Modulating charge transfer through cyclic D,L-α-peptide self-assembly

Article abstract of DOI:10.1002/chem.200400923

We describe a concise, solid support-based synthetic method for the preparation of cyclic D,L-α-peptides bearing 1,4,5,8- naphthalenetetracarboxylic acid diimide (NDI) side chains. Studies of the structural and photoluminescence properties of these molecules in solution show that the hydrogen bond-directed self-assembly of the cyclic D,L-α-peptide backbone promotes intermolecular NDI excimer formation. The efficiency of NDI charge transfer in the resulting supramolecular assemblies is shown to depend on the length of the linker between the NDI and the peptide backbone, the distal NDI substituent, and the number of NDIs incorporated in a given structure. The design rationale and synthetic strategies described here should provide a basic blueprint for a series of self-assembling cyclic D,L-α-peptide nanotubes with interesting optical and electronic properties.

Full text of DOI:10.1002/chem.200400923

FULL PAPER
Modulating Charge Transfer through Cyclic d,l-a-Peptide Self-Assembly
W. Seth Horne, Nurit Ashkenasy, and M. Reza Ghadiri*[a]
Abstract: We describe a concise, solid
support-based synthetic method for the
preparation of cyclic d,l-a-peptides
bearing 1,4,5,8-naphthalenetetracarbox-
ylic acid diimide (NDI) side chains.
Studies of the structural and photolu-
minescence properties of these mole-
cules in solution show that the hydro-
gen bond-directed self-assembly of the
cyclic d,l-a-peptide backbone pro-
motes intermolecular NDI excimer for-
mation. The efficiency of NDI charge
transfer in the resulting supramolecular
assemblies is shown to depend on the
length of the linker between the NDI
and the peptide backbone, the distal
NDI substituent, and the number of
NDIs incorporated in a given structure.
The design rationale and synthetic
strategies described here should pro-
vide a basic blueprint for a series of
self-assembling cyclic d,l-a-peptide
nanotubes with interesting optical and
electronic properties.
Keywords: charge transfer · cyclic
peptides · nanotubes · self-assem-
bly · supramolecular chemistry
Introduction
chains and might offer a level of control over the long-range
order in the resulting materials.[1,10b,14]
Cyclic d,l-a-peptides are the archetypical members of a
growing class of organic tubular supramolecular struc-
tures[1–8] with promising potential applications in biological[9]
and materials[10] settings. As a result of increasing interest in
the field of molecular electronics,[11] theoretical calculations
have been used to assess the conductive properties of self-
assembling peptide nanotubes.[12] It has been proposed that
the cyclic d,l-a-peptide structures should possess wide band
gaps (Eg >4 eV) that could potentially be tuned through ap-
propriate modification of the cyclic peptide.[12d] However, it
has been determined that natural amino acid side chains
cannot be used to decrease the band gap to levels sufficient
for potential use in molecular electronics applications. Since
many organic semiconducting and conducting materials are
based on one-dimensional stacking of aromatic molecules
through p–p interactions and partial charge transfer,[13] we
envisioned that cyclic peptide self-assembly might be useful
in controlling and directing the stacking of aromatic side
Among aromatic molecules that have found utility in the
design of conductive materials, naphthalenediimide deriva-
tives have attracted considerable attention due to their ten-
dency to form n-type materials, as opposed to most other or-
ganic molecules, used to fabricate p-type semiconductors.[15]
High-conductivity materials based on NDI-derivatized den-
drimers and polymers have also been reported.[16] We postu-
lated that the intermolecular interactions of NDIs could be
directed and/or promoted by the display of such species as
side chains of cyclic d,l-a-peptides. It was envisioned that
controlling aromatic ring interactions and geometry through
peptide backbone-directed self-assembly[17] might provide a
rational supramolecular approach to conductive materials
engineering. To these ends, we present here a model system
for probing hydrogen bond-directed intermolecular NDI–
NDI interactions in solution. We report methods developed
for the synthesis of NDI-modified cyclic d,l-a-peptides, ex-
amine their propensity for self-assembly by NMR, and
probe the efficiency of intermolecular NDI–NDI charge
transfer by fluorescence measurements.
[a] W. S. Horne,+ Dr. N. Ashkenasy,+ Prof. M. R. Ghadiri
Departments of Chemistry and Molecular Biology and The Skaggs
Institute for Chemical Biology
Results and Discussion
The Scripps Research Institute
10550 North Torrey Pines Rd., La Jolla, CA 92037 (USA)
Fax : (+1)858-784-2798
Design: Cyclic d,l-a-peptides can form cylindrical b-sheet
ensembles through hydrogen bond-directed ring stacking.[2]
Interruption of the hydrogen bonding network on one face
of the cyclic peptide subunit through backbone N-alkylation
E-mail: ghadiri@scripps.edu
[+] These authors contributed equally to this work.
