Programming the supramolecular helical polymerization of dendritic dipeptides via the stereochemical information of the dipeptide

Article abstract of DOI:10.1021/ja200280h

Many natural biomacromolecules are homochiral and are built from constituents possessing identical handedness. The construction of synthetic molecules, macromolecules, and supramolecular structures with tailored stereochemical sequences can detail the rel

Full text of DOI:10.1021/ja200280h

ARTICLE
pubs.acs.org/JACS
Programming the Supramolecular Helical Polymerization of Dendritic
Dipeptides via the Stereochemical Information of the Dipeptide
Brad M. Rosen,† Mihai Peterca,†,‡ Kentaro Morimitsu,† Andrꢀes E. Dulcey,† Pawaret Leowanawat,†
Ana-Maria Resmerita,† Mohammad R. Imam,† and Virgil Percec*,†
†Roy & Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
‡Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6396, United States
S Supporting Information
b
ABSTRACT: Many natural biomacromolecules are homochiral
and are built from constituents possessing identical handedness.
The construction of synthetic molecules, macromolecules, and
supramolecular structures with tailored stereochemical se-
quences can detail the relationship between chirality and
function and provide insight into the process that leads to the
selection of handedness and amplification of chirality. Dendritic
dipeptides, previously reported from our laboratory, self-assem-
ble into helical porous columns and serve as fundamental
mimics of natural porous helix-forming proteins and supramolecular polymers. Herein, the synthesis of all stereochemical
permutations of a self-assembling dendritic dipeptide including homochiral, heterochiral, and differentially racemized variants is
reported. A combination of CD/UVꢀvis spectroscopy in solution and in film, X-ray diffraction, and differential scanning calorimetry
studies in solid state established the role of the stereochemistry of the dipeptide on the thermodynamics and mechanism of self-
assembly. It was found that the highest degree of stereochemical purity, enantiopure homochiral dendritic dipeptides, exhibits the
most thermodynamically favorable self-assembly process in solution corresponding to the greatest degree of helical order and
intracolumnar crystallization in solid state. Reducing the stereochemical purity of the dendritic dipeptide through heterochirality or
by partially or fully racemizing the dendritic dipeptide destructively interferes with the self-assembly process. All dendritic dipeptides
were shown to coassemble into single columns regardless of their stereochemistry. Because these columns exhibit no
deracemization, the thermodynamic advantage of enantiopurity and homochirality suggests a mechanism for stereochemical
selection and chiral amplification.
’ INTRODUCTION
most frequently the result of helical growth triggered by the
formation of a chiral nucleus. Helical cooperative growth is
fundamental in biological self-assembly such as the supramole-
cular polymerization of proteins21,24,25 and can be utilized to
program biomimetic supramolecular polymerizations. Unlike many
stereogenic synthetic polymers, which can be prepared as homo-
chiral (e.g., isotactic), heterochiral (e.g., syndiotactic), or racemic
(e.g., atactic), biopolymers such as proteins, polysaccharides, and
nucleic acids exist almost exclusively in the homochiral form
derived from enantiomerically pure building blocks. Therefore, it
is difficult to probe the interrelationship of small numbers of
stereocenters, their function, and the mechanism of chiral
amplification that could result in the current level of stereopurity
in nature. Fortuitously, synthetic systems have emerged that
allow for the mimicry of the helical cooperative growth found in
nature,3 but with the flexibility to the relationship between fewer
stereocenters.
