Synthesis and recognition properties of aromatic amide oligomers: Molecular zippers

Article abstract of DOI:10.1021/ja0012671

A series of amide oligomers have been prepared from isophthalic acid and a bisaniline derivative. These compounds assemble into double-stranded zipper complexes in solution via hydrogen-bonding and edge-to-face aromatic interactions. The stability and str

Full text of DOI:10.1021/ja0012671

8856
J. Am. Chem. Soc. 2000, 122, 8856-8868
Synthesis and Recognition Properties of Aromatic Amide Oligomers:
Molecular Zippers
Adrian P. Bisson, Fiona J. Carver, Drake S. Eggleston,† R. Curtis Haltiwanger,†
Christopher A. Hunter,* David L. Livingstone,‡ James F. McCabe, Carmen Rotger,§ and
Alan E. Rowan|
Contribution from the Krebs Institute for Biomolecular Science, Department of Chemistry, UniVersity of
Sheffield, Sheffield S3 7HF, UK, SmithKline Beecham, The Frythe, Welwyn, Hertfordshire AL6 9AR, UK,
SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, Philadelphia, PennsylVania 19406
ReceiVed April 11, 2000
Abstract: A series of amide oligomers have been prepared from isophthalic acid and a bisaniline derivative.
These compounds assemble into double-stranded zipper complexes in solution via hydrogen-bonding and edge-
to-face aromatic interactions. The stability and structures of the complexes have been determined by 1H NMR
spectroscopy in chloroform solution. The stability of the complexes increases with increasing chain length,
indicating cooperativity between the individual recognition sites in the oligomers. Oligomers which are
complementary form more stable complexes than non-complementary systems with overhanging ends. Addition
of polar solvents such as methanol destabilizes the complexes, because it competes for hydrogen-bonding
interactions which appear to be the main driving force for binding in this system.
Introduction
Self-assembly of linear oligomers into double- and triple- and
higher-order multistranded complexes is a common structural
motif in biology (Figure 1).1-3 In addition to its utility for the
formation of multicomponent complexes with functional proper-
ties, the zipper motif is of fundamental importance for processes
such as self-replication and the behavior of biological fibers
such as muscle.4,5 In recent years, chemists have begun to
prepare synthetic systems based on this principle. Lehn has used
copper coordination by bipyridine oligomers to demonstrate the
cooperative assembly of double- and triple-stranded complexes,
deMendoza has assembled double-stranded complexes of guani-
dinium oligomers around sulfate anions, and Anderson has used
coordination of DABCO by zinc porphyrins to assemble ladder
complexes of porphyrin oligomers.6-8 We describe here the
Figure 1. The zipper motif.
† SmithKline Beecham, The Frythe, Welwyn, Hertfordshire AL6 9AR,
UK.
accidental discovery of a new structural motif which leads to
the formation of zipper structures by hydrogen-bonding interac-
tions.9
‡ SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, Phila-
delphia, Pennsylvania 19406.
§ Current address: Department of Chemistry, Universitat de les Illes
Balears, 07071 Palma de Mallorca, Spain.
(6) Koert, U.; Harding, M. M.; Lehn, J.-M. Nature 1990, 346, 339;
Kra¨mer, R.; Lehn, J.-M.; Cain, A. D.; Fischer, J. Angew. Chem., Int. Ed.
Engl. 1993, 32, 703; Lehn, J.-M.; Rigault, A. Angew. Chem., Int. Ed. Engl.
1988, 27, 1095; Garret, T. M.; Koert, U.; Lehn, J.-M.; Riguet, A.; Meyer,
D.; Fischer, J. J. Chem. Soc., Chem. Commun. 1990, 557; Kramer, R.; Lehn,
J. M.; Decian, A.; Fischer, J. Angew. Chem., Int. Ed. Engl. 1993, 32, 703-
706; Zarges, W.; Hall, J.; Lehn, J. M. HelV. Chim. Acta 1991, 74, 1843-
1852; Lehn, J. M. Pure Appl. Chem. 1994, 66, 1961-1966; Garrett, T. M.;
Koert, U.; Lehn, J. M. J. Phys. Org. Chem. 1992, 5, 529-532; Kra¨mer, R.;
Lehn, J. M.; Marquis-Rgault, A. Proc. Natl. Acad. Sci. U.S.A. 1993, 90,
5394-5398; Pfeil, A.; Lehn, J. M. J. Chem. Soc., Chem. Commun. 1992,
838-840.
(7) SanchezQuesada, J.; Seel, C.; Prados, P.; deMendoza, J.; Dalcol, I.;
Giralt, E. J. Am. Chem. Soc. 1996, 118, 277-278.
(8) Anderson, H. L. Chem. Commun. 1999, 2323-2331; Taylor, P. N.;
Anderson, H. L. J. Am. Chem. Soc. 1999, 121, 11538-11545; Anderson,
H. L. Inorg. Chem. 1994, 33, 972-981; Taylor, P. N.; Huuskonen, J.;
Rumbles, G.; Aplin, R. T.; Williams, E.; Anderson, H. L. Chem. Commun.
1998, 909-910.
| Current address: Department of Organic Chemistry, NSR Centre,
University of Nijmegen, The Netherlands.
(1) Horton, R. H.; Moran, L. A.; Ochs, R. S.; Rawn, D. J.; Scrimgeour,
G. K. Principles of Biochemistry; Prentice Hall International, Inc.: London,
1992.
(2) Po¨rschke, D. Biopolymers 1971, 10, 1989-2013; Amirikyan, B. R.;
Vologodskii, A. V.; Lyubchenko, Y., L. Nucleic Acids Res. 1981, 9, 5469-
5480.
(3) Wendt, H.; Baici, A.; Bosshard, H. R. J. Am. Chem. Soc. 1994, 116,
6973-6974; O’Neil, K. T.; Hoess, R. H.; Degrado, W. F. Science 1990,
249, 774.
(4) Watson, J. D.; Crick, F. H. C. Nature 1953, 4356, 737-738; von
Kiedrowski, G. Angew. Chem., Int. Ed. Engl. 1986, 25, 932-935; von
Kiedrowski, G.; Sievers, D. Nature 1994, 369, 221-224.
(5) Petruska, J. A.; Hodge, A. J. Biochemistry 1964, 3, 871-876; Huxley,
H. E. Science 1969, 164, 1356-1364; Davis, J. S.; Buck, J.; Greene, E. P.
FEBS Lett. 1982, 140, 293-297; Huxley, H. E.; Brown, W. J. Mol. Biol.
1967, 30, 383-434.
10.1021/ja0012671 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/30/2000

Aromatic Amide Oligomers: Molecular Zippers
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8857
Figure 2. Proposed structure of the oligoamide dimer which accounts for the changes in chemical shift shown in Figure 3. The key structural motif
of a hydrogen-bond flanked by two edge-to-face aromatic interactions is highlighted.
Scheme 1
The synthetic route which we have developed to macrocyclic
receptors and [2]-catenanes involves the preparation of linear
diamides such as H2N-BIB-NH2 (Scheme 1) which are
subsequently cyclized.10 In Scheme 1, an excess of H2N-B-
NH2 was used to reduce the amounts of higher oligomers formed
in this statistical reaction. However, significant amounts of
H2N-BIBIB-NH2 were produced and isolated. The 1H NMR
spectrum of this compound in CDCl3 differs significantly from
that of the shorter oligomer H2N-BIB-NH2 (Figure 2): the
Figure 3. 1H NMR spectra in CDCl3. (a) H2N-BIB-NH2, (b) H2N-
signals due to the aromatic protons, t and d, on the isophthaloyl
BIBIB-NH2, (c) H2N-BIBIB-NH2 after the addition of a few drops
of CD3OD.
rings show significant upfield shifts in the longer oligomer; the
signals due to the amide protons, n, are shifted downfield by
∼1 ppm; the signals due to the aniline aromatic protons, a, are
shifted downfield slightly, and the signal due to the isophthaloyl
of CD3OD (Figure 2). These observations suggested that the
aromatic singlet, s, is unaltered. The shifts were strongly
longer oligomer H2N-BIBIB-NH2 was forming an inter-
concentration dependent and decreased dramatically on addition
molecular complex which involved H-bonding and aromatic
(9) Bisson, A. P.; Hunter, C. A. J. Chem. Soc., Chem. Commun. 1996,
1723-1724.
interactions. CPK models were used to construct structures of
a dimeric complex consistent with the NMR data (Figure 3).
Amide-amide H-bonds lead to downfield shifts of the signals
due to the amide protons, n. Intermolecular edge-to-face
aromatic interactions between the I and B subunits cause the
large upfield shifts on d and t and the small downfield shift on
(10) Hunter, C. A. J. Chem. Soc., Chem. Commun. 1991, 11, 749-751;
Hunter, C. A.; Purvis, D. H. Angew. Chem., Int. Ed. Engl. 1992, 31, 792-
795; Hunter, C. A. J. Am. Chem. Soc. 1992, 114, 5303-5311; Carver, F.
J.; Hunter, C. A.; Shannon, R. J. J. Chem. Soc., Chem. Commun. 1994,
1277-1280; Adams, H.; Carver, F. J.; Hunter, C. A. J. Chem. Soc., Chem.
Commun. 1995, 809-810.