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DOI: 10.1002/chem.200400923
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restricts the self-assembly to antiparallel cylindrical dimers
(Figure 1a).[18,19] Such assemblies represent the asymmetric
unit of the parent extended peptide nanotube and have
proven to be useful models for probing of the nanotube
structure, self-assembly process, and functional proper-
ties.[10a,17–20] Here we have used this strategy to investigate
the design and optical properties of NDI-functionalized self-
assembling cyclic d,l-a-peptides.
Modeling suggests that NDI-modified side chains could
adopt productive charge-transfer geometries in the context
of the cyclic d,l-a-peptide dimer (Figure 1b, c). Accordingly,
peptides 1–5 were designed to probe the influence of linker
length, distal NDI substituent, and number of NDI amino
acid side chains on the dimer self-assembly and optical
properties. Peptides 1–3, each with a single NDI side chain,
were designed to evaluate the effects of steric bulk of the
distal NDI substituent (methyl in 3 versus isobutyl in 1 and
2). The effect of linker length was examined by comparison
of the properties of cylindrical dimers derived from peptides
1 and 2. Peptides 4 and 5, each bearing two NDI side chain
functionalities, were designed similarly in order to examine
the role of multiple NDI substitutions and linker length. It
should be noted that ring symmetry is an important design
consideration in these molecules, as it determines the
number of non-equivalent dimeric assemblies that a given
cyclic peptide can form.[17,19] In the flat ring conformation
adopted by an eight-residue cyclic d,l-a-peptide in a nano-
tube context, the backbone is C4 symmetric with the axis of
rotation perpendicular to the plane of the ring.[2b,19] Accord-
ingly, the dimer shown in Figure 1a represents only one of
four possible diastereomeric assemblies differing in the
cross-strand pairing of homochiral amino acids. Depending
on the peptide sequence, one or more of these dimers may
be equivalent. Therefore, the C1 symmetric peptides 1–3 can
each form four different diastereomeric assemblies (Fig-
ure 1d), whereas the C2-symmetric eight-residue peptides 4
Figure 1. a) Schematic representation of hydrogen bond-directed dimerization of backbone N-methylated cyclic d,l-a-peptides with generic side chains
R1–R4 (for clarity most side chains are not depicted in dimeric assembly). b) Calculated model of one possible dimer of peptide 3 viewed from the top
and c) from the side (most side chains and protons omitted for clarity). d) Schematic illustration depicting overlap of NDI side chains (diamonds) in the
four possible dimeric assemblies available to the C1-symmetric peptides 1, 2, and 3.
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Modulating Charge Transfer
FULL PAPER
and 5 can each form a maximum of two diastereomers. This
is an important consideration, as inter-subunit NDI–NDI in-
teractions should only be possible in dimeric species in
which the aromatic side chains are juxtaposed across each
other on opposite rings.
of one equivalent of a primary amine to the same reaction
vessel, followed by overnight heating at reflux, yields naph-
thalene monoimides 8a–c in good isolated yield and purity
by a simple filtration workup.
We found that the dicarboxylic acid moieties in 8a–c
could be directly converted into imides by condensation
with primary amines in DMF at temperatures above 1108C
without the need to isolate the corresponding anhydrides
first.[16c,24] In one example of the use of monoimides (8) in
the synthesis of cyclic d,l-a-peptides (Scheme 2), the four
Synthesis: We investigated three synthetic routes toward the
desired cyclic peptides bearing NDI side chains. These
routes included preparation from an NDI-functionalized
amino acid,[21] post-synthetic modification[16c] of cyclic d,l-a-
peptides, and modification of natural amino acid side chains
during the course of solid-phase peptide synthesis.[22] For the
synthesis of peptides 1–5 we found the last approach to be
most general and synthetically convenient. Central to each
of these approaches is the preparation of unsymmetrically
substituted NDIs. Symmetrical NDIs such as N,N’-dibutyl-
1,4,5,8-naphthalenetetracarboxylic acid diimide (7) can be
prepared by condensation of 1,4,5,8-naphthalenetetracar-
boxylic acid dianhydride (6) with two equivalents of a pri-
mary amine (Scheme 1).[23] Unsymmetrical NDIs present a
Scheme 1. Preparation of symmetrical and unsymmetrical NDI deriva-
tives.
Scheme 2. Use of naphthalene monoimides in the post-synthetic modifi-
cation of cyclic d,l-a-peptides.
greater challenge and have typically been prepared from
anhydride 6 by condensation with 1:1 mixtures of two differ-
ent primary amines, leading to statistical mixtures of prod-
ucts. We have found a modification of a reported synthesis
of NDI cyclophanes[24] to be a convenient alternative to this
approach (Scheme 1). After complete hydrolysis of a sus-
pension of 6 (20 mm in water) with KOH, reacidification to
pH 6.2 with H3PO4 leads to the formation of the diacid
naphthalenetetracarboxylic acid monoanhydride. Addition
free amine lysine side chains of peptide 9 were converted
into diimides by heating at 1158C with Cbz-ethylenedia-
mine-modified monoimide 8c in DMF. Removal of the Cbz
protecting groups and purification yielded tetra-NDI-substi-
tuted peptide 10 in 38% overall yield for the two steps.