Supramolecular polymers1,2 are analogues of covalent poly-
mers, wherein monomers are not linked by covalent bonds, but
rather by the intermolecular interactions that define the realm of
supramolecular chemistry.3 Like covalent polymers, supramole-
cular polymers can be classified by their chemical structure and
topology and by their mechanism of polymerization.4ꢀ6 Supramo-
lecular polymerization is facilitated by intermolecular interactions
that mediate the connection between monomers, such as
H-bonding,7ꢀ12 πꢀπ and donorꢀacceptor interactions,11ꢀ16 ionic
interactions,17 and hostꢀguest interactions.18 As delineated in a
recent review by Meijer,6 the thermodynamics of linear supra-
molecular polymerization can be either isodesmic or coopera-
tive/anticooperative. In the isodesmic model,19,20 the Gibbs free
energy (ΔG) of monomer addition is independent of the degree
of polymerization, whereas in the cooperative13,21ꢀ23 or antic-
ooperative supramolecular polymerization models the ΔG of
monomer addition will increase or decrease following the for-
mation of an oligomeric nucleus, respectively. Cooperativity can
have a number of structural or environmental origins, but it is
Received: January 11, 2011
Published: March 10, 2011
r
2011 American Chemical Society
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Figure 1. The structures of homochiral and heterochiral dendritic dipeptides (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-Ala-OMe and the color code of the
dipeptide used in the molecular models illustrating the cross-section of the porous columns. (a) Color code of LꢀL, DꢀD, LꢀD, and DꢀL dipeptides used
for molecular models to illustrate the cross-sections of the supramolecular columns self-assembled from enantiopure homo- and heterochiral dendritic
dipeptides (ꢀCH3 from the Boc group of Tyr, blue; ꢀCH3 of the methylester and methyl of Ala, white; C, gray; O, red; NꢀH, green). (b) Color code of
LꢀL, DꢀD, LꢀD, and DꢀL dipeptides used to illustrate the cross-sections of the supramolecular columns self-assembled from the different racemic variants
LꢀDL, DꢀDL, DLꢀL, DLꢀD, and DLꢀDL explained in Figure 2 (ꢀCH3 from Boc group of Tyr, blue; O, red; NꢀH, green; C in LꢀD and DꢀL, gray; C and ꢀCH3
groups of Ala in LꢀL and DꢀD, light blue and orange, respectively; ꢀCH3 groups of Ala in LꢀD and DꢀL, white). (c) Structure of the second generation
dendron (4-3,4-3,5)12G2-.
Benzyl ether dendrons with specific primary structure func-
tionalized with aliphatic or semifluorinated alkyl groups2e,f,15b
self-assemble in solution and in solid state providing access to a
multitude of periodic lattices and quasi-periodic arrays.2g They
provide insight into the mechanism of self-assembly and access to
the design of new self-organized structures.26ꢀ29 Typical libraries
utilized in the discovery process are comprised of mostly achiral
dendrons.26,30ꢀ32 The attachment of dipeptides to the apex of
wedge-shaped self-assembling benzyl-ether dendrons33aꢀd in-
duces asymmetry that is amplified through self-assembly into
supramolecular helical porous columns that are stereochemically
programmed and allosterically regulated.8,33e Similarly, the at-
tachment of dipeptides to the apex of cone-shaped self-assem-
bling dendrons provides hollow chiral spherical supramolecular
dendrimers.34 Adaptation of the Cochran, Crick, and Vand
helical diffraction theory35 to columnar supramolecular dendri-
mers demonstrated internal helical order generated from den-
dritic dipeptides in their supramolecular columns.33b,36,37 The
architecture of the internal structure of the supramolecular
porous column and the self-assembly mechanism of dendritic
dipeptides are of considerable interest in the design of related and
unrelated complex functional systems such as self-repairing
supramolecular electronic materials,15,38 porous protein
mimics,33 supramolecular containers,34 thixotropic gels,39 and
nanomechanical actuators.40
Figure 2. The enantiomeric composition of racemized dendritic
dipeptides.
handedness of one stereocenter of the dipeptide can exhibit a
preference for the same handedness in the second R-amino acid
providing a mechanism for homochiral amplification. The am-
plification of homochirality can lead to increased intracolumnar
order and to the emergence of function derived from chiral
recognition and enhancement.
