was capable of enhanc-
ing the reaction rate by 400-fold relative to the reference
reaction.17 Shown in Table 2 are the rate enhancements of each
methylation reaction by oligomers 3a-c relative to 2.
0.026 ( 0.001 12.6 ( 0.7
0.027 ( 0.001 13.5 ( 1
38.5 ( 2
As can be seen in Table 2, the smallest rate enhancement
observed was in the reaction of 5e with oligomer 3a. Despite
what appears to be a significant rate reduction in Figure 4, 3a
is still able to enhance the reaction rate by 45-fold compared to
the reference reaction with 2. To test the limits of the mPE
helical cavity’s ability to enhance the methylation rate, a DMAP-
modified 17-mer with methyl groups lining the cavity interior
was synthesized (3d). Oligomers of this type have been
previously shown to fold into a more stable conformation and
to more effectively exclude guests due to the decreased cavity
space.19 Additionally, an extremely bulky methylating agent,
Branched Methyl Alkylsulfonate
2-butyl (5a)
0.023 ( 0.001 12.7 ( 0.6
16.7 ( 0.5
20 ( 0.7
4.3 ( 0.7
1.9 ( 0.1
22.5 ( 3
42.1 ( 3
18.7 ( 0.4
2.9 ( 0.2
3.7 ( 0.2
3-pentyl (5b) 0.019 ( 0.001 15.4 ( 1
4-heptyl (5c) 0.020 ( 0.001
5-nonyl (5d) 0.021 ( 0.001
6-undecyl (5e) 0.025 ( 0.001
1.9 ( 0.2
1.3 ( 0.1
1.2 ( 0.1
1.76 ( 0.03
1-adamantyl methyl sulfonate (8) was used to further reduce
the binding affinity (Table 3).32 The relative rates of these
substrates are shown in comparison to relative rates of other
branched methylating agents in Figure 6.
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A R T I C L E S
Smaldone and Moore
Figure 5. Second-order rate coefficients of methylating agents with control
trimer 2 ((a) linear substrates, (b) branched substrates). Kinetic data were
measured at 25 °C in acetonitrile. Trimer 2 concentrations ranged from 15
to 25 µM using excess methyl alkylsulfonate (5000 equiv).
Figure 4. Second-order rate coefficients for linear (a) and branched (b)
methyl alkylsulfonates with 3a-c. Kinetic data were measured at 25 °C in
acetonitrile with oligomers in the concentration range of 3-4 µM and 5000
equiv of methyl sulfonate.
Table 2. Relative Methylation Rates (k(3a-c)/k(2))
13mer (3a)
15mer (3b)
17mer (3c)
Discussion
Linear Methyl Alkylsulfonates
There are several general trends observed in Figure 4. All of
the oligomers react significantly faster than reference compound
2. For each member of the linear series, the rate of methylation
increases with increasing length of oligomers 3a-c. This
difference can be fairly dramatic given that the oligomer length
only changes by four monomer units from the shortest oligomer
(3a) to the longest (3c). This trend suggests that the recognition
capability of the cavity is a significant factor in determining
methylation rate, which is consistent with previous observations
involving this system.17,22 In our communication, relative rate
increases of ∼400-fold using methyl iodide as a methylating
agent were observed.17 However, in the study reported here,
both larger (as high as 1600-fold, 5b) and smaller (18-fold, 8)
rate increases were observed, depending on the methylating
agent used (Table 2). These rate increases are based on the
comparison to the rate of reference compound 2, which is
assumed to approximate an upper limit of the background
reaction (kbackground). Unlike the behavior with 3a-c, the methyl
sulfonates methylate 2 with similar rate coefficients. Referring
to the model described in eq 1, the observed rate differences in
methyl (4a)
ethyl (4b)
68 ( 12
95 ( 10
93 ( 5
130 ( 10
220 ( 10
150 ( 10
140 ( 10
130 ( 20
380 ( 20
470 ( 30
740 ( 40
900 ( 60
n-propyl (4c)
n-butyl (4d)
n-heptyl (4e)
n-octyl (4f)
n-decyl (4g)
n-undecyl (4h)
200 ( 20
130 ( 20
360 ( 30
490 ( 40
520 ( 60
640 ( 40
230 ( 10
255 ( 40
830 ( 110
1000 ( 270
1000 ( 70
1500 ( 110
Branched Methyl Alkylsulfonates
2-butyl (5a)
3-pentyl (5b)
4-heptyl (5c)
5-nonyl (5d)
6-undecyl (5e)
490 ( 34
600 ( 54
74 ( 10
52 ( 4
650 ( 39
780 ( 47
170 ( 28
75 ( 7
870 ( 140
1600 ( 130
730 ( 40
110 ( 10
45 ( 4
68 ( 4
150 ( 12
Table 3. Adamantyl Sulfonate (8) and Rate Coefficient with
Oligomer 3d and Reference Compound 2
1
3
1
3
oligomer
k2 (M-1 s-
×
10-
)
k2(2) (M-1 s-
×
10-
)
k2 (oligomer)/k2(2)
3c
3d
200
70
3.9 ( 0.3
3.9 ( 0.3
51
18
(32) It should be noted that the inherent reactivity of 8 is much higher than
those of methylating agents 4a-h and 5a-e, making a direct comparison
with these substrates difficult. However, since the relative rate enhancement
parameter is a ratio of oligomer rate to control rate, these values can be
directly compared. The reasons for the inherent rate differences are not
intuitive and have yet to be explained.