Naphthalene monoimides were also incorporated onto pep-
tides by on-resin conversion of lysine or ornithine side chain
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M. R. Ghadiri et al.
NMR structural characterization: NMR was utilized to
probe the three-dimensional structures and assembly of pep-
1
tides 1–5 in CDCl3. The H NMR spectra at low concentra-
tions (ꢀ200 mm) are sharp and consistent with the prepon-
derance of monomeric species in solution. The spectra of
peptides 4 and 5 show peaks for only four different residues,
indicating that these peptides maintain an apparent C2 sym-
metry in solution. For each peptide, an increase in concen-
tration leads to a new set of peaks consistent with hydrogen-
bonded dimeric species in slow exchange (on the NMR
timescale) with the monomer.[19a] The concentration-depen-
dent monomer/dimer ratio was used to determine the ap-
parent self-association constants (Ka values) (Table 1). In
Table 1. Association constants as determined by NMR spectroscopy.
[b]
Cpd
Sequence[a]
Ka [mꢁ1
]
1
2
3
4
5
7
cyclo[Ala-Leu-MeAla-Leu-LysNDI-iBu-Leu-MeAla-Leu]
cyclo[Ala-Leu-MeAla-Leu-OrnNDI-iBu-Leu-MeAla-Leu]
cyclo[Ala-Leu-MeAla-Leu-LysNDI-Me-Leu-MeAla-Leu]
cyclo[(LysNDI-iBu-Leu-MeAla-Leu)2]
116
192
119
52
87
0.4
cyclo[(OrnNDI-iBu-Leu-MeAla-Leu)2]
dibutyl-NDI
[a] Italic residues indicate d enantiomers; MeAla
= N-methylalanine.
[b] Details of the calculations can be found in the Experimental Section.
the calculation of the association constants, all possible dia-
stereomeric ensembles formed by a given peptide were con-
sidered equivalent, so the Ka values in Table 1 reflect the
overall propensity for self-association demonstrated by each
1
peptide. The H NMR data fit well with the self-association
model, and the results of the calculations show that peptides
in CDCl3 form dimeric species with Ka values ranging from
51 to 192mꢁ1.
Direct comparison of the association constants for the
non-symmetric peptides 1–3 with those of the C2-symmetric
peptides 4 and 5 is complicated by two factors. The non-
equivalent diastereomeric assemblies that can be formed
through the dimerization of the peptide give rise to an en-
tropy of mixing term that varies with the number and popu-
lation of those assemblies.[25] In addition, a free energy term
arising from the symmetry difference between the peptide
monomer and dimer contributes a symmetry component—
independent of the inherent chemical propensity to self-as-
sociate—to the observed Ka.[26] Calculations for the C1- and
C2-symmetric peptides, however, show that the energetic
contributions from these two terms cancel if it is assumed
that a statistical mixture of dimeric assemblies is formed.
The differences in the binding constants of the various
molecules provide some insight into the effect of the NDI
modification on assembly of the peptide backbone. Compar-
ison of the single-NDI-containing peptides 1 and 2 with the
bis-NDI peptides 4 and 5, respectively, show a twofold de-
crease in the binding constants accompanying the incorpora-
tion of an additional NDI side chain. This suggests that mul-
tiple NDIs on a cyclic peptide would tend to destabilize
Scheme 3. On-resin conversion of side chain amines into imides.
amines into imides (Scheme 3). A representative synthesis
began with the preparation of linear peptide 11 by standard
Fmoc solid-phase peptide synthesis methods, with use of
MTT-protected (MTT
= e-4-methyltrityl) lysine. Resin-
bound 11 was treated with dilute TFA to remove the MTT
protecting groups, and the resulting free amines were con-
verted into imides by stirring the resin with an excess of 8b
in DMF at 1108C. The NDI-modified linear peptide was
cleaved from the resin by treatment with TFA and purified
by preparative HPLC to yield 12 in 28% overall yield.
Treatment of 12 with (7-azabenzotriazol-1-yloxy) tripyrroli-
dinophosphonium hexafluorophosphate (PyAOP) and diiso-
propylethylamine at 0.7 mm in DMF led to formation of the
desired cyclic product 4 in 71% isolated yield. This synthetic
approach was also used to prepare peptides 1, 2, 3, and 5.
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Chem. Eur. J. 2005, 11, 1137 – 1144

Modulating Charge Transfer
FULL PAPER
dimer formation. Comparison of 4 with 5 and of 1 with 2
show ꢀ60% decreases in Ka for the lysine-based linkers, in-
dicating that the dimer is more stable when the NDI group
is tethered closer to the peptide backbone. The similar asso-
ciation constants for 1 and 3 indicate that the distal NDI
substituent has little impact on intermolecular peptide self-
association.
NDI-containing peptides 1, 2, and 3 and also for the control
compound 7 at 1.65 mm in CDCl3. The formation of exci-
mers is indicated by the presence of a broad peak with a
maximum at 492 nm, red-shifted with respect to the mono-
meric peaks at wavelengths of 434 and 408 nm due to
charge delocalization. As would be expected from the pep-
tide self-assembly observed by NMR, all three peptides (1–
3) show enhanced excimer peak intensity relative to the
control compound 7. These effects can be seen throughout
the concentration range (0.1–5 mm) studied (Figure 2b).