’ RESULTS AND DISCUSSION
Herein, a single dendritic dipeptide with only two stereocen-
ters, (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-Ala-OMe, was pre-
pared in all of its possible stereoisomeric forms, including
homochiral, heterochiral, as well as singly and fully racemic
combinations of R-amino acids. The study of the supramolecular
polymerization of these stereoisomeric dendritic dipeptides in
solution via CD/UVꢀvis spectroscopy and modeling of the
helical cooperative growth process in tandem with differential
scanning calorimetry (DSC) and X-ray diffraction (XRD) ex-
periments in solid state established a helical cooperative growth
mechanism and demonstrated how the stereochemical informa-
tion of the dipeptide is amplified through the supramolecular
polymerization process. Furthermore, it was shown how the
Design and Synthesis of Dendritic Dipeptides. The den-
dron (4-3,4-3,5)12G2-X self-assembles in solution and self-
organizes in the bulk state with a diversity of apex functionalities
(X), including dipeptides.33 When the dipeptide fragments are
separated from the dendron sheath, they crystallize into an
orthorhombic lattice derived from their inherent linear
conformation.33a This is markedly different from their barrel-
stave helical supramolecular structure of the dipeptide generated
by the self-assembly of the dendritic dipeptide.33a Therefore, the
self-assembly of the dendritic dipeptides (4-3,4-3,5)12G2-CH2-
Boc-X-Tyr-Y-Ala-OMe is driven by the dendron periphery and is
sterochemically programmed by the dipeptide.33e To fully ela-
borate the relationship between the two stereocenters, the
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Scheme 1. Synthesis of the New Dendritic Dipeptides (4-3,4-3,5)12G2-CH2-Boc-Tyr-Ala-OMea
a Reagents and conditions: (i) di-tert-butyl dicarbonate, Et3N, dioxane/H2O, 0 °C, 24 h; (ii) NMM, CDMT, EtOAc, 2 h; (iii) K2CO3, DMF, 70 °C.
solution-phase supramolecular polymerization and solid-state
self-organization of all four homochiral (LꢀL, DꢀD) and hetero-
chiral (LꢀD, DꢀL) permutations of the dipeptide stereochemistry
must be studied in depth (Figure 1).
mixture of D-Tyr-D-Ala, D-Tyr-L-Ala, L-Tyr-D-Ala, and L-Tyr-L-
Ala, DLꢀDL, is obtained (Figure 2, red rectangle).
Ultimately, the TyrꢀAla dipeptides can be coupled to a
dendron to form four stereoisomeric dendritic dipeptide variants,
LꢀL, DꢀD, LꢀD, and DꢀL, obtained in nine different combinations
that in addition to the four stereoisomers mentioned contain
LꢀDL, DꢀDL, DLꢀL, DLꢀD, and DLꢀDL. For this study, five new
partially or fully racemized dendritic dipeptides were synthe-
sized: (4-3,4-3,5)12G2-CH2-Boc-DL-Tyr-L-Ala-OMe, (4-3,4-
3,5)12G2-CH2-Boc-DL-Tyr-D-Ala-OMe, (4-3,4-3,5)12G2-CH2-
Boc-L-Tyr-DL-Ala-OMe, (4-3,4-3,5)12G2-CH2-Boc-D-Tyr-DL-
Ala-OMe, and (4-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-DL-Ala-
OMe (Scheme 1). The previously reported homochiral and
heterochiral benzyl ether33a,e and naphtyl ether33g dendritic
dipeptides were synthesized according to previously reported
procedures. Boc-DL-Tyr-OH was prepared in 95% by treating DL-
Tyr-OH with di-tert-butyl dicarbonate and Et3N in a 50/50
mixture of dioxane and H2O. Nonracemic dipeptides were
prepared in 62ꢀ87% yield via 2-chloro-4,6-dimethoxy-1,3,5-
triazine (CDMT)42-mediated coupling of Boc-DL-Tyr-OH,
Nevertheless, the synthesis and analysis of the four enantio-
pure dendritic dipeptides does not address the mechanism of
chiral amplification during self-assembly and self-organization.