3a-c could arise from varied binding affinities of the methyl-
ating agents to the oligomer cavity. Typically, in supramolecular
systems, molecules that occupy 55% of the host cavity show
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Foldamers as Reactive Sieves
A R T I C L E S
Figure 7. Cartoon representations of possible alkyl chain orientation during
methylation for branched (left) and linear (right) series methylating agents.
The entire cavity may be utilized during methylation with branched
substrates. Red ball ) DMAP unit.
methylating agent must be located in the center of the cavity
for the reaction to occur (Figure 7). This may be very relevant
when considering that 5b has the fastest rate not only of the
branched reagents but also of all methylating agents tested. The
location of the methyl sulfonate ester in the middle of substrate
5b may align the methylating group directly in front of the
DMAP nitrogen. The effect of holding reactive species together
in close proximity and in proper orientation is known to give
substantial rate enhancements and selectivities in biological and
physical organic model systems,35 and supramolecular ones.11
Assuming this model to be applicable here, one expects the
“ideal” R group to match the length of the oligomer’s cavity
and for the alkyl chain length at which the rate is maximum to
increase as the oligomer gets longer. This level of substrate
specificity is not observed, although oligomer 3c appears to have
a much larger preference for 5c than oligomers 3a,b (Figure
6). It is possible that the optimum methylating agent for
oligomers longer than 17 units would be a 4-heptyl chain (5c)
rather than a 3-pentyl (5b). However, we did not investigate
this possibility.
A much different rate profile is observed for the linear-type
methylating agents. One might imagine that the substrate’s alkyl
group only protrudes from one end of the oligomer cavity
(Figure 7), thereby limiting access of the active methyl group
to the front of the DMAP nitrogen. Clearly this would impact
the rate of reaction for similarly sized, but linear shaped,
methylating agents. This explanation does not, however, account
for why the largest rate belongs to 4h whose terminal carbons
would seem to be too far away to have such a profound effect
on the reaction rate. To explain the differences between the rates
of 4h and 4g, the oligomer, or substrate must alter its structure
in some way such that there is interaction between distant
carbons. This could also explain why the addition of only four
PE monomer units to the foldamer backbone has statistically
significant effects on the methylation rate (3a to 3b to 3c).
Individual monomers lengthen the cavity very little in the
canonical, compact, folded structure but increase the fully
extended backbone chain length substantially more. Therefore,
one possibility is that these seemingly small additions to the
oligomer backbone are important because the foldamer exists
as an ensemble of conformations, some of which are stretched
or partially unfolded from a compact helical structure. However,
it is known that longer oligomers give a more stable helix, and
therefore they are unlikely to spend more time in an unfolded
Figure 6. Relative rates of reaction for branched-type methylating agents
including 8. Kinetic data were measured at 25 °C in acetonitrile with
oligomers in the concentration range of 3-4 µM and excess methyl
alkylsulfonate (5000 equiv).
the highest binding affinity.33 However, this approximation does
not appear to correlate with the methylation data when taken
as a whole (see Supporting Information). One possible explana-
tion for this anomaly is the fact that the host molecules used to
define the “55% rule” were relatively rigid in structure, whereas
oligomers 3a-d contain many degrees of conformational
flexibility. The cavity may expand or the chain may unfold to
generate a larger cavity volume. This hypothesis is discussed
in more detail later in this section.
The reaction rates of linear substrates 4a-h with oligomers
3a-c show a general trend of increasing methylation rate with
increasing length of the substrate’s alkyl chain even though
several of the linear substrates (4g and 4h) occupy more than
70% of the cavity volume.34 In contrast to the linear substrates,
the branched methylating agents 5a-e show a maximum rate
with 5b. The rate of methylation with the branched series for
all three oligomers plummets significantly at 5d and decreases
little beyond that (5e). Qualitatively, the behavior of the
branched substrates is consistent with our expectations of
reactive sieving. The reaction of 5e with all oligomers is much
slower than that of 4h despite the comparable size and volume
of these two substrates. This indicates that the reactive group
of 5e may be less favorably positioned for reaction in the bound
state compared to that of 4h. The opposite behavior is seen when
4d is compared to its branched counterpart 5b; linear sulfonate
4d is much slower in comparison to 5b, despite their similar
sizes. The behavior displayed by these examples indicates that
shape, rather than size is the most important factor that
contributes to the differential reactivity. This may be the result
of differing oligomer conformations when a guest is present,
or differing substrate orientation with respect to the DMAP unit
in the bound state.
As 3a-d all contain the DMAP functional group in the
middle of their backbones, it is obvious, but worth noting, that
if the reactive conformation of the oligomers is accurately
modeled by a helical shape the methyl sulfonate of any
(33) Mecozzi, S.; Rebek, J., Jr. Chem. Eur. J. 1998, 4, 1016-1022.