Although the practical range of peptide concentrations
that can be studied (as determined by the magnitude of Ka)
is above the region in which rigorous quantitative analysis
of the fluorescence data is possible, some qualitative differ-
ences are clear. Differences in excimer peak intensity sug-
gest that, in addition to the enhanced effective concentra-
tion brought about by peptide backbone-directed self-as-
sembly, other structural parameters also seem to play a role
in the formation of NDI excimers. It is evident that peptide
3 has a much higher propensity than 1 for the formation of
NDI excimers. Since the NMR data show similar association
constants for the two peptides, the difference in excimer for-
mation can be attributed to the reduced steric hindrance
from the distal NDI methyl group in 3 in relation to the
branched isobutyl moiety in 1, allowing more productive in-
teractions between the aromatic rings.
Fluorescence characterization: Charge delocalization as a
consequence of aromatic ring stacking provides the basis of
the electronic properties observed in high-order NDI aggre-
gates. Charge transfer within an NDI dimer in solution leads
to the formation of excimers, which can be conveniently
monitored by fluorescence spectroscopy.[27] Thus, the role of
cyclic peptide backbone self-assembly in enhancing NDI–
NDI interactions was probed through fluorescence measure-
ments. Figure 2a shows the fluorescence spectra for single-
The length of the tether between the peptide backbone
and the NDI substituent also seems to influence NDI exci-
mer formation. Peptide 1 shows more pronounced excimer
formation than the control compound 7, while 2—which by
NMR has an association constant almost twice that of 1—
shows excimer peak intensity closer to that of the control
compound. This suggests that the shorter ornithine-based
linker between the NDI and the cyclic peptide backbone in
2 does not allow the necessary flexibility for the NDI side
chains on adjacent peptide strands to adopt an orientation
suitable for efficient charge transfer. In contrast with the
effect of linker length on peptide dimerization, the addition-
al degrees of freedom offered by the lysine-based linker in
this case allow more favorable intermolecular NDI interac-
tions relative to the shorter ornithine.
As discussed above, in the non-symmetrically substituted
peptide 3, the dimer in which the NDI side chains are juxta-
posed across from each other represents only one of four
possible diastereomeric assemblies (Figure 1d). In calcula-
tion of the apparent association constants reported in
Table 1, these dimers were all considered equivalent. It is
reasonable to assume that only the assembly in which the
NDI side chains overlap would be productive with respect
to intermolecular excimer formation (Figure 1b, c). Howev-
er, this dimer is probably the least stable and therefore least
populated of the four, as the other three have the bulky
NDI moiety paired with less sterically demanding alanine
side chains. Although peptides 4 and 5 show Ka values two
orders of magnitude larger than that of 7 by NMR spectros-
copy, efforts to probe the efficiency of the intermolecular
NDI charge transfer in these C2-symmetric peptides were
Figure 2. a) Fluorescence spectra of 1.65 mm solutions of peptides 1, 2, 3,
and control compound 7 in CDCl3 (lex = 330 nm). b) The change in exci-
mer intensity as a function of peptide concentration (lines are shown to
guide the eye).
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M. R. Ghadiri et al.
standard): d
=
178.0, 169.1, 147.6, 134.0, 131.6, 129.5, 127.5, 124.8,
not informative, due to interference by intramolecular NDI
interactions. The fluorescence spectrum of each exhibits a
large concentration-independent excimer peak (data not
shown). This peak remains even at concentrations at which
29.6 ppm; ESI-TOF MS: found: 298.0360 [MꢁH]ꢁ; calcd 298.0357).
Monoimide 8c: This compound was prepared by treatment of 1,4,5,8-
naphthalenetetracarboxylic acid dianhydride (6, 1.163 g, 4.34 mmol) with
N-Cbz-ethylenediamine hydrochloride (1.0 g, 4.33 mmol) as described for
2a. The reaction yielded the product (1.129 g, 56%) as a pale tan solid.
1H NMR (400 MHz, [D6]DMSO): d = 8.50 (d, J = 8 Hz, 2H), 8.07 (d, J
= 8 Hz, 2H), 7.4–7.2 (m, 6H), 4.94 (s, 2H), 4.16 (t, J = 6 Hz, 2H),
1
the H NMR indicates that only monomers exist in solution
for both peptides, suggesting that there is enough flexibility
in the peptide backbone to allow productive intramolecular
interaction between NDI side chains. As would be expected,
this intramolecular NDI excimer formation depends on
linker length and is more pronounced in 4 than 5.
3.60 ppm (q, J
4 equiv triethylamine to improve solubility): d
=
6 Hz, 2H); 13C NMR (150 MHz, [D6]DMSO with
170.8, 163.6, 156.2,
=
146.3, 137.2, 129.9, 128.7, 128.1, 127.5, 127.4, 126.3, 125.7, 121.6, 64.9,
38.2 ppm; ESI-TOF MS (m/z) found: 461.0989 [MꢁH]ꢁ; calcd 461.0990.
