Sequence dependence of methylation rate enhancement in meta- phenyleneethynylene foldamers

Article abstract of DOI:10.1039/b716122k

The methylation rates of a meta-phenyleneethynylene (mPE) oligomer with a terminally-attached 4-dimethylaminopyridine (DMAP) residue are reported for a series of linear and branched methyl sulfonates; these data show that selective methylation is enhanced

Full text of DOI:10.1039/b716122k

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Sequence dependence of methylation rate enhancement in
meta-phenyleneethynylene foldamersw
Ronald A. Smaldone and Jeffrey S. Moore*
Received (in Austin, TX, USA) 18th October 2007, Accepted 3rd December 2007
First published as an Advance Article on the web 3rd January 2008
DOI: 10.1039/b716122k
The methylation rates of a meta-phenyleneethynylene (mPE)
oligomer with a terminally-attached 4-dimethylaminopyridine
(DMAP) residue are reported for a series of linear and branched
methyl sulfonates; these data show that selective methylation is
enhanced by locating the DMAP unit at the midpoint of the
sequence, allowing the foldamer cavity to function as a reactive
sieve.
In addition to the ability of 1 to differentiate between the
substrates, it also was observed to enhance the methylation
rate compared to the background rate. The relative rate is
defined as the rate of methylation of the foldamer (koligomer
)
divided by the rate of methylation of the appropriate control
(kbackground). To determine the relative rate enhancement, the
methylation of control molecules 5 and 6 were measured. Since
the DMAP unit of 2 is attached to the foldamer at only the
2-position (compared to the 2,6-disubstituted DMAP of 1), a
new control was synthesized (6) to provide a more accurate
background rate approximation (Fig. 1).17 Oligomers 5 and 6
are too short to fold, and thus their rates can be taken as an
approximation of the rate in the absence of binding.
The use of supramolecular architectures to mimic the catalytic
and molecular recognition behavior of biological systems has
been extensively researched over the past several decades.1–4
The realization of enhanced reaction rates through molecular
recognition within purely synthetic systems could potentially
help to provide an understanding of the fundamental concepts
of bioreactivity. Investigations of mPE foldamers have
recently begun to address the relationship between enhanced
reaction rates and molecular recognition in abiological
oligomers.5–12
In our previous work, the methylation of oligomer 1 by a
series of linear methylating agents showed an increase in rate
mPE foldamers can adopt a solvophobically-driven helical
conformation, which forms a well-defined cavity known to
have molecular recognition capability.5,13–15 Our group has
previously demonstrated that mPE foldamers modified with a
4-dimethylaminopyridine (DMAP) unit can enhance the rate
of methylation of the DMAP nitrogen by iodomethane up to
400-fold.7 In a recent publication, we demonstrated that these
foldamers were not only capable of accelerating the rate of
methylation, but also of differentiating between reactive guests
based on their size and shape, a behavior we described as
‘‘reactive sieving’’.16 In our previous studies, the reactive
DMAP unit was positioned at the midpoint of the foldamer
backbone (1). A testable consequence of the reactive sieving
hypothesis is that substrate discrimination will diminish as the
reactive group is moved away from the center of the helical
cavity. End-functionalized oligomer 2 was thus synthesized
(Fig. 1) and subjected to the series of linear (3a–h) and
branched (4a–e) methylating agents used in our initial study.
Here, we report the rates of methylation, determined by
UV/vis spectroscopy, and compare the results to oligomers
having DMAP at their center.16
Departments of Chemistry, and Materials Science and Engineering,
University of Illinois at Urbana-Champaign, 600 South Mathews
Avenue, Urbana, IL 61801, USA. E-mail: jsmoore@uiuc.edu;
Fax: +1 217-244-8024; Tel: +1 217-244-5289
w Electronic supplementary information (ESI) available: Character-
ization of compounds, second order rate coefficients (k2) for oligomers
2, 5, and 6 with each methylating agent, and methods for obtaining
methylation rates. See DOI: 10.1039/b716122k
Fig. 1 Center-functionalized oligomer 1, end-functionalized oligomer
2, control molecules (5 and 6) and all the methylating agents used in
this study (3a–h and 4a–e).
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Fig. 2 Left: Comparison of the second order rate coefficients (k2) between oligomers 1 and 2 for linear methylating agents 3a–h. Right: Plot of
koligomer/kbackground for 3a–h on a logarithmic scale. Kinetic data were measured by UV/vis spectroscopy at 25 1C in acetonitrile, with oligomers in
the concentration range 3–4 mM and 5000 equiv. of methyl sulfonate. For more details see the ESI.w
Table 1 koligomer/kbackground values for oligomers 1 and 2
(Table 1). To illustrate the vast disparity in the ability of 2 to
enhance the rate of reaction in comparison to oligomer 1, these
values are plotted in Fig. 2 on a log scale.
Linear
17mer (2)
17mer (1)
Methyl (3a)
Ethyl (3b)
Propyl (3c)
Butyl (3d)
Heptyl (3e)
Octyl (3f)
2.2
2.5
2.7
4.1
130
220
230
255
Center-functionalized oligomer 1 exhibited reactive sieving
behavior when subjected to branched methylating agents
4a–e.16 However, placement of the DMAP group at the end