8858 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Bisson et al.
aniline, A, which are used to terminate the I-B oligomers and
differentiate the two components of a complex, facilitating
structure determination by two-dimensional 1NMR spectroscopy
(Figure 4).
Results and Discussion
Synthesis. The oligomers were prepared according to Schemes
2-8 using sequential acid chloride-aniline amide coupling
reactions. Several reactions involve statistical functionalization
of one end of a bifunctional molecule, but the reactions can be
carried out on a large scale, and the products are easily separated
by chromatography. AIA, TBT and the complex formed
between them have been described in detail elsewhere, but the
results of the binding experiments are included here for
comparison with the other systems.11
Figure 4. The building blocks used to make the zipper components.
The 1H NMR labeling scheme and shorthand subunit nomenclature are
also illustrated. Protons which are not labeled in this diagram are
unaffected by the formation of zipper complexes.
We have also investigated the use of solid-phase synthesis
for the preparation of these compounds (Scheme 9). In this
approach, statistical reactions to desymmetrize bifunctional
compounds are avoided, and a large excess of reagents can be
used to achieve high efficiency in each step. In the first step,
isophthaloyl dichloride was attached to the resin by esterifica-
tion. The following steps involved amide coupling using an
alternating sequence of diamine and diacid chloride. Finally,
the chain was capped with tert-butylbenzoyl chloride, and the
Scheme 2
1
resin was cleaved with trifluoroacetic acid. The H NMR and
mass spectra of the crude products indicated clean formation
of the two required zippers shown in Scheme 9, TBI-OH and
TBIBI-OH. Although this procedure was not used to prepare
the compounds discussed below, due to the small scale and the
fact that a subsequent coupling reaction is still required to cap
the free acid end of the oligomer, this approach offers an
attractive alternative for the future preparation of longer zippers
of well-defined length without isolating intermediates.
a. s is on the outside of the complex and so is unaffected by
complexation. However, definitive proof of this zipper structure
was elusive.
Binding Studies. The assembly of the zipper complexes was
1
Assuming that the structure in Figure 3 is accurate, it possible
to define the minimal structural motif responsible for recognition
in this system: it contains two edge-to-face aromatic interactions
and one H-bond (Figure 3). In principle, repeating this monomer
unit would afford self-complementary amides of any desired
length. We therefore set about synthesising a series of amide
oligomers based on this fundamental unit. These systems feature
two capping groups, tert-butyl benzoyl, T, and diisopropyl
investigated using H NMR spectroscopy in CDCl3/CD3OD
(95:5) and CDCl3 where solubility permitted. All of the
1
compounds have concentration dependent H NMR spectra.
Self-association constants were determined by dilution experi-
ments, and the results are summarized in Table 1. The data could
be fit equally well to dimerization or non-cooperative linear
polymerization models, but given the evidence for the formation
of dimers presented below, the values quoted are for dimeriza-
Scheme 3

Aromatic Amide Oligomers: Molecular Zippers
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8859
1
Table 1. Self-Association Constants (M-1) from H NMR Dilution
Scheme 4
Experiments (N ) Number of Amides in Each Molecule)
compound
N
CDCl3/CD3OD (95:5)
CDCl3
AT
AIA
TBT
AIBT
AIBIA
TBIBT
AIBIBT
AIBIBIA
TBIBIBT
1
2
2
3
4
4
5
6
6
<1a
<1a
<1a
<1a
<1a
<1a
20 ( 3
26 ( 3
12 ( 2
1070 ( 190
730 ( 200
640 ( 170
85 (15
b
85 ( 30
b
b
b
a Values for these association constants cannot be determined with
any relibility because the complexes only reach about 20% saturation
at the maximum concentration accessible. b Compounds are not suf-
ficiently soluble to perform the experiment.
Scheme 5
Consequently, AT, AIA, and TBT form dimers with one
hydrogen-bond, AIBT, AIBIA, and TBIBT form dimers with
three hydrogen-bonds, and AIBIBT, AIBIBIA, and TBIBIBT
form dimers with five hydrogen-bonds, and within each group
of compounds, the self-association constants are very similar.
The limiting complexation-induced changes in chemical shift
are shown in Table 2. The pattern is very similar to that noted
previously for H2N-BIB-NH2 and H2N-BIBIB-NH2. The
amide protons, n, all experience downfield shifts indicative of
hydrogen-bonding interactions (the magnitude of this shift is
somewhat less in the presence of methanol due to the displace-
ment of hydrogen-bonded solvent). The d and t protons on the
I subunits experience upfield shifts, while s is unaffected by
dimerization. The a protons on the B subunits experience small
downfield shifts. This pattern is characteristic of an edge-to-
face interaction between I and B. Although the data is not
complete for each complex, the magnitudes of the changes
provide some support for the structures in Figures 5-7. The
dimerization-induced changes in chemical shift on the ends of
AIBIA and TBIBT are significantly smaller than the changes
observed in the self-complementary systems. In particular, the
amide protons move 0.3-0.4 ppm rather than 0.7-0.9 ppm in
CDCl3/CD3OD (95:5), which suggests that they spend half as
much time hydrogen-bonded in the dimer as illustrated in Figure
5.
Scheme 6
Further evidence for the structures of the complexes comes
from X-ray crystallography.12,13 The crystal structures of AT
and AIA in Figure 5 show very clearly the basic interaction
motif inferred for the complexes in solution: each amide is
involved in an intermolecular hydrogen-bond which is flanked
by two edge-to-face aromatic interactions. These structures
imply that polymerization should take place in solution for AT
and AIA, but the self-association constants for these systems
are very small, so at the concentrations studied, the major bound
species will be dimer. A 2-dimensional ROESY experiment was
performed on AIBT at a concentration of 98 mM in CDCl3/
CD3OD (95:5) (60% dimer), and the clearly identifiable
intermolecular NOEs provide good evidence for the zipper
structure shown in Figure 5. It is possible that some of the other
cross-peaks observed in this experiment are due to inter-
molecular interactions in the complex; however, it is difficult
to distinguish intramolecular from intermolecular NOEs, and
the only NOEs shown in Figure 5 are those between protons
which are too far apart in the molecule to be caused by
intramolecular interactions. The 1H NMR spectrum of AIBIBT
tion. All of the complexes are less stable in the presence of
methanol, which suggests that hydrogen-bonding is the main
driving force for complexation. There is a significant increase
in the magnitude of the self-association constant as the length
of the oligomer increases. This reflects the increase in the
number of hydrogen-bonding sites as the number of amides
increases, but the trend is not uniform along the series. The
compounds fall into three distinct groups: AT, AIA, and TBT
all have negligible self-association constants; AIBT, AIBIA,
and TBIBT have significantly larger self-association constants,
and AIBIBT, AIBIBIA, and TBIBIBT self-associate strongly.
This observation is consistent with the dimer structures which
are shown in Figures 5-7. AT, AIBT, and AIBIBT are self-
complementary oligomers and can maximize the number of
intermolecular hydrogen-bonds in the dimer. The other dimers
all have overhanging ends with amides which are not H-bonded.
(11) Bisson, A. P.; Hunter, C. A.; Morales, J. C.; Young, K. Chem. Eur.
J. 1998, 4, 845-851.
(12) Adams, H.; Carver, F. J.; Hunter, C. A.; Morales, J. C.; Seward, E.
M. Angew. Chem., Int. Ed. Engl. 1996, 35, 1542-1544.