In conclusion, these studies indicate that cyclic d,l-a-pep-
tide self-assembly can be an effective process for templating
directed aromatic side chain–side chain interactions. It
might therefore be expected that the design rationale de-
scribed here, coupled with the efficient synthetic process,
should allow access to a variety of cyclic d,l-a-peptide se-
quences bearing NDI side chains for use in the construction
of self-assembling peptide nanotube analogues with novel
optical and electronic properties.
Cyclic peptide 9: Peptide 9 was prepared by the previously reported
methodology from Fmoc-Lys-OAllyl attached through the amine of the
lysine side chain to 2-Cl-Trt resin.[28] The crude material was purified by
preparative RP-HPLC. ESI-TOF MS (m/z) found: 1561.9134 [M+H]+;
calcd 1561.9141.
NDI derivatization of a peptide in solution—synthesis of 10: Peptide 9
(11 mg, 5.5 mmol assuming a salt with four molecules of trifluoroacetate
per peptide) and 8c (12.6 mg, 27.3 mmol) were suspended in DMF
(5 mL). The mixture was heated to 1158C under argon and stirred over-
night. The resulting solution was allowed to cool to room temperature
and concentrated to dryness. The remaining solid was washed (2ꢂ2 mL)
with phosphate buffer (pH 8.0), the supernatant was discarded, and the
solid was dried under high vacuum. The crude solid was dissolved in
TFA/trimethylsilyl trifluoromethanesulfonate/cresol (10:2:2, 200 mL).
After 1 h, diethyl ether (2 mL) was added, and the resulting suspension
was centrifuged. The supernatant was discarded, and the solid was
washed twice more with diethyl ether (2 mL). The crude peptide was pu-
rified by preparative RP-HPLC to yield the product (6.4 mg, 38% assum-
ing a salt with eight molecules of trifluoroacetate per peptide) as an off-
white solid. 1H NMR (600 MHz, CDCl3/[D]TFA, all signals were broad,
probably due to aggregation; integration of amide NH at 6.93 ppm was
lower than 8 due to partial exchange with TFA): d = 8.93 (brs, 16H),
6.93 (brs, 7H), 4.91 (brs, 8H), 4.79 (brs, 8H), 4.31 (brs, 8H), 3.82 (brs,
8H), 3.37 (brs, 8H), 2.00 (brs, 32H), 1.65 ppm (brs, 16H); ESI-TOF MS
(m/z): found: 1097.4841 [M+2H]2+; calcd 1097.4840.
Experimental Section
General: The Fmoc-amino acids, resins used for solid-phase peptide syn-
thesis, and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-
fluorophosphate (HBTU) were all purchased from Novabiochem. NMR
solvents were obtained from Cambridge Isotope Labs. N-Cbz-ethylenedi-
amine hydrochloride was purchased from TCI America. (7-Azabenzotria-
zol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyAOP),
1,4,5,8-naphthalenetetracarboxylic acid dianhydride (6), and all other sol-
vents and reagents were purchased from Aldrich. DMF used in coupling
and cyclization steps was dried over 4 ꢁ molecular sieves. All other re-
agents and solvents were used as received. Reversed-phase HPLC was
carried out on C18 columns with use of water/acetonitrile/TFA gradients
between 99:1:0.1 and 10:90:0.1. NMR spectra were obtained on Bruker
AMX 400, DRX 500, or DRX 600 spectrometers. UV/Vis measurements
were made on a Cary 100 Bio UV/visible Spectrophotometer. Fluores-
cence spectra were acquired on an Aminco Bowman Series 2 Lumines-
cence Spectrometer.
Representative NDI derivatization of a peptide on solid support—synthe-
sis of 12
1. Protected linear peptide on resin: Fmoc-Lys(MTT) Wang polystyrene
resin (139 mg, 0.100 mmol) was weighed into a sintered glass peptide syn-
thesis vessel and was allowed to swell in CH2Cl2 for 45 min, and then in
DMF for 10 min. The resin was treated with piperidine/DMF (20%, 2ꢂ
8 min) to remove the Fmoc group, and washed with DMF (3ꢂ). A so-
lution of Fmoc-d-leucine (142 mg, 0.40 mmol), HBTU (148 mg,
0.39 mmol), and diisopropylethylamine (175 ml, 1.0 mmol) in DMF
(3 mL) was allowed to prereact for 2 min and then added to the resin.
The resin suspension was agitated for 30 min, drained, and washed with
DMF (3ꢂ). This deprotection/coupling cycle was repeated to provide the
full-length linear peptide 11. Coupling reactions following N-methylala-
nine residues were performed twice to ensure complete reaction.