R-Amino acids can exist in either the dextrorotatory (D) or
levorotatory form (L). Biologically synthesis of R-amino acids is
highly enantioselective providing exclusively the L-form, while
the D isomer can be prepared efficiently through asymmetric
synthesis.41 However, if one or both of the R-amino acids are not
obtained through stereoselective synthesis and are subsequently
coupled, a variety of partially and fully racemized dipeptides can
be prepared (Figure 2). If Tyr is prepared in a racemic fashion
and coupled to L-Ala, a 50:50 mixture of D-Tyr-L-Ala and L-Tyr-L-
Ala will be obtained. This mixture is herein referred to as DLꢀL
(Figure 2, orange parallelogram). Likewise, if Tyr is prepared in a
racemic fashion and coupled to D-Ala, a 50:50 mixture of D-Tyr-
D-Ala and L-Tyr-D-Ala will be generated. This mixture is referred
to as DLꢀD (Figure 2, green parallelogram). If, on the other hand,
Ala is prepared in racemic form and coupled with D-Tyr, a 50:50
mixture of D-Tyr-D-Ala and D-Tyr-L-Ala, DꢀDL, will be formed
(Figure 2, blue rectangle). Conversely, when Ala is racemic and
coupled with L-Tyr, a 50:50 mixture of L-Tyr-D-Ala and L-Tyr-L-
Ala, LꢀDL, is accessed (Figure 2, red rectangle). Finally, if both Ala
and Tyr are prepared racemic and coupled, a 25:25:25:25
Boc-L-Tyr-OH, or Boc-D-Tyr-OH with L-Ala-OMe HCl, D-Ala-
3
OMe HCl, or DL-Ala-OMe HCl respectively. Etherification of
3
3
(4-3,4-3,5)12G2-CH2Cl with the partially racemized dipeptides in
DMF using K2CO3 as base provided the dendritic dipeptides (4-3,4-
3,5)12G2-CH2-Boc-DL-Tyr-L-Ala-OMe, (4-3,4-3,5)12G2-CH2-Boc-
DL-Tyr-D-Ala-OMe, (4-3,4-3,5)12G2-CH2-Boc-L-Tyr-DL-Ala-OMe,
and (4-3,4-3,5)12G2-CH2-Boc-D-Tyr-DL-Ala-OMe in 26ꢀ53%
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Scheme 2. Synthesis of the New Dendritic Dipeptides (6 Np-3,4-3,5)12G2-CH2-Boc-Tyr-Ala-OMe and (6 Np-3,4-3,5)dm8*G2-
CH2-Boc-Tyr-Ala-OMea
a Reagents and conditions: (i) LiAlH4, THF, 0 °C to room temperature; (ii) SOCl2, DTBMP, 0 °C to room temperature; (iii) 1, K2CO3, DMF, 80 °C;
(iv) 2, PPh3, DIAD, THF, room temperature.
yield, respectively. Alternatively, etherification of (4-3,4-3,5)dm8*G2-
CH2Cl with the fully racemized dipeptide in DMF using K2CO3 as
base provided (4-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-DL-Ala-OMe
in 37%.
Finally, (6 Np-3,4-3,5)dm8*G2-CH2OH and (6 Np-3,4-3,5)
dm8*G2-CH2Cl were prepared through an analogous method
(Scheme 2). The syntheses of the (6 Np-3,4)12G1CH2-
CO2CH3 and (6 Np-3,4)dm8*G1CH2-CO2CH3 intermediates
were described previously.43 The first generation dendrons were
reduced to their corresponding alcohols with LiAlH4. Treatment
with SOCl2 provided the generation one dendritic chlorides,
which were alkylated onto methyl 3,5-dihydroxybenzoate in the
presence of K2CO3 as base to yield (6 Np-3,4-3,5)12G2-
CO2CH3 (74%) and (6 Np-3,4-3,5)dm8*G2-CO2CH3 (74%).
After reduction to the second generation alcohols, the (6 Np-3,4-
3,5)12G2-CH2OH and (6 Np-3,4-3,5)dm8*G2-CH2OH were
etherified with either Boc-L-Tyr-L-Ala-OMe, Boc-DL-Tyr-L-Ala-
OMe, or Boc-DL-Tyr-DL-Ala-OMe under Mitsunobu conditions
to provide the dendritic dipeptides (6 Np-3,4-3,5)12G2-CH2-
Boc-L-Tyr-L-Ala-OMe, (6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-
Tyr-L-Ala-OMe, and (4 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-
DL-Ala-OMe in 41%, 34%, and 36% yield, respectively. Detailed
synthesis and analysis is available in the Supporting Information.
Homochiral versus Heterochiral Dendritic Dipeptides.