8860 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Bisson et al.
Scheme 7
Scheme 8
Scheme 9
was too broad to permit any useful 2-dimensional experiments
on this system. The self-association constant for AT is too small
for a significant amount of dimer to be present.
of this complex in the same way. In all three cases, the
association constant is more than an order of magnitude larger
than the dimerization constants for the individual molecules,
confirming the formation of complexes which maximize the
number of hydrogen-bonding interactions between complemen-
tary partners (Figure 8). Dimerization of the individual com-
ponents therefore does not complicate analysis of the dilution
experiments on the more stable zipper complexes, and the
titrations on the less stable zipper complexes were carried out
at a concentration where dimerization was insignificant. Re-
analysis of the data, taking into account the competing
The zipper complexes formed by complementary pairs of
1
oligomers were also characterized by H NMR spectroscopy
using both titration and dilution experiments. The results are
summarized in Table 3, and the limiting complexation-induced
changes in chemical shift are listed in Table 4. The 1:1
stoichiometry of AIA‚TBT and AIBIA‚TBIBT was confirmed
by Job plot experiments, but the components of AIBIBIA‚
TBIBIBT were not sufficiently soluble to allow characterization

Aromatic Amide Oligomers: Molecular Zippers
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8861
Figure 5. Proposed structures of dimers held together by one hydrogen-bond in solution. Portions of the X-ray crystal structures of AT and AIA
are also shown.
Figure 6. Proposed structures of dimers held together by three hydrogen bonds in solution. Intermolecular NOEs observed in ROESY experiments
are shown.
dimerization equilibria, gave very similar results. The 1H NMR
spectrum of AIBIBIA‚TBIBIBT was too broad to allow any
useful two-dimensional experiments, but the structures of the
other two complexes were confirmed by ROESY experiments

8862 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Bisson et al.
Figure 7. Proposed structures of dimers held together by five hydrogen bonds in solution.
Table 2. Limiting Complexation-Induced Changes in1H NMR Chemical Shift (ppm) Calculated by Extrapolating Dilution Data for Formation
of Dimeric Complexes in CDCl3 and CDCl3/CD3OD (95:5) (see Figure 4 for Proton Labeling Scheme)a
amides
A subunit
I subunit
B subunit
T subunit
compound
AIBT
(CDCl3)
n
i
h
d
t
s
a
m
e
f
+1.8
+1.5
+1.2
b
-0.1
-0.2
-0.4
-0.6
-1.6
0.0
+0.2
+0.2
b
-0.3
b
AIBT
(CDCl3/CD3OD)
AIBIA
(CDCl3/CD3OD)
TBIBT
(CDCl3/CD3OD)
AIBIBT
(CDCl3/CD3OD)
AIBIBIA
(CDCl3/CD3OD)
TBIBIBT
-0.1
-0.2
-0.6
-0.6
-0.4
-0.5
-0.4
-1.7
-1.2
-1.0
0.0
0.0
0.0
0.0
0.0
0.0
+0.2
+0.2
+0.2
-0.1
-0.1
0.0
-0.3
-0.4
+0.3
+0.7
+0.4
+0.7
+0.9
b
b
0.0
+0.2
b
0.0
b
-0.1
-0.2
-0.2
0.0
0.1
-0.3
b
-1.5
-1.5
-1.5
-1.6
-1.1
b
+0.7
b
b
b
b
-0.4
+0.1
b
-0.1
-0.1
(CDCl3/CD3OD)
a Errors are of the order of (20%. Where more than one proton was observed in each category, these are listed in order from the end of the
zipper (starting with the A subunit) toward the other end or toward the center in symmetrical systems. In many cases, the different protons within
a class were not resolved in the spectrum, and the number quoted represents an composite value for the multiplet. b These signals were not sufficiently
well-resolved during the titration/dilution experiment to allow determination of reliable chemical shift changes.
1
Table 3. Association Constants (M-1) from H NMR Dilution and
Titration Experiments
(Figure 8). The limiting complexation-induced changes in
chemical shift show exactly the same pattern as discussed for
complex
CDCl3/CD3OD (95:5)
CDCl3
the other complexes and confirm that these systems adopt the
same zipper structure (Table 4). We have used the complexation-
induced changes in chemical shift for AIA‚TBT to determine
the full three-dimensional structure of the complex in solution,
and this agrees with qualitative interpretation of the data shown
in Figure 8.14
These experiments all show that the amide oligomers form
dimeric zipper complexes in solution. The data for comple-
mentary binding partners are collected in Table 5. The average
AIA‚TBT
18 ( 3a
45 ( 1a
14000 ( 6000b
c
AIBIA‚TBIBT
240 ( 11a
AIBIBIA‚TBIBIBT
55000 ( 35000b
a Measured by a titration experiment. b Measured by a dilution
experiment. c Neither the compounds nor the complex are sufficiently
soluble to be studied in this solvent.
complexation-induced changes in chemical shift for the different
classes of proton are essentially identical indicating that

Aromatic Amide Oligomers: Molecular Zippers
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8863
Table 4. Limiting Complexation-Induced Changes in1H NMR Chemical Shift (ppm) Calculated by Extrapolating Dilution or Titration Data
for Formation of a 1:1 Complex (see Figure 4 for Proton Labeling Scheme)a
amides
A subunit
I subunit
B subunit
T subunit
complex
n
i
h
d
t
s
a
m
e
f
AIA
TBT
(CDCl3)
AIA
TBT
(CDCl3/CD3OD)
AIBIA
TBIBT
(CDCl3)
AIBIA
+1.4
+1.1
-0.1
-0.1
-0.1
0.0
-0.2
-0.4
-1.6
0.0
+0.2
0.0
-0.3
-0.3
-0.2
-0.5
+0.6
-0.1
-0.2
-0.1
-0.4
-1.6
0.0
b
+0.2
0.0
-0.5
b
b
-0.4
-0.4
-1.8
-1.8
0.0
0.0
+0.2
+0.2
+0.3
+0.1
0.0
0.0
b
+0.5
+0.5
+0.5
+0.4
b
-0.4
-0.5
-0.5
-1.4
-1.3
b
0.0
0.0
b
0.0
TBIBT
+0.1
+0.1
+0.2
0.0
-0.1
b
-0.2
-0.3
(CDCl3/CD3OD)
AIBIBIA‚TBIBIBT
(CDCl3/CD3OD)
b
-0.1
b
b
b
a Errors are of the order of (20%. Where more than one proton was observed in each category, these are listed in order from the end of the
zipper toward the center. In some cases, the different protons within a class were not resolved in the spectrum, and the number quoted represents
an composite value for the multiplet. b These signals were not sufficiently well-resolved during the titration/dilution experiment to allow determination
of reliable chemical shifts.
Figure 8. Proposed structures of the zipper complexes formed between two complementary but different oligomers. Intermolecular NOEs observed
in ROESY experiments are shown.
the complexes all have similar structures. The stability of the
complexes (∆Gobs) increases with the length of the oligomer
and decreases on addition of competitive hydrogen-bonding
solvents such as methanol. Although, complementary binding
partners form the most stable complexes, non-complementary
oligomers will bind. For example, we have carried out a titration
of AIA into TBIBT in CDCl3 at a concentration where TBIBT
is not significantly dimerized. A Job plot indicates that the
stoichiometry of the complex is 2:1 (the maximum occurs for
a mole fraction of approximately 0.6 AIA), and the microscopic
association constants for the first and second binding interactions
are 40 ( 4 M-1 and 50 ( 6 M-1 respectively (Figure 9). These
binding constants are essentially identical to the value for the
AIA‚TBT complex in chloroform (Table 3), and the complex-
ation-induced changes in chemical shift are also very similar
to those observed for the AIA‚TBT complex (Table 4, Figure
9). This indicates that AIA binds to TBIBT in exactly the same
way as it binds to TBT, and that the binding of the first molecule
of AIA has no effect on the second binding site. This augurs
well for the use of these molecules in template-directed
synthesis.
Figure 10 shows how the stability of the zipper complexes