Monoimide 8a: 1,4,5,8-Naphthalenetetracarboxylic acid dianhydride (6,
2.0 g, 7.46 mmol) was weighed into a 500-mL flask. Water (350 mL) was
added, followed by KOH (1m, 35 mL). In some cases, heat, sonication,
and/or additional KOH were used to dissolve the starting material com-
pletely. After the solid had dissolved, the solution was acidified to pH 6.4
with H3PO4 (1m). Isobutylamine (0.741 mL, 7.46 mmol) was added, and
the solution was again acidified to pH 6.4 with H3PO4 (1m). The reaction
vessel was fitted with a reflux condenser, and the mixture was heated to
1108C, stirred overnight, allowed to cool to room temperature, and fil-
tered. Acetic acid (5 mL) was added to the filtrate, and a white solid pre-
cipitated from the solution. The solid was collected by filtration, washed
with water, and dried under high vacuum to yield the desired product
2. Conversion of resin-bound Lys(MTT) into Lys(NDI) and cleavage
from resin: The resin bearing 11 was washed with CH2Cl2 (3ꢂ1 min) and
treated with a CH2Cl2/triethylsilane/trifluoroacetic acid mixture (93:5:2;
3ꢂ2 min followed by 3ꢂ10 min) to remove the lysine MTT protecting
groups. The resin was then washed sequentially with CH2Cl2, DMF,
DMF/disopropylethylamine (95:5), and again with DMF. The resin was
transferred to a 20 mL vial, to which 8a (1.5 equiv relative to resin-
bound amines, 102 mg, 0.30 mmol) was added, followed by DMF (8 mL).
The suspension was heated to 1108C and stirred for 6 h. The reaction
mixture was allowed to cool to room temperature and filtered through a
fritted syringe. The resin was washed thoroughly (5ꢂDMF, 3ꢂCH2Cl2,
3ꢂMeOH) and dried under high vacuum. The peptide was cleaved from
the resin by treatment with TFA/H2O (95:5) for 3 h. The cleavage mix-
ture was collected by filtration and the resin was washed twice with TFA.
The filtrates were combined and concentrated under vacuum to afford an
oily residue. Water was added, and the mixture was sonicated to produce
a suspension of a cream-colored solid. This mixture was frozen and
1
(1.714 g, 67%) as an off-white solid. H NMR (400 MHz, [D6]DMSO): d
= 8.51 (d, J = 7 Hz, 2H), 8.07 (d, J = 7 Hz, 2H), 3.90 (d, J = 7 Hz,
2H), 2.12 (m, 1H), 0.90 ppm (d, J = 7 Hz, 6H); 13C NMR (100 MHz,
[D6]DMSO): d = 169.7, 163.3, 130.3, 128.6, 128.1, 128.0, 125.5, 123.4,
46.6, 26.9, 20.2 ppm; MALDI-FTMS: found: 342.0972 [M+H]+; calcd
342.0964.
Monoimide 8b: This compound was prepared by treatment of 1,4,5,8-
naphthalenetetracarboxylic acid dianhydride (6, 1.0 g, 3.73 mmol) with
methylamine hydrochloride (252 mg, 3.73 mmol) as described for 8a. The
reaction yielded the product (890 mg, 80%) as a pale yellow solid. 1H
NMR (500 MHz, D2O): d = 8.56 (d, J = 8 Hz, 2H), 8.05 (d, J = 8 Hz,
2H), 3.47 ppm (s, 3H); 13C NMR (125 MHz, NaOD/D2O, DSS as internal
1142
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Chem. Eur. J. 2005, 11, 1137 – 1144

Modulating Charge Transfer
FULL PAPER
lyophilized to yield crude product. Purification by preparative RP-HPLC
on a C18 column yielded the trifluoroacetate salt of the product (46 mg,
28%) as an off-white solid. MALDI-FTMS: found: 1507.7926 [M+H]+;
calcd 1507.7871.
Linear precursor to 5: The linear peptide was synthesized from Fmoc-
Orn(MTT) Wang polystyrene resin (204 mg, 0.10 mmol) and purified as
described above for 12 to yield the trifluoroacetate salt of the product
(39 mg, 24%) as
a white solid. MALDI-FTMS: found: 1479.7511
[M+H]+; calcd 1479.7558).
Cyclic 4: Linear peptide 12 (46 mg, 28 mmol) was dissolved in DMF
(40 mL). PyAOP (44 mg, 85 mmol) was added, followed by diisopropyl-
ethylamine (30 ml, 170 mmol). The reaction mixture was stirred for 2.5 h
at room temperature and concentrated under vacuum. Water/acetoni-
trile/TFA (1:1:0.001, 8 mL) was added, and the residue was sonicated to
create a suspension. After centrifugation, the supernatant was removed.