Homochiral dendritic dipeptides are defined as having identical
stereochemistry for both R-amino acids. They are (4-3,4-3,5)12G2-
CH2-Boc-D-Tyr-D-Ala-OMe (DꢀD) and (4-3,4-3,5)12G2-CH2-Boc-
L-Tyr-L-Ala-OMe (LꢀL).33a Heterochiral dendritic dipeptides are
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defined as having opposing stereochemistry for the two R-amino
acids. In this case, they are (4-3,4-3,5)12G2-CH2-Boc-D-Tyr-L-Ala-
OMe (DꢀL) and (4-3,4-3,5)12G2-CH2-Boc-L-Tyr-D-Ala-OMe
(LꢀD). The two homochiral dendritic dipeptides are enantiomers
of each other, as are the two heterochiral dendritic dipeptides,
whereas the sets of homochiral and heterochiral dipeptides are
diasteromers. The stereochemical relationships of the dendritic
dipeptides manifest themselves structurally through enantiomeric
and diastereomeric conformations (Figure 3). These conformations
were determined via structural and retrostructural analysis of the
self-organized dendritic dipeptides.33 Helical diffraction theory was
used to elucidate the spatial disposition of the dendritic dipeptides
that give rise to the features observed in the oriented fiber X-ray
diffraction pattern.36 These structures are markedly different from
the lowest energy conformations observed for the individual
dendritic dipeptides.
The self-assembly of homochiral and heterochiral dendritic
dipeptides can be analyzed both in solid state and in solution. In
the solid state, both homochiral and heterochiral dendritic
dipeptides self-assemble into helical porous columns that self-
organize into hexagonal columnar lattices, Φh. The pore dimen-
sions of homochiral dendritic dipeptides (Dpore) have been
found to be slightly smaller than those observed for heterochiral
dendritic dipeptides (Figure 4).33a,e A similar self-assembly
process occurs in solution (1.6 ꢁ 10ꢀ4 M in cyclohexane).
CDꢀUVꢀvis spectroscopy (Figure 5aꢀd) indicates that the
sign of the Cotton effect and, therefore, the handedness of the
supramolecular helix are determined by the stereochemistry of
the Tyr residue and that the structural features of the columns are
regulated by the stereochemistry of the Ala residue. The
Figure 3. Molecular models of the four enantiopure dendritic dipep-
tides (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-Ala-OMe obtained from the
structural and retrostructural analysis of their supramolecular porous
columns. For clarity and simplicity, their ꢀC12H25 alkyl tails are
represented by ꢀCH3.
Figure 4. Self-assembly of homochiral (top) and heterochiral (bottom) dendritic dipeptides in porous supramolecular columns via a helical cooperative
growth. Schematic and analysis of self-assembly via supramolecular polymerization in solution and the corresponding side-view and cross-section of the
porous supramolecular columns determined from XRD analysis in solid state. The color code of the dipeptides used in the cross-section of the
supramolecular porous column is explained in Figure 1a.
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Figure 5. CD (blue) and UVꢀvis (red) of homochiral (a,b) and heterochiral (c,d) dendritic dipeptides (1.6 ꢁ 10ꢀ4 M in cyclohexane). Degree of
aggregation as a function of temperature for homochiral (e) and heterochiral (f) dendritic dipeptides calculated from UVꢀvis spectra.
dominance of the Tyr stereochemistry is attributed to its direct
connection to the dendritic periphery, through the phenolic
residue. The self-assembled columnar structures found in the
solid state have been demonstrated to be largely analogous to
those in solution because the structures of homochiral and
heterochiral dendritic dipeptides were found to be persistent in
both states according to solution and thin film CD/UVꢀvis
spectroscopy.33a
The self-assembly of dendritic dipeptides in solution is a form
of supramolecular polymerization assisted by cooperative helical
growth.4 Like the Tobacco Mosaic Virus (TMV)24 capsid
proteins that served as a biological inspiration for self-assembling
supramolecular dendrimers,2f,44 the dendritic dipeptides are
expected to nucleate into short single turns of the helix (e.g., lock-
washer) followed by elongation or growth by addition of further
dendritic dipeptides and/or by the stacking of already nucleated
lock-washer.24,25,45 The thermodynamics of this supramolecular
polymerization can be extracted and modeled by the methods
described by Meijer46ꢀ49 and van der Schoot.23,50ꢀ52 In this
approach, peak intensity maxima were selected from UVꢀvis
spectra. Typically, peaks in the UVꢀvis spectra at about 230 nm
were chosen for these experiments, and both heating and cooling
cycles were investigated. At equivalent temperature and concen-
tration, the ellipticities of the CD spectra of enantiomeric
dendritic dipeptides do not always exhibit the same magnitude
for identical enantiomeric purity. This is because the CD signal
measured from self-assembled dendritic dipeptides is sensitive
not only to the degree of aggregation but also to the kinetics of
formation of helical order in the column. For this reason, the
thermodynamics of supramolecular polymerization was deter-
mined from the UVꢀvis absorbance intensity profile, which is
less sensitive to the perfection of the helical structure. The UV
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Figure 6. DSC traces upon heating of homochiral (LꢀL) (a) and heterochiral (LꢀD) (b) (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-Ala-OMe with various
annealing times prior to isotropization. The associated enthalpy changes are indicated in parentheses (kcal/mol).