8864 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Bisson et al.
Table 5. Summary of Complexation Data for Complementary Zipper Complexes. Average Complexation-Induced Changes in Chemical Shift
(ppm), Observed Free Energy of Binding, ∆Gobs, and Statistically Corrected Free Energy of Binding, ∆Gc, (kJ mol-1) in CDCl3 and CDCl3/
CD3OD (95:5)
proton†
CDCl3
CDCl3/CD3OD
complex
e
f
a
h
d
t
∆Gobs
∆Gc
∆Gobs
∆Gc
AIA‚TBT
-0.3
-0.3
-0.2
-0.2
b
-0.5
-0.4
-0.3
b
+0.2
+0.2
+0.2
+0.2
+0.2
-0.1
-0.2
-0.1
-0.1
-0.1
-0.4
-0.6
-0.4
-0.3
b
-1.6
-1.7
-1.6
-1.5
b
9.5 ( 0.1
11.1 ( 0.4
23.7 ( 1.0
-
7.8 ( 0.1
11.1 ( 0.4
22.1 ( 1.0
-
7.2 ( 0.4
7.5 ( 0.4
13.7 ( 0.1
17.4 ( 0.4
27.2 ( 1.6
5.5 ( 0.4
7.5 ( 0.4
11.9 ( 0.1
17.4 ( 0.4
25.5 ( 1.6
(AIBT)2
AIBIA‚TBIBT
(AIBIBT)2
AIBIBIA‚TBIBIBT
b
-
-
1
a See Figure 4 for H NMR labeling scheme. The average value for each class of proton is quoted. b These signals were not sufficiently well-
resolved during the titration/dilution experiment to allow determination of reliable chemical shifts.
Figure 9. The 2:1 complex formed between AIA and TBIBT. The limiting complexation-induced changes in chemical shift are shown.
Figure 10. The statistically corrected free energy of binding in CDCl3
and CDCl3/CD3OD (95:5) (-∆Gc) plotted against the length of the
oligomer (N). N is the number of repeats of the recognition motif (two
edge-to-face π-π interactions and one hydrogen bond). Error bars for
most of the points lie within the symbol. The curve illustrates the trend
and is not a fit to any function.
Figure 11. Schematic representations of (a) the heterodimeric zipper
AIBIBT and (b) the homodimeric zipper AIBIA‚TBIBT. The I and
T groups in each complex are numbered to allow differentiation of
degenerate conformations. The heterodimeric complexes can adopt two
different types of conformation, whereas the homodimeric zippers can
only adopt one.
(∆Gc) increases as the number of binding interactions (N)
increases. The data in this graph have been corrected for
(13) AIA crystallized as colorless prisms from a mixture of acetonitrile
and ethanol, and there is one molecule of ethanol solvate per molecule of
AIA in the crystal. Lattice parameters were determined from the setting
angles of 25 reflections well distributed in reciprocal space measured on
an Enraf Nonius CAD-4 diffractometer. Intensity data were collected on
the diffractometer using graphite monochromated molybdenum radiation
and an ω - 2θ variable speed scan technique. Three orientation controls
were monitored to assess any crystal movement during the experiment. The
intensities of three standard reflections measured at the beginning, end and
every hour of exposure time showed a variation of 8% over the course of
the experiment. Data were corrected for this variation and for Lorentz and
polarization effects. Equivalent reflections were averaged. Crystal data and
refinement details are presented in Table 1 of the Supporting Information.
The structure was solved by direct methods using the SHELXS program
and refined using the SHELXL-93 program. Atomic positions were
eventually refined with anisotropic displacement parameters. Parameters
for hydrogen attached to nitrogen were refined. Other hydrogen atoms were
included in idealised positions which rode on the atom to which they are
attached. Isotropic displacement factors were assigned as a constant (1.2)
times Ueq of the attached atom. The full-matrix least-squares refinement
(on E2) coverged (∆/σmax ) 0.00) to values of the conventional crystal-
lographic residuals R ) 0.046 for observed data and R ) 0.058 (wR2 )
statistical effects: the components of the homodimeric zipper
complexes are directional, and these complexes can therefore
only be assembled in a head-to-tail arrangement. The het-
erodimeric complexes, on the other hand, are composed of
symmetrical molecules and can therefore be assembled in two
different degenerate conformations (Figure 11). Thus, to make
a true comparison of the stability constants, the statistical term
has been factored out by dividing the association constants for
the heterocomplementary systems by 2 (to give ∆Gc in Table
5).9 A smooth trend is only observed when this correction is
applied to the data, that is, ∆Gobs does not follow the same
pattern. The graph in Figure 10 appears to have a slight
curvature, but there is insufficient data to draw any firm
conclusions. The upward curvature could be caused by fraying
at the ends of the zipper or by positive enthalpic cooperativity,
so that the addition of further binding interactions causes a
greater increase in stability than the addition of previous binding
interactions. Williams has shown that positive enthalpic coop-
erativity of this sort is reflected in the complexation-induced
changes in chemical shift, but in our system, this effect is not
2
0.140) for all data. The function minimized was Σw(Fo2 - Fc )2. Weights,
w, were eventually assigned to the data as w ) 1/[σ2(Fo ) + (0.0670P)2 +
2
2
2
1.8373P] where P ) [MAX(Fo , 0) + 2Fc ]/3. A final difference Fourier
map was featureless with residual density between +0.36 and -0.21 eÅ-3
Values of the neutral atom scattering factors were taken from the
International Tables for X-ray Crystallography.
.
(14) Hunter, C. A.; Packer, M. J. Chem. Eur. J. 1999, 5, 1891-1897.