The solid was washed twice more by the same procedure. The resulting
pellet was suspended in water, sonicated, and lyophilized to yield the
Cyclic 5: The linear precursor (39 mg, 24.4 mmol) was cyclized as de-
scribed for 4 to yield the product (33 mg, 93%) as an off-white solid. 1H
NMR (500 MHz, CDCl3): d = 8.70 (s, 8H), 7.55 (d, J = 8 Hz, 2H), 6.78
(d, J = 10 Hz, 2H), 6.55 (d, J = 7 Hz, 2H), 5.21 (q, J = 7 Hz, 2H), 4.84
(dd, J = 7, 8 Hz, 2H), 4.72 (dd, J = 6, 6 Hz, 2H), 4.47 (td, J = 10,
4 Hz), 4.19 (m, 4H), 4.04 (d, J = 7 Hz, 4H), 2.81 (s, 6H), 2.2 (m, 2H),
1.98 (m, 2H), 1.85–1.40 (m, 18H), 1.30 (d, J = 7 Hz, 6H), 0.98 (d, J =
7 Hz, 12H), 0.92 ppm (m, 24H); MALDI-FTMS: found: 1483.7228
[M+Na]+; calcd 1483.7272.
Concentration-dependent NMR for N-Me cyclic peptides:[19a] All spectra
were obtained in CDCl3 (99.96% from Cambridge Isotope Labs). A
stock solution of freshly dried peptide was made in CDCl3, and this so-
lution was sonicated and centrifuged to remove any insoluble material.
The concentration of this stock solution was determined by absorption
spectroscopy (NDI e380 = 29850 cmꢁ1 mꢁ1). The stock solution was then
diluted to make samples at the desired concentrations (at least three dif-
ferent concentrations for each peptide). 1H NMR spectra were obtained
on a Bruker DRX 500 or DRX 600 spectrometer. As the monomer and
dimer species are in slow exchange on the NMR timescale, peaks for
both species were visible. The data were fit to the model given in Equa-
tions (1) and (2),where [A] and [A2] are the concentrations of monomer
and dimer, respectively, and Ctot is the total concentration.
1
product (30 mg, 71%) as an off-white solid. H NMR (600 MHz, CDCl3):
d = 8.55 (s, 8H), 7.59 (d, J = 8 Hz, 2H), 6.82 (d, J = 10 Hz, 2H), 6.55
(d, J = 7 Hz, 2H), 5.25 (q, J = 7 Hz, 2H), 4.87 (dd, J = 7, 8 Hz, 2H),
4.65 (dd, J = 6, 6 Hz, 2H), 4.46 (dt, J = 4, 10 Hz, 2H), 4.10 (m, 4H),
4.00 (d, J = 7 Hz, 4H), 2.83 (s, 6H), 2.19 (m, 2H), 1.96 (m, 2H), 1.9–1.7
(m, 8H), 1.68–1.36 (m, obscured by H2O), 1.32 (d, J = 7 Hz, 6H), 0.97–
0.93 (overlapping doublets, 24H), 0.90 (d, J = 7 Hz, 6H), 0.85 ppm (d, J
=
7 Hz, 6H); MALDI-FTMS: found: 1489.7760 [M+H]+; calcd
1489.7766).
Linear precursor to 1: Linear peptide was synthesized from Fmoc-Ala
Wang polystyrene resin (141 mg, 0.10 mmol) and purified as described
above for 12 to yield the trifluoroacetate salt of the product (27 mg,
21%) as a white solid. MALDI-FTMS: found: 1145.6621 [M+H]+; calcd
1145.6605.
Cyclic 1: The linear precursor (27 mg, 21.4 mmol) was cyclized as de-
scribed for 4. The product was purified by RP-HPLC on a C18 column to
yield the desired product (12 mg, 50%) as a white solid. 1H NMR
(600 MHz, CDCl3): d = 8.75 (d, J = 2 Hz, 4H), 7.58 (d, J = 8 Hz, 1H),
7.51 (d, J = 9 Hz), 6.86 (d, J = 9 Hz, 1H), 6.80 (d, J = 10 Hz, 1H), 6.66
(d, J = 6 Hz, 1H), 6.57 (d, J = 7 Hz, 1H), 5.24 (m, 2H), 4.85 (m, 2H),
4.59 (m, 2H), 4.46 (m, 2H), 4.15 (t, J = 8 Hz, 2H), 4.06 (d, J = 7 Hz,
2H), 2.82 (overlapping s, 6H), 2.23 (m, 1H), 1.37 (d, J = 7 Hz, 3H), 1.32
(d, J = 7 Hz, 6H), 1.95–1.40 (m, obscured by H2O), 1.0–0.8 ppm (over-
lapping d, 30H); MALDI-FTMS: found: 1149.6313 [M+Na]+; calcd
1149.6319.
½A2ꢂ
ð1Þ
ð2Þ
K ¼
2
½Aꢂ
Ctot ¼ 2 ½A2ꢂ þ ½Aꢂ
The integrated intensities of the backbone N-methyl groups were used to
measure the ratio of the two species. A variable x was defined according
to Equation (3), where Idimer is the integrated intensity of dimer N-methyl
peaks and Imonomer is the integrated intensity of monomer N-methyl peaks.
Linear precursor to 2: Linear peptide was synthesized from Fmoc-Ala
Wang polystyrene resin (141 mg, 0.10 mmol) and purified as described
above for 12 to yield the trifluoroacetate salt of the product (8 mg, 6%)
Idimer
2 Imonomer
½A2ꢂ
½Aꢂ
ð3Þ
x ꢃ
¼
as
a
white solid. MALDI-FTMS: found: 1131.6441 [M+H]+; calcd
Combining Equations (1)–(3) gives Equation (4).