of the chain greatly reduced the ability of the mPE foldamer to
differentiate between the substrates, leading to nearly identical
rate coefficients for 4a–e (Fig. 3). As seen with the linear
substrates, the relative rates of methylation of the branched
substrates with 2 are uniformly diminished in comparison to 1.
In this case, however, all of the relative rates are very similar
(Table 1).
7.3
830
12.5
12.6
22.8
1000
1000
1500
Decyl (3g)
Undecyl (3h)
Branched
17mer (2)
3.3
5.5
4.2
3.8
17mer (1)
870
1600
730
110
2-Butyl (4a)
3-Pentyl (4b)
4-Heptyl (4c)
5-Nonyl (4d)
6-Undecyl (4e)
It is possible that the flexibility of the oligomer backbone
is responsible for the observed change in reactive sieving
behavior. One rationale, proposed by Menger, posits
that holding reactive groups in proximity to one another could
result in the large rate enhancements seen in enzymes and
intramolecular reactions.18 Molecular dynamics simulations
of the mPE foldamer system have indicated that residues at
the end of the chain exhibit larger fluctuations than those at
the center of the backbone when folded.19 Since the DMAP
group of 1 is at the center of the backbone, it may be held
more rigidly in place near bound substrates by the folded
structure than the DMAP of end-functionalized oligomer 2.
Although oligomer 2 maintains some of the ability displayed
4.6
150
in correspondence with an increase in the R-group chain
length (Fig. 2). When the second order rate coefficients (k2)
of 2 are plotted in comparison with the rates of 1, it can be seen
that for substrates 3a–h, the trend of increasing rate with
increasing length of the alkyl chain is still evident, although
diminished. When the relative rates of reaction are calculated
for the methylation of 2, it is revealed that the rate enhance-
ments of the end-functionalized foldamer are also significantly
diminished with respect to center-functionalized oligomer 1
Fig. 3 Left: Comparison of second order rate coefficients (k2) between oligomers 1 and 2 for linear methylating agents 4a–e. Right: Plot of
koligomer/kbackground for 4a–e on a logarithmic scale. The conditions for the measuring kinetics are the same as those in Fig. 2.
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by its center-functionalized analog to differentiate linear sub-
strates, the reaction rates of the branched methylating sub-
strates are essentially identical to one another. This may
indicate the presence of an alternate reactive backbone con-
formation that is not capable of reactive sieving, but can still
bind the methylating substrate, thereby leading to a small rate
acceleration.
Notes and references
1 M. M. Conn and J. Rebek, Jr, Chem. Rev., 1997, 97, 1647–1668.
2 D. M. Vriezema, M. C. Aragones, J. A. A. W. Elemans, J. J. L. M.
Cornelissen, A. E. Rowan and R. J. M. Nolte, Chem. Rev., 2005,
104, 1445–1490.
3 R. Breslow and S. D. Dong, Chem. Rev., 1998, 98, 1997–2011.
4 R. Breslow, Acc. Chem. Res., 1995, 28, 146–153.
5 H. Abe, N. Masuda, M. Waki and M. Inouye, J. Am. Chem. Soc.,
2005, 127, 16189–16196.
In conclusion, we have shown that the reactive sieving
ability of mPE foldamers is dependent on the oligomer se-
quence. End-functionalized oligomer 2 was much less efficient
at differentiating linear substrates 3a–h in comparison with
oligomer 1. In the case of branched substrates 4a–e, no
significant selectivity was observed, and in both cases, the
reaction rate enhancements were substantially lower than
those observed with 1. The decrease of the methylation rate
enhancement and loss of selectivity observed with oligomer 2
may indicate that the foldamer backbone is sufficiently flexible
at the ends of chain, requiring its reactive group to be placed in
a structurally-stable position (i.e., the midpoint of the back-
bone) in order to achieve sieving. Since sequence determines
the position of the reactive unit in the folded cavity, we
conclude that reactive sieving is most effective for midpoint
placement. Future investigations of reactive mPE foldamers
will attempt to modulate oligomer flexibility and rule out
alternate conformations through systematic restriction of the
backbone’s ability to unfold by using the precise placement of
chemical cross-linkers.
6 C. Dolain, C. Zhan, J.-M. Leger, L. Daniels and I. Huc, J. Am.
Chem. Soc., 2005, 127, 2400–2401.
7 J. M. Heemstra and J. S. Moore, J. Am. Chem. Soc., 2004, 126,
1648–1649.
8 R. B. Prince, S. A. Barnes and J. S. Moore, J. Am. Chem. Soc.,
2000, 122, 2758–2762.
9 A. Tanatani, M. J. Mio and J. S. Moore, J. Am. Chem. Soc., 2001,
123, 1792–1793.
10 M. Waki, H. Abe and M. Inouye, Chem.–Eur. J., 2006, 12,
7839–7847.
11 R. A. Smaldone and J. S. Moore, Chem.–Eur. J., DOI: 10.1002/
chem.200701503.
12 H.-P. Yi, J. Wu, K.-L. Ding, X.-K. Jiang and Z.-T. Li, J. Org.
Chem., 2007, 72, 870–877.
13 R. B. Prince, J. G. Saven, P. G. Wolynes and J. S. Moore, J. Am.
Chem. Soc., 1999, 121, 3114–3121.
14 A. Tanatani, M. J. Mio and J. S. Moore, J. Am. Chem. Soc., 2001,
123, 1792–1793.
15 M. Inouye, M. Waki and H. Abe, J. Am. Chem. Soc., 2004, 126,
2022–2027.
16 R. A. Smaldone and J. S. Moore, J. Am. Chem. Soc., 2007, 129,
5444–5450.
17 A. C. Spivey and S. Arseniyadis, Angew. Chem., Int. Ed., 2004, 43,
5436–5441.
18 F. M. Menger, Acc. Chem. Res., 1985, 18, 128–134.
19 O. Lee and J. G. Saven, J. Phys. Chem. B, 2004, 108,
11988–11994.
The authors would like to thank the National Science
Foundation for supporting this work (CHE-0642413).
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