Aromatic Amide Oligomers: Molecular Zippers
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8865
Experimental Section
The preparation of H2N-B-NH2, AIA, and TBT have been
described previously.10,11 All other reagents were purchased from the
1
Aldrich Chemical Co. and used without further purification. The H
NMR signals are assigned using the subunit identifiers, A, B, I, and
T, to indicate the location the corresponding proton in a particular part
of the molecule.
Synthesis of AT. Et3N (2.25 mmol; 0.31 mL) and 2,6-diisopropyl
aniline (1.5 mmol; 0.28 mL) were dissolved in dry CH2Cl2 (15 mL).
tert-Butyl benzoyl chloride (2.25 mmol; 0.42 mL) was then added
dropwise over 10 min. The reaction was allowed to stir for 10 hours
and then washed with 1 M HCl (2 × 25 mL) and 1 M NaOH (2 × 25
mL). The organic phase was then dried over Na2SO4 (anhydrous). The
Na2SO4 was removed by filtration and the organic phase reduced to
dryness on a rotary evaporator. The yellow solid produced was
recrystallized from CH2Cl2/pet ether (40-60) to yield the desired
product as a white solid (589 mg; 78%); mp > 270 °C. δH in CDCl3
(ppm): 7.88(d, 2H, T Ar-CH); 7.65(s, 1H, NH); 7.52(d, 2H, T Ar-
CH); 7.35(t, 1H, A Ar-CH); 7.20(d, 2H, A Ar-CH); 3.15(sept, 2H,
A CHMe2); 1.35(s, 9H, T CMe3); 1.20(d, 12H, A CHMe2). δC in CDCl3
(ppm): 166.5; 154.9; 146.7; 133.3; 132.0; 128.1; 127.8; 125.7; 123.4;
35.1; 31.4; 28.7; 24.0; 23.7. FAB[+ve] m/z ) 338, C23H31NO requires
337. CHN: Calculated C ) 81.90, H ) 9.20, N ) 4.15. Found C )
81.83, H ) 9.30, N ) 4.08.
Figure 12. Average limiting complexation-induced changes in chemi-
cal shift of protons d and t (∆∂) plotted as a function of the stability
of the zipper complexes (-∆Gobs).
Synthesis of AI-COCl. A mixture of 2,6-diisopropylaniline (5.0
g, 0.03 mol) and triethylamine (5.75 mL, 0.04 mol) in CH2Cl2 (50 mL)
was added in a dropwise fashion to a stirred solution of isophthaloyl
dichloride (84 g, 0.4 mol) in CH2Cl2 (200 mL) over a 3 h period at
room temperature. Following the addition, the mixture was stirred at
room temperature for a further 20 h, before concentration in vacuo
and purification by flash column chromatography (CH2Cl2:cyclohex-
ane). Recrystallization from CH2Cl2/pet ether(40-60) gave AI-COCl
as cream needles (8.2 g, 86%); mp 178-179 °C. δH in CDCl3 (ppm):
8.65(s, 1H, I Ar-CH); 8.35(d, 1H, I Ar-CH); 8.22(d, 1H, I Ar-CH);
7.65(t, 1H, I Ar-CH); 7.60(s, 1H, NH); 7.40(t, 1H, A Ar-CH); 7.25-
(d, 2H, A Ar-CH); 3.10(sept, 2H, A CHMe2); 1.2(d, 12H, A CHMe2).
δC in CDCl3 (ppm): 170.0; 165.4; 146.3; 135.4; 134.2; 133.7; 130.8;
129.7; 129.6; 128.7; 128.4; 123.6; 29.0; 23.6. FAB[+ve] m/z ) 344,
C20H22NO2Cl requires 343. IR in C2H2Cl4 solution (cm-1): 3422; 2992;
2981; 1753; 1678; 1600; 1495; 1471;1423; 1387; 1364. CHN: Cal-
culated C ) 69.97, H ) 6.41, N ) 4.08. Found C ) 69.69, H ) 6.37,
N ) 3.86.
Synthesis of TB-NH2. Et3N (1.0 mL, 0.0137 mol) and H2N-B-
NH2 (8.43 g, 0.0262 mol) were dissolved in dry CH2Cl2 (75 mL). To
this vigorously stirring solution was added dropwise over 5 h a solution
of tert-butyl benzoyl chloride (0.7 mL, 3.74 mmol) in dry CH2Cl2 (225
mL). The reaction was allowed to stir overnight before being washed
with 1 M HCl (2 × 300 mL) to remove the excess H2N-B-NH2. The
organic phase was dried over Na2SO4 (anhydrous) and then filtered.
Flash column chromatography on silica, eluting with 60% pet ether
(40-60)/ethyl acetate, yielded the product as the first major band.
Recrystallization from CH2Cl2/pet ether(40-60) gave a white solid
(0.873 g, 49%); mp 251-252 °C. δH in 5% CD3OD in CDCl3 (v/v)
(ppm): 7.75(d, 2H, T Ar-CH); 7.44(d, 2H, T Ar-CH); 6.92(s, 2H, B
Ar-CH); 6.80(s, 2H, B Ar-CH); 2.20(m, 16H, B Me, B c-hexyl);
1.50-1.40(m, 6H, B c-hexyl); 1.55(s, 18H, T CMe3). δC in d6-DMSO
(ppm): 165.3; 154.7; 148.1; 140.8; 136.7; 135.3; 132.8; 132.2; 127.8;
126.7; 126.4; 125.6; 121.6; 44.6; 37.0; 35.1; 31.4; 26.4; 23.1; 18.9;
18.7. FAB[+ve] m/z ) 482, C33H42N2O requires 482. IR in C2H2Cl4
solution (cm-1): 3459; 2937; 2860; 1646; 1566; 1524; 1493; 1375.
Figure 13. Melting curves for the zipper complexes in CDCl3/CD3-
OD (95:5). The curves simply illustrate the trends and do not represent
fits to a specific function.
observed. Figure 12 shows how the average limiting complex-
ation-induced changes in chemical shift for signals t and d vary
as a function of the overall free energy of binding: both values
are essentially constant.
Cooperative assembly of zipper motifs can be characterized
by a cooperative melting transition when the system is heated.2,6
Melting of the zipper complexes was investigated by variable
1
temperature H NMR spectroscopy in CDCl3/CD3OD (95:5).
The average chemical shift the signals due to the d protons was
monitored over the range 297-377 K, and the results are plotted
in Figure 13. The complexes clearly dissociate on heating, and
the more stable complexes are more difficult to dissociate, but
the fully associated low-temperature limit is difficult to reach,
and so it is not possible to draw any conclusions about the shape
of the melting curves or the extent of cooperativity.
Conclusions
The amide oligomers formed from isophthalic acid and
bisaniline, H2N-B-NH2, assemble into stable double-stranded
complexes held together by hydrogen-bonding interactions. As
the length of the oligomer increases, the stability of the
corresponding complex increases, indicating significant coop-
erativity in the intermolecular interactions along the chain.
Selectivity in recognition relies entirely on length in this system,
since the stability is determined solely by the number of
hydrogen-bonding interactions that can be made. Future work
will focus on methods for engineering sequence-selectivity into
the zipper assembly process.
Synthesis of AIB-NH2. H2N-B-NH2 (5.93 mmol; 1.9 g) and Et3N
(0.593 mmol; 82 µl) were dissolved in dry CH2Cl2 (25 mL), and to
this solution was added dropwise over 3 h the AI-COCl (203 mg,
0.593 mmol) in CH2Cl2 (75 mL). The reaction was allowed to stir for
5 h. Flash column chromatography on silica, eluting with 1% EtOH/
CH2Cl2, yielded the desired product and the excess H2N-B-NH2 as
the first major band. These mixed fractions were then washed with 1
M HCl (2 × 500 mL) to remove the excess H2N-B-NH2 and then
dried over Na2SO4 (anhydrous). The Na2SO4 was removed by filtration
and the organic solution reduced to dryness on the rotary evaporator,