1131.6448.
Cyclic 2: The linear precursor (8 mg, 6.4 mmol) was cyclized as described
for 4. The product was purified by RP-HPLC on a C18 column to yield
the desired product (4.2 mg, 59%) as an off-white solid. 1H NMR
(600 MHz, CDCl3): d = 8.75 (d, J = 8 Hz, 2H), 8.72 (d, J = 8 Hz, 2H),
7.61 (d, J = 7 Hz, 1H), 7.46 (d, J = 8 Hz, 1H), 6.83 (d, J = 9 Hz, 1H),
6.77 (d, J = 8 Hz, 1H), 6.66 (brs, 1H), 6.57 (brs, 1H), 5.21 (brs, 2H),
4.83 (m, 2H), 4.66 (m, 1H), 4.56 (m, 1H), 4.48 (m, 1H), 4.44 (m, 1H),
4.15 (m, 2H), 4.06 (d, J = 8 Hz, 2H), 2.28 (s, 6H), 2.0–1.2 (overlapping
multiplets obscured by H2O peak), 1.35 (d, J = 7 Hz, 3H), 1.31 (d, J =
7 Hz, 6H), 1.0–0.87 ppm (overlapping doublets, 36H); MALDI-FTMS:
found: 1113.6343 [M+H]+; calcd 1113.6343.
2x2 þ x
ð4Þ
Ctot
¼
K
The equilibrium constant for dimerization (K) was found from the in-
verse of the slope of the linear fit of Ctot against (2x2 +x) for each experi-
mental concentration.
Self-association constant of 7 by NMR spectroscopy:[29] NDI control com-
pound 7 demonstrated concentration-dependent chemical shifts over the
1 to 50 mm range. This concentration-dependent behavior was modeled
as a monomer and dimer in equilibrium and in fast exchange on the
NMR timescale. The data was modeled in terms of the self-association
equilibrium shown in Equations (1) and (2) above. For a given Ctot and
an arbitrary value of K, [A] can be found from the root of Equation (5),
Linear precursor to 3: The linear peptide was synthesized (from monoi-
mide 8b) on Fmoc-Ala Wang polystyrene resin (141 mg, 0.10 mmol) and
purified as described above for 12 to yield the trifluoroacetate salt of the
product (16 mg, 13%) as a white solid. MALDI-FTMS: found: 1103.6113
[M+H]+; calcd 1103.6135.
where [A] is greater than 0 and less than Ctot
.
2
ð5Þ
2 ½Aꢂ K þ ½AꢂꢁCtot ¼ 0
Cyclic 3: The linear precursor (16 mg, 13.1 mmol) was cyclized as de-
scribed for 4. The product was purified by RP-HPLC on a C18 column to
yield the desired product (8 mg, 56%) as an off-white solid. 1H NMR
(600 MHz, CDCl3): d = 8.76 (s, 4H), 7.57 (d, J = 8 Hz, 1H), 7.49 (d, J
= 8 Hz, 1H), 6.85 (d, J = 10 Hz, 1H), 6.79 (d, J = 10 Hz, 1H), 6.63 (d,
J = 6 Hz, 1H), 6.55 (d, J = 7 Hz, 1H), 5.24 (m, 2H), 4.86 (m, 2H), 4.59
(m, 2H), 4.46 (m, 2H), 4.15 (t, J = 8 Hz, 2H), 3.59 (s, 3H), 2.82 (s, 3H),
2.81 (s, 3H), 1.9–1.4 (overlapping multiplets), 1.36 (d, J = 7 Hz, 3H),
1.31 (d, J = 7 Hz, 6H), 1.23 (s, 3H), 0.98–0.84 ppm (overlapping dou-
blets, 24H); ESI-TOF MS: found: 1085.6030 [M+H]+; calcd 1085.6030.
If equilibrium between monomer and dimer in fast exchange is assumed,
the chemical shift for a given proton in 7 follows Equation (6), where d
is the observed chemical shift, d1 is the chemical shift of the monomer,
and d2 is the chemical shift of the dimer.
2 K½Aꢂ
ð6Þ
d ¼
2 ðd2ꢁd1Þ þ d1
Ctot
Thus, observed d values for each experimentally determined Ctot are used
Chem. Eur. J. 2005, 11, 1137 – 1144
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1143

M. R. Ghadiri et al.
with an arbitrary K in Equation (7) to determine d1 and d2 by linear re-
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.
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Acknowledgements
We thank the National Institute of Health (GM52190) and the Air Force
Office of Scientific Research (F49620–00–1–0283) for financial support.
W.S.H. thanks the National Science Foundation for a Predoctoral Fellow-
ship, and N.A. thanks the Fulbright Foundation for a Postdoctoral Fel-
lowship.
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Received: September 9, 2004
Published online: December 29, 2004
1144
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1137 – 1144