Table 1. Thermal Transitions and Enthalpy Changes of Supramolecular Structures Assembled from Dendritic Dipeptides
dipeptide
tannealing
thermal transitions (°C) and corresponding enthalpy changes (kcal/mol)
for the 10 °C/min heating DSC experiments without and with annealing
dendron
stereochemistry XꢀY =
(min)
(4-3,4-3,5)12G2-
LꢀL, DꢀD
0
180
0
Φh,g 59 Φh 96 (5.9) i
Φh,g 59 ꢀannealing at 95 °Cꢀ Φhk 105 (13.3) i
Φh,g 56 Φh 94 (5.5) i
(4-3,4-3,5)12G2-
LꢀD, DꢀL
180
900
0
Φh,g 56 ꢀannealing at 85 °Cꢀ Φhio 100 (5.4) i
Φh,g 56 ꢀannealing at 85 °Cꢀ Φhio 100 (7.6) i
Φh,g 55 Φh 94 (5.3) i
(4-3,4-3,5)12G2-
(4-3,4-3,5)12G2-
(4-3,4-3,5)12G2-
LꢀDL, DꢀDL
DLꢀL, DLꢀD
DLꢀDL
180
0
Φh,g 55 ꢀannealing at 80 °Cꢀ Φh 94 (5.6) i
Φh,g 55 Φh 94 (5.9) i
180
0
Φh,g 55 ꢀannealing at 80 °Cꢀ Φh 94 (6.1) i
Φh,g 55 Φh 93 (5.4) i
180
0
Φh,g 55 ꢀannealing at 80 °Cꢀ Φh 93 (5.9) i
Φh,g 45 Φh 62 (3.5) i
(4-3,4-3,5)dm8*G2-
DLꢀDL
DLꢀL
(6 Np-3,4ꢀ3,5)dm8*G2-
(6 Np-3,4-3,5)dm8*G2-
0
Φh,g 60 Φh 116 (4.8) i
DLꢀDL
0
Φh,g 60 Φh 116 (4.8) i
180
Φh,g 61 ꢀannealing at 100 °Cꢀ Φh 116 (4.8) i
absorbances for these peaks were rescaled such that 1.0
corresponds to the low temperature maximum or minimum
intensity (i.e., maximum aggregation in the temperature range
explored) and 0 corresponds to the high temperature maximum
or minimum peak intensity (i.e., the molecularly dissolved
species). For non-nucleated, isodesmic models of supramole-
cular polymerization, a sigmoidal relationship between the
degree of aggregation and the temperature would have to be
observed, whereas in a nucleated or cooperative helical growth
model, a nonsigmoidal relationship between the degree of
aggregation and temperature is expected.51,52 Thermodynamic
data can be obtained by fitting with the equation for the
elongation domain according to Meijer (eq 1),51b where he is
the molar enthalpy for polymerization, and Te is the elongation
temperature, or the point at which nucleation changes into
elongation. For the cooperative helical growth model, Te can be
viewed as the temperature at which a complete turn of the helix
is formed allowing for enhanced he through structural reinfor-
cement from the chiral nucleus.