8866 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Bisson et al.
to yield the desired product as a white solid (0.32 g; 85%); mp >270
°C. δH in 5% CD3OD in CDCl3 (v/v) (ppm): 8.60(s, 1H, NH); 8.49(s,
1H, I Ar-CH);8.40(s, 1H, NH); 8.06(m, 2H, I Ar-CH); 7.51(t, 1H, I
Ar-CH); 7.36(t, 1H, A Ar-CH);7.23(d, 2H, A Ar-CH); 7.03(s, 2H,
B Ar-CH); 6.85(s, 2H, B Ar-CH); 3.15(sept, 2H, A CHMe2); 2.23-
(m, 10H, B Me, B c-hexyl); 2.15(s, 6H, B Me); 1.65-1.55(m, 6H, B
c-hexyl); 1.20(d, 12H, A CHMe2). δC in CDCl3 (ppm): 166.0; 165.0;
148.8; 146.4; 140.1; 135.2; 135.0; 134.7; 130.8; 130.6; 130.3; 129.4;
128.7; 127.1; 126.0; 123.6; 121.5; 44.9; 37.2; 28.9; 26.5; 23.7; 23.0;
18.9; 18.1. FAB[+ve] m/z ) 630, C42H51N3O2 requires 629. IR in KBr
disk (cm-1): 3429; 2961; 2934; 2863; 1648; 1510; 1471; 1383; 1362.
37.2; 26.5; 23.0; 18.7; 18.1. FAB[+ve] m/z ) 775, C52H62N4O2 requires
774. IR in KBr disk (cm-1): 3431; 2933; 2858; 1654; 1492.
H2N-BIBIB-NH2: mp 243 °C. δH in d6-DMSO (ppm): 9.80(s,
4H, NH); 8.50(s, 2H, I Ar-CH); 8.15(d, 4H, I Ar-CH); 7.65(t, 2H, I
Ar-CH); 7.10(s, 2H, B Ar-CH); 7.00(s, 2H, B Ar-CH); 6.80(s, 2H,
B Ar-CH); 4.35(s, 4H, NH2); 2.25(m, 8H, B c-hexyl); 2.20(s, 12H, B
Me); 2.16(s, 12H, B Me); 2.07(s, 12H, B Me); 1.65-1.55(m, 12H, B
c-hexyl). δC in CDCl3 (ppm): 165.6; 165.5; 148.6; 147.3; 140.0; 137.8;
135.6; 135.0; 133.7; 131.8; 131.1; 127.1; 121.7; 44.8; 18.7; 18.0. FAB-
[+ve] m/z ) 1228, C82H94N6O4 requires 1226. IR in KBr disk (cm-1):
3425; 2934; 2858; 1654; 1493.
Synthesis of AIBT. The AIB-NH2 (1.89 × 10-4 mol; 119 mg)
and Et3N (2.84 × 10-4 mol; 40 µl) were dissolved in dry CH2Cl2 (10
mL). tert-Butyl benzoyl chloride (2.84 × 10-4 mol; 53 µl) was then
added and the reaction allowed to stir for 5 h. The reaction was then
washed with 1 M HCl (2 × 20 mL) and 1 M NaOH (2 × 20 mL)
before the organic phase was dried over Na2SO4 (anhydrous). The Na2-
SO4 was removed by filtration and the organic solution reduced to
dryness on the rotary evaporator, to yield a yellow solid. The products
were separated by preparative TLC mixture eluting with 2% EtOH/
CH2Cl2 to yield the desired product as the lowest band. The product
was recrystallized from CH2Cl2/pet ether(40-60) to give a white solid
(115 mg; 77%); mp 214-215 °C. δH in d6-DMSO (ppm): 9.90(s, 1H,
NH); 9.85(s, 1H, NH); 9.55(s, 1H, NH); 8.55(s, 1H, I Ar-CH); 8.20-
(m, 2H, I Ar-CH); 7.92(d, 2H, T Ar-CH); 7.70(t, 1H, I Ar-CH);
7.53(d, 2H, T Ar-CH); 7.37(t, 1H, A Ar-CH); 7.23(d, 2H, A Ar-
CH); 7.10(s, 4H, B Ar-CH); 3.15(sept, 2H, A CHMe2); 2.30(m, 4H,
B c-hexyl); 2.22(s, 6H, B Me); 2.15(s, 6H, B Me); 1.65-1.55(m, 6H,
B c-hexyl); 1.35(s, 9H, T CMe3); 1.20(2d,12H, A CHMe2). δC in d6-
DMSO (ppm): 166.2; 165.2; 165.1; 154.7; 147.2; 146.9; 146.6; 135.6;
135.5; 135.4; 135.3; 133.2; 133.1; 132.9; 132.1; 130.6; 129.2; 128.2;
127.8; 127.6; 126.6; 125.7; 123.4; 45.2; 36.7; 31.4; 28.7; 26.3; 24.0;
23.8; 23.2; 19.0. FAB[+ve] m/z ) 791, C53H63N3O3 requires 789. IR
in C2H2Cl4 solution (cm-1): 3422; 2992; 2980; 2969; 2937; 2867; 1668;
1609; 1490; 1470; 1383.
Synthesis of TBIB-NH2. Et3N (2.89 mmol; 0.4 mL) and H2N-
B-NH2 (2.89 mmol; 2.23 g) were dissolved in dry CH2Cl2 (50 mL),
and to this solution was added dropwise over 2 h tert-butyl benzoyl
chloride (0.41 mmol; 77 µl) in dry CH2Cl2 (100 mL). The reaction
was then allowed to stir for 8 h. The reaction mixture was then made
up to 500 mL by adding CH2Cl2 and extracted with 1 M HCl (2 × 500
mL). The aqueous phase was made basic with NaOH pellets and
extracted with CH2Cl2 (3 × 300 mL). The organic solvent was then
removed on a rotary evaporator. Flash column chromatography on silica,
eluting with 50% ethyl acetate/pet ether (40-60), yielded the desired
product as the first band. The product was recrystallized from CH2-
Cl2/pet ether (196 mg; 51%) to give a white solid; mp 210-211 °C.
δH in CDCl3 (ppm): 8.45(s, 1H, I Ar-CH); 7.95(m, 2H, I Ar-CH);
7.80(m, 3H, NH, T Ar-CH); 7.70(s, 1H, NH); 7.45(m, 3H, NH, T
Ar-CH); 7.23(t, 1H, I Ar-CH); 7.05(s, 2H, B Ar-CH); 7.03(s, 2H,
B Ar-CH); 7.00(s, 2H, B Ar-CH); 6.85(s, 2H, B Ar-CH); 3.45(bs,
2H, NH2); 2.20(m, 14H, B Me, B c-hexyl); 2.17(s, 6H, B Me); 2.10(s,
6H, B Me); 1.65-1.55(m, 12H, B c-hexyl); 1.35(s, 9H, T CMe3). δC
in CDCl3 (ppm): 166.1; 165.5; 165.4; 155.2; 148.6; 147.3; 140.1; 137.7;
135.3; 134.9; 134.3; 134.1; 131.6; 131.4; 131.3; 131.1; 130.5; 128.8;
127.2; 127.1; 126.9; 126.0; 125.5; 121.5; 45.0; 44.9; 37.3; 36.9; 34.9;
26.5; 23.0; 18.8; 18.7; 18.1. FAB[+ve] m/z ) 936, C63H74N4O3 requires
934. IR in KBr disk (cm-1): 3431; 2935; 2859; 1654; 1493; 1376.
Synthesis of TBIBT. Et3N (6.38 × 10-4 mol; 0.1 mL) and H2N-
BIB-NH2 (3.19 × 10-4 mol; 247 mg) were dissolved in dry CH2Cl2
(75 mL). tert-Butyl benzoyl chloride (6.38 × 10-4 mol; 0.12 mL) was
then added and the reaction allowed to stir for 4 h. The reaction was
then washed with 1 M HCl (2 × 50 mL) and 1 M NaOH (2 × 50 mL)
before being dried over Na2SO4 (anhydrous). The Na2SO4 was removed
by filtration and the solvent removed under reduced pressure. Flash
column chromatography on silica, eluting with 2% EtOH/CH2Cl2, gave
the desired product as the second band. The first band was impurity.
The product was recrystallized form CH2Cl2/pet ether (40-60) to give
a white solid (302 mg; 86%); mp 239-240 °C. δH in d6-DMSO
(ppm): 9.80(s, 2H, NH); 9.55(s, 2H, NH); 8.53(s, 1H, I Ar-CH); 8.15-
(d, 2H, I Ar-CH); 7.92(d, 4H, T Ar-CH); 7.68(t, 1H, I Ar-CH);
7.55(d, 4H, T Ar-CH); 7.15(s, 8H, B Ar-CH); 2.35-2.25(m, 8H, B
c-hexyl); 2.2(s, 12H, B Me); 2.17(s, 12H, B Me) 1.60-1.55(m, 12H,
B c-hexyl); 1.35(s, 18H, T CMe3). δC in CDCl3 (ppm): 165.9; 155.0;
147.5; 147.1; 135.1; 131.6; 131.4; 127.2; 126.9; 125.4; 45.0; 36.8; 34.9;
31.2; 26.3; 22.9; 18.7;18.6. FAB[+ve] m/z ) 1096, C74H85N4O4 requires
1094 IR in C2H2Cl4 solution (cm-1): 3422; 2982; 2970; 2939; 2863;
1670; 1609; 1491.
Synthesis of TBIBIA. TBIB-NH2 (1.07 × 10-4 mol; 100 mg) and
Et3N (2.68 × 10-4 mol; 37 µl) were dissolved in dry CH2Cl2 (10 mL),
and the AI-COCl (2.14 × 10-4 mol; 73 mg) in dry CH2Cl2 (10 mL)
was added dropwise over 20 min. The reaction was then allowed to
stir for 4 h. The solvent was then removed under reduced pressure on
the rotary evaporator. The desired product was separated by preparative
TLC eluting with 2% EtOH/CH2Cl2 to yield the product as the lowest
band. Recrystallization from CH2Cl2/MeOH/Pet ether (40-60) gave a
white solid (122 mg; 92%); mp 252-253 °C. δH in d6-DMSO (ppm):
9.92(s, 1H, NH); 9.80(m, 3H, NH); 9.55(s, 1H, NH); 8.52(s, 1H, I
Ar-CH); 8.50(s, 1H, I Ar-CH); 8.25-8.10(m, 4H, I Ar-CH); 7.90-
(d, 2H, T Ar-CH); 7.75-7.62(m, 2H, I Ar-CH); 7.52(d, 2H, T Ar-
CH); 7.32(t, 1H, A Ar-CH); 7.21(d, 2H, A Ar-CH); 7.15-7.07(m,
8H, B Ar-CH); 3.14(sept, 2H, A CHMe2); 2.35-2.25(m, 8H, B
c-hexyl); 2.23-2.12(m, 24H, B Me); 1.60-1.45(m, 12H, B c-hexyl);
1.39(s, 9H, T CMe3); 1.22-1.10(2d, 12H, A CHMe2). δC in 5% CD3-
OD in CDCl3 (v/v) (ppm): 165.8; 147.3; 146.6; 135.6; 134.5; 134.3;
Synthesis of AIBIA. AI-COCl (3.30 mmol; 1.13 g) was dissolved
in dry CH2Cl2 (15 mL), and to this solution was added over 20 min a
solution of H2N-B-NH2 (1.32 mmol; 425 mg) and Et3N (3.95 mmol;
0.55 mL) in dry CH2Cl2 (30 mL). The reaction was allowed to stir for
2 h and then washed with 1 M HCl (2 × 200 mL), 1 M NaOH (2 ×
200 mL), and water (2 × 200 mL). The organic phase was then dried
over Na2SO4 (anhydrous). The Na2SO4 was removed by filtration and
the organic solution reduced to dryness on the rotary evaporator. Flash
column chromatography on silica, eluting with 1% EtOH/CH2Cl2, gave
the desired product as the third band. The product was recrystallized
from CH2Cl2/MeOH/pet ether (40-60) to give a white solid (876 mg;
71%); mp >270 °C. δH in 5% CD3OD in CDCl3 (v/v) (ppm): 8.52(s,
2H, I Ar-CH); 8.15(m, 4H, I Ar-CH); 7.57(t, 2H, I Ar-CH); 7.35(t,
2H, A Ar-CH); 7.22(d, 2H, A Ar-CH); 7.13(s, 4H, B Ar-CH); 3.15-
(sept, 2H, A CHMe2); 2.25(m, 16H, B Me, B c-hexyl); 1.65-1.45(m,
6H, B c-hexyl); 1.22(d, 12H, A CHMe2). δC in d6-DMSO (ppm): 166.2;
165.2; 147.2; 146.6; 135.5; 135.4; 135.2; 133.1; 133.0; 130.6; 129.2;
128.2; 127.5; 126.6; 123.5; 45.2; 36.7; 28.7; 23.8; 23.5; 23.2; 19.0.
FAB[+ve] m/z ) 937, C62H72O4N4 requires 936. IR in C2H2Cl4 solution
(cm-1): 3414; 3295; 2994; 2933; 2866; 1646; 1584; 1517; 1496; 1469.
Synthesis of H2N-BIB-NH2, H2N-BIBIB-NH2. H2N-B-NH2
(33.67 mmol; 10.857 g) and Et3N (10.36 mmol; 1.44 mL) were
dissolved in dry CH2Cl2 (50 mL). To this solution was added dropwise
over 2 h a solution of isophthaloyl dichloride (5.179 mmol; 1.05 g) in
dry CH2Cl2 (100 mL). The reaction was then left to stir for 8 h. Flash
column chromatography on silica, eluting with 100% CHCl3 and finally
2.0% EtOH/CHCl3, yielded H2N-BIB-NH2 as the second band (white
solid 2.94 g; 73%) and H2N-BIBIB-NH2 as the third band (white
solid 671 mg; 11%). The first band was unreacted H2N-B-NH2.
H2N-BIB-NH2: mp 179-180 °C. δH in CDCl3 (ppm): 8.45(s,
1H, I Ar-CH); 8.00(d, 2H, I Ar-CH); 7.50(m, 3H, NH, I Ar-CH);
7.20(s, 2H, B Ar-CH); 6.85(s, 2H, B Ar-CH); 3.45(s, 4H, NH2); 2.25-
(m, 20H, B Me, B c-hexyl); 2.10(s, 12H, B Me); 1.65-1.55(m, 12H,
B c-hexyl). δC in CDCl3 (ppm): 165.3; 148.7; 140.1; 137.7; 134.8;
134.7; 131.0; 130.3; 129.1; 127.2; 127.1; 126.9; 126.0; 121.6; 44.9;