(34) Cavity volumes were calculated using the program Cerius2, version 4.10;
Accelrys Inc. www.accelrys.com. See Supporting Information for a
complete table of calculated volumes.
(35) Menger, F. M. Acc. Chem. Res. 1985, 18, 128-134.
9
J. AM. CHEM. SOC. VOL. 129, NO. 17, 2007 5449

A R T I C L E S
Smaldone and Moore
Figure 8. Illustration of generic mPE oligomer (no DMAP unit) with methyl groups lining the interior (left) and 8 (middle). The side view of the oligomer
is shown at the right.
conformation.20 An alternative explanation is that the substrate
changes its shape to adjust to the cavity. Rebek36 and others37
have explored the conformation and reactivity of alkyl chains
in hydrophobic environments. In particular, Rebek and co-
workers demonstrated that alkyl chains are capable of adopting
a helical conformation where each carbon has gauche, rather
than anti conformations, allowing it to pack more efficiently
into confined spaces. It is possible that either a long enough
alkyl chain has not been used to elicit a decline in reaction rate
as was seen with the branched-type agents (methyl alkylsul-
fonates with carbon chains containing more than 11 carbons
are not soluble in acetonitrile) or enough freedom of movement
is maintained such that only an asymptotic maximum is reached.
Sufficiently long branched-type guests may be bound too
restrictively, potentially in a less reactive orientation.
complex that is sufficiently stable such that the reaction rates
remain elevated. Such “induced fit”-type behavior has been
observed in enzymes.40
Additional experiments are in progress to further understand
the origin of discrimination for these reactions. Future investiga-
tions may include studies of water-soluble guests in more polar
solvents to reduce the conformational flexibility of the mPE
helix, or the use of modified oligomers that are covalently
restricted from unfolding (i.e., chemical cross-linking of the
oligomer). The incorporation of catalytic functional moieties
into the interior cavity to explore the effect of mPE oligomers
on more complex reactions is also a future goal of this research,
and results will be reported in due course.
Conclusions
Additional evidence for flexibility of the foldamer is found
in Table 3 and Figure 6. A bulky, inflexible substrate such as
8 might be expected to react at equal to, or even more slowly
than the rate of the background methylation reaction (i.e., the
methylation of reference compound 2). However, it is observed
that with 3c the methylation is ∼50-fold faster than with 2. In
an attempt to further slow the methylation, 3d was synthesized.
Its interior methyl groups are expected to block the interior
cavity for guest molecules. Even in this case, the methylation
rates were still ∼20 times faster than that of the control.
Regardless, the computer models shown in Figure 8 indicate
that 8 would be unlikely to fit into the helical cavity formed by
3d without some kind of conformational rearrangement of the
helical structure.39 The fraction of cavity volume occupied by
8 in 3d would also appear to be extremely prohibitive in a rigid,
collapsed conformation. The volume of 8 is 206 Å3 which
occupies 83% of the cavity of 3d. Attempts to tune the reactivity
by modulating the solvent polarity were also carried out. mPE
oligomers are well-known to form more compact helical
structures in solvent mixtures more polar than pure acetonitrile38
(e.g., acetonitrile:water). However, the methyl alkylsulfonate
esters tested here were insufficiently soluble in these mixtures
to obtain useful data. It may be that the flexibility of the
oligomer allows it to adjust its structure to form a host-guest
Described in this article is the use of foldamer-based
molecular recognition to modulate chemical reactivity. mPE
oligomers 3a-c exhibit variable reactivity toward substrates
even though the substrates differ minimally in size and shape.
In contrast, the reference trimer shows no significant substrate
discrimination. Additionally, the flexible nature of the host
appears to allow it to accommodate guests of different shape
and size, although the rate of methylation for each guest is
significantly different. Sieve-like behavior was observed for
branched substrates, and our studies have also revealed that the
“small, medium, and large” designations are overly simplistic
as reactivity is governed by both substrate shape and size. It
appears that guest shape is a more relevant factor, possibly in
orienting the reactive groups in a certain manner. This system
represents a promising foundation for developing foldamers that
involve covalent catalysis and that function as reactive sieves.
Acknowledgment. This work was supported by the National
Science Foundation (NSF CHE 03-45254 and CHE-06-42413).
Supporting Information Available: Synthetic scheme for the
methods of preparation of the various methyl sulfonates and
experimental details for preparations of previously unreported
methyl alkylsulfonates. This material is available free of charge
via the Internet at http://pubs.acs.org.
(36) Purse, B. W.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 2530-
2534.
(37) Geng, Y.; Romsted, L. S.; Menger, F. J. Am. Chem. Soc. 2006, 128, 492-
JA067670A
501.
(38) Stone, M. T.; Moore, J. S. Org. Lett. 2004, 6, 469-472.
(39) Pictures were rendered using Spartan04 Student Edition, v1.0.2; Wave-
function, Inc. www.wavefun.com.
(40) Koshland, D. E. J. Angew. Chem., Int. Ed. 1994, 33, 2375-2378.
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5450 J. AM. CHEM. SOC. VOL. 129, NO. 17, 2007