2
½ð ꢀ he=RTe
ÞðT ꢀ T ÞꢂÞ
ð1Þ
e
Φ ¼ ΦSATð1 ꢀ e
This thermodynamic analysis was applied to the supramole-
cular polymerization of homochiral and heterochiral dendritic
dipeptides (4-3,4-3,5)12G2-CH2-Boc-D-Tyr-D-Ala-OMe, (4-
3,4-3,5)12G2-CH2-Boc-L-Tyr-L-Ala-OMe,
(4-3,4-3,5)12G2-
CH2-Boc-D-Tyr-L-Ala-OMe, and (4-3,4-3,5)12G2-Boc-L-Tyr-D-
Ala-OMe (Figure 5e,f).
As expected, enatiomeric pairs (4-3,4-3,5)12G2-CH2-Boc-D-Tyr-
D-Ala-OMe/(4-3,4-3,5)12G2-CH2-Boc-L-Tyr-L-Ala-OMe and (4-3,
4-3,5)12G2-CH2-Boc-D-Tyr-L-Ala-OMe/(4-3,4-3,5)12G2-CH2-Boc-
L-Tyr-D-Ala-OMe exhibit nearly identical self-assembly profiles. By
fitting these profiles with the model for helical cooperative growth, it
was found that the homochiral dendritic dipeptides transition from
nucleation to elongation at 24 °C and exhibit a molar enthalpy of
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at lower temperature. To simulate the self-assembly process in
the bulk state, the homochiral and heterochiral dendritic dipep-
tides were annealed just below TΦꢀI for 60, 120, 180, and 900
min (Figure 6). For both homochiral and heterochiral dendritic
dipeptides, annealing resulted in the appearance of a second
endothermic peak at higher temperature, which becomes more
pronounced with increased annealing time. For the homochiral
dendritic dipeptide, annealing for 120 or 180 min provided a
complete shift in the isotropization by þ9 °C and an increase in
the enthalpy change associated with the first-order transition
from ordered state to isotropic melt of 125%. These increases
correspond to an intra- and intercolumnar crystallization process.
However, for the heterochiral dendritic dipeptide, both transi-
tions were still evident, even after 900 min of annealing. In this
case, the new isotropization temperature is shifted by þ6 °C and
is accompanied by only a 38% increase in the enthalpy change
associated with the first-order transition from the ordered to
melt state.
The increased isotropization temperature and enthalpy
change following the annealing of homochiral and heterochiral
dendritic dipeptides is associated with changes to the order of the
self-organized structures. WAXS performed on the oriented
fibers indicate a slow transformation from a Φh phase to an
k
ordered Φh phase following annealing of the homochiral
dendritic dipeptide, as evidenced by significant amplification of
5.0 Å registry features33b relative to the short-range order diffuse
broad peak at 4.5 Å (Figure 7a,c). In contrast, the WAXS fiber
pattern collected after annealing from the heterochiral dendritic
dipeptide exhibits the 5.0 Å registry features,33b but lacks the
additional wide angle features of the Φhk phase corresponding to
intra- and intercolumnar long-range order, as indicated by the
blue arrows in Figure 7c. In excellent agreement with the
enthalphy changes calculated in Table 1, the XRD experiments
revealed that the chirality of the second R-amino acid plays an
important role in the formation of an ordered columnar phase or
an intracolumnar ordered phase for the homochiral and hetero-
chiral dendritic dipeptides, respectively. Furthermore, the com-
bined XRD and DSC annealing experiments revealed that the
intracolumnar crystallization, observed in both structures, is
significantly faster in the case of homochiral structures.
Dendritic Dipeptides with One Racemized r-Amino Acid.
Four dendritic dipeptides were prepared wherein one of their R-
amino acids, Tyr or Ala, was racemic: (4-3,4-3,5)12G2-CH2-
Boc-DL-Tyr-D-Ala-OMe, (4-3,4-3,5)12G2-CH2-Boc-DL-Tyr-L-
Ala-OMe, (4-3,4-3,5)12G2-CH2-Boc-D-Tyr-DL-Ala-OMe, and
(4-3,4-3,5)12G2-CH2-Boc-L-Tyr-DL-Ala-OMe. As described in
Figure 2, each of these racemized structures represents a 50:50
mixture of diastereomeric homochiral and heterochiral dendritic
dipeptides. The racemization of a single stereocenter of the
dendritic dipeptide