Aromatic Amide Oligomers: Molecular Zippers
J. Am. Chem. Soc., Vol. 122, No. 37, 2000 8867
131.7; 131.0; 127.2; 126.7; 125.3; 123.4; 44.7; 37.0; 31.4; 28.7; 23.5;
22.7; 18.7. FAB[+ve] m/z ) 1243, C83H94N5O5 requires 1240. IR in
C2H2Cl4 solution (cm-1): 3419; 3318; 2998; 2980; 2968; 2938; 2863;
1664; 1584; 1501; 1470.
mL sample. From this sample, 0.4 mL was removed and replaced by
0.4 mL of solvent. After shaking to mix the solvents, a second 1H NMR
spectrum was recorded. This procedure was repeated until there was
no further change in chemical shift or the sample was too dilute to
record a spectrum (10-5 M). For signals that moved more than 0.01
ppm over the whole concentration range, the chemical shifts at each
concentration were recorded and fitted to a dimerization or polymer-
ization isotherm using purpose written software on an Apple Macintosh
microcomputer, NMRDil_Dimer or NMRDil_Agg. These programs use
a Simplex procedure to fit the experimental data to the following
equations to determine the optimum solutions for the association
constant, and the bound and free chemical shifts.
Synthesis of AIBIBIA. AI-COCl (8.95 × 10-4 mol; 306 mg) was
taken up in dry CH2Cl2 (25 mL), and to this solution were added H2N-
BIB-NH2 (4.48 × 10-4 mol; 346 mg) and Et3N (8.95 × 10-4 mol;
0.13 mL) in dry CH2Cl2 (25 mL). The reaction was allowed to stir for
3 h. Flash column chromatography on silica, eluting with 1.5% EtOH/
CH2Cl2, gave the product as the second band. Recrystallization from
CH2Cl2/MeOH/pet ether (40-60) gave the product as a white solid
(378 mg; 55%); mp 260-261 °C. δH in d6-DMSO (ppm): 9.90(s, 2H,
NH); 9.80(m, 4H, NH); 8.55(s, 2H, I Ar-CH); 8.50(s, 1H, I Ar-
CH); 8.25-8.12(m, 6H, I Ar-CH); 7.70(t, 3H, I Ar-CH); 7.32(t, 2H,
A Ar-CH); 7.22(d, 4H, A Ar-CH); 7.13(s, 8H, B Ar-CH); 3.12-
(sept, 2H, A CHMe2); 2.35-2.25(m, 8H, B c-hexyl); 2.23-2.16(m,
24H, B Me); 1.60-1.45(m, 12H, B c-hexyl); 1.22-1.10(2d, 24H, A
CHMe2). δC in d6-DMSO (ppm): 166.2; 165.1; 147.1; 146.6; 135.5;
132.9; 130.5; 129.2; 127.5; 126.6; 123.5; 45.2; 28.7; 24.0; 23.2; 19.0.
FAB[+ve] m/z ) 1391, C92H104N6O6 requires 1388. IR in C2H2Cl4
solution (cm-1): 3419; 3317; 2993; 2971; 2937; 2865; 1665; 1602;
1584; 1500; 1470.
NMRDil_Dimer fits the data to a dimerization isotherm by solving
the following equations.
1 + 4K [A] - {1 + 8K [A] }
x
d
0
d
0
[AA] )
(1)
(2)
(3)
8Kd
[A] ) [A]0 - 2[AA]
2[AA]
[A]0
[A]
δobs
)
δd +
δf
Synthesis of TBIBIBT. Et3N (9.84 × 10-4 mol; 0.14 mL) and H2N-
BIBIB-NH2 (4.92 × 10-4 mol; 605 mg) were dissolved in dry CH2-
Cl2 (75 mL), and to this solution was added tert-butyl benzoyl chloride
(9.84 × 10-4 mol; 0.2 mL). The reaction was allowed to stir for 10
hours. The reaction mixture was then washed with 1 M HCl (2 × 100
mL), 1 M NaOH (2 × 100 mL), and H2O (2 × 100 mL) before being
dried over Na2SO4 (anhydrous). Na2SO4 was then removed by filtration
and the organic solution reduced to dryness on a rotary evaporator.
The product was isolated by recrystallizing from CH2Cl2/MeOH/pet
ether (40-60) giving a white solid (672 mg; 88%); mp 270-271 °C.
δH in 5% CD3OD in CDCl3 (v/v) (ppm): 8.52(s, 2H, I Ar-CH); 7.97-
(d, 4H, I Ar-CH); 7.84(d, 4H, T Ar-CH); 7.50(d, 4H, T Ar-CH);
7.20-7.05(m, 14H, I Ar-CH, B Ar-CH); 2.35-2.15(m, 48H, B Me,
B c-hexyl); 1.65-1.50(m, 18H, B c-hexyl); 1.39(s, 18H, T CMe3). δC
in d6-DMSO (ppm): 165.3; 165.1; 154.7; 147.3; 147.1; 146.9; 135.6;
135.5; 135.3; 133.2; 132.9; 132.1; 130.6; 129.1; 127.8; 127.4; 126.6;
125.7; 45.2; 36.6; 31.4; 26.5; 23.2; 19.0. FAB[+ve] m/z ) 1547,
[A]0
where
[A]0 is the total concentration
[A] is the concentration of unbound free species
[AA] is the concentration of dimer
Kd is the dimerization constant
δf is the free chemical shift
δd is the limiting bound chemical shift of the dimer
NMRDil_Agg fits the data to a noncooperative linear polymerization
isotherm by solving the following equations.
C
104H118N6O6 requires 1546. IR in C2H2Cl4 solution (cm-1): 3421; 3307;
2
[Agg] ) [A]0 1 -
(4)
3002; 2980; 2970; 2938; 2862; 1664; 1603; 1492.
{
}
1 + {1 + 4K[A] }
x
0
General Procedure for Solid-Phase Synthesis of Zippers. Three
hundred milligrams of the Novasyn K HMPB resin (Novabiochem,
0.09 mMol/g) was dried overnight under vacuum in the presence of
silica gel as a desiccant. The resin was then placed in a dry pipet and
washed with 5 mL of dry dichloromethane. A solution of 1 mmol of
the reagent in 7 mL of dry DCM and 360 µL of pyridine was prepared
for each synthetic step. This solution was run through the resin five
times. The excess of reagent was removed by washing with 7 mL of
dry DCM, and the procedure was repeated for the next reagent. When
the synthesis was complete, the resin was washed with 10 mL of
methanol and dried under vacuum. The cleavage of the zippers was
carried out by washing the resin with 20 mL of a solution of DCM/
TFA (9:1) twice and then 10 mL of DCM and 10 mL of methanol.
The fractions were combined and neutralized with solid sodium
hydrogen carbonate, washed with water and dried over anhydrous Na2-
SO4. The solvent was removed on a rotary evaporator, and the white-
yellow residue was analyzed by FAB mass spectrometry and 1H NMR
spectroscopy.
[A] ) [A]0 - [Agg]
(5)
(6)
[Agg]
[A]0
[A]
δobs
)
δb +
δf
[A]0
where
[A]0 is the total concentration
[A] is the concentration of sites which are unbound
(this is the sum of the free species and the ends of the aggregate
which are not bound)
[Agg] is the concentration of sites involved in intermolecular
interactions in the aggregate
TBI-OH: δH in d6-DMSO (ppm): 9.85 (s, 1H); 9.55 (s, 1H); 8.55
(s, 1H); 8.20 (d, 1H); 8.17 (d, 1H); 7.90 (d, 2H); 7.68 (t, 1H); 7.53 (d,
2H); 7.16 (s, 4H); 2.26 (m, 4H); 2.22 (s, 12H); 1.4 (m, 4 H); 1.27 (s,
9H). FAB[+ve] m/z ) 631, C41H46N2O4 requires 630.
K is the association constant for chain extension of the aggregate
δf is the free chemical shift
TBIBI-OH: δH in d6-DMSO (ppm): 9.80 (s, 2H); 9.76 (s, 1H);
9.51 (s, 1H); 8.49 (s, 1H); 8.45 (s, 1H); 8.14 (m, 6H); 7.87 (t, 1H);
7.63 (m, 4H); 7.49 (d, 2H); 7.06 (s, 8H); 2.25 (m, 8H); 2.11 (m, 24H);
1.5 (m, 8H); 1.26 (s, 9H). FAB[+ve] m/z ) 1084, C71H79N4O6 requires
1083.
δb is the limiting bound chemical shift of the bound sites in the
aggregate
Dilution experiments were also performed on mixtures of com-
pounds, especially when the zipper complex was very stable. In this
case, samples of the compounds, arbitrarily designated host and guest,
were accurately weighed and mixed in an approximately 1:1 molar
ratio. This mixture was then dissolved in an accurately measured volume
1H NMR Dilution Experiments. A sample of known concentration
(of the order 10-100 mM) in a chosen solvent (CDCl3 or CDCl3/CD3-
1
OD) was prepared, and a H NMR spectrum was recorded on a 0.8

8868 J. Am. Chem. Soc., Vol. 122, No. 37, 2000
Bisson et al.
of solvent (typically to give a 25 mM solution). 1H NMR spectra were
recorded with progressive dilution of the sample as outlined above.
The dilution data were fit to a 1:1 binding isotherm using purpose
written software an Apple Macintosh microcomputer, NMRDil_HG.
This program use a Simplex procedure to fit the experimental data to
the following equation to determine the optimum solutions for the
association constant, the bound chemical shift in the HG complex, and
if required, the free chemical shift of the unbound species.
1 + 4KdH([H] - [HG]) - {1 + 8KdH([H]0 - [HG])}
x
0
[HH] )
[GG] )
8KdH
(10)
1 + 4KdG([G] - [HG]) - {1 + 8KdG([G]0 - [HG])}
x
0
8KdG
(11)
1 + K([G]0 - [GG])([H]0 - [HH])
1 + K[H] [G] - {(1 + K[H] [G] )2 - 4 K2[H] [G] }
[HG] )
-
x
0
0
0
0
0
0
2K
[HG] )
{(1 + K([G] - [GG])([H] - [HH]))2 - 4K2([G] - [GG])([H] - [HH])}
2K
x
0
0
0
0
(7)
2K
(12)
(13)
[H] ) [H]0 - [HG]
(8)
(9)
[H] ) [H]0 - 2[HH] - [HG]
[G] ) [G]0 - 2[GG] - [HG]
[HG]
[H]0
[H]
δobs
)
δb +
δf
[H]0
(14)
(15)
[HG]
[H]0
2[HH]
[H]0
[H]
where
δobs
)
δb +
δd +
δf
[H]0
[H]0 is the total concentration of host
[G]0 is the total concentration of guest
where
[HH] is the concentration of host dimer
[GG] is the concentration of guest dimer
[H] is the concentration of unbound free host
[HG] is the concentration of host‚guest complex
K is the association constant for formation of the host‚guest
complex
KdG is the guest dimerization constant
δf is the free chemical shift of the host
KdH is the host dimerization constant
δb is the limiting bound chemical shift of the host‚guest complex
δd is the limiting bound chemical shift of the host dimer
1H NMR Titration Experiments. A 3.0 mL sample of host of
known concentration was prepared in a chosen solvent (CDCl3 or
CDCl3/CD3OD). The concentration of the host solution was chosen so
that the host was not significantly dimerized (determined from the
dilution experiment). A portion (0.8 mL) of this solution was removed,
and a 1H NMR spectrum was recorded. An accurately weighed sample
of the guest was then dissolved in the remaining 2.2 mL of host solution.
This solution was almost saturated with guest to allow access to the
top of the binding isotherm and contained host so that the host
concentration remained constant during the titration. Aliquots of guest
solution were added successively to the NMR tube containing the host
solution, the tube was shaken to mix the host and guest solutions, and
All experiments were performed at least twice. The association
constant for a single run was calculated as the mean of the values
obtained for each of the signals followed during the titration weighted
by the observed changes in chemical shift. The association constants
from different runs were then averaged. Errors are quoted at the 95%
confidence limits (twice the standard error). For a single run, the
standard error was determined using the standard deviation of the
different association constants determined by following different signals.
The curve-fitting programs described above are available from the
author on request.
Job Plot Experiments. For each component of the complex, 10
mL solutions of accurately measured and identical concentrations (in
the range 6-10 mM) were prepared. The two solutions were then
combined to give a series of samples of identical total concentration
but conatining different mole fractions (ø) of the two components. The
1H NMR spectrum of each sample was then recorded, and these spectra
were used to produce a graph of (∆δ × ø) against ø, the Job plot
(∆δ ) δobserved - δ ø)1.0).15
1
the H NMR spectra were recorded after each addition. For signals
that moved more than 0.01 ppm, the chemical shifts at all concentrations
of guest were recorded and analyzed using purpose-written software
on an Apple Macintosh microcomputer, NMRTit_HG, NMRTit_HGG,
or NMRTit_HG+HH+GG. These programs use a Simplex procedure
to fit the data to the appropriate binding model to yield the association
constant, the bound chemical shift in the HG complex, and if required,
the free chemical shift of the unbound species.
NMRTit_HG and NMRTit_HGG was described in detail elsewhere.11
NMRTit_HG+HH+GG fits the data to a 1:1 binding isotherm for
formation of the host‚guest complex but in addition takes into account
the presence of dimeriation equilibria for both the host and guest. The
method starts by assuming that [HG] ) 0, so that eqs 10 and 11 can
be solved exactly for [HH] and [GG]. These values of are then used to
solve eq 12 for [HG]. Equations 13 and 14 give the concentrations of
free host [H] and free guest [G]. At this point, [H] + [HH] + [HG] *
[H]0, and [G] + [GG] + [HG] * [G]0, so that the value of [HG] from
eq 12 is used in eqs 10 and 11 to reevaluate [HH] and[GG], and the
procedure is carried out repetitively until [H] + [HH] + [HG] ) [H]0,
and [G] + [GG] + [HG] ) [G]0. This allows the set of simultaneous
equations to be solved for the concentrations of all species present.
Acknowledgment. We thank the EPSRC (A.P.B.), the
University of Sheffield (F.J.C.), the New Zealand government
(A.E.R.), the Spanish government (C.R.), and the Lister Institute
(C.A.H.) for financial support.
Supporting Information Available: X-ray crystal structure
data for AIA (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA0012671
(15) Job, P. Ann. Chim. 1928, 113, 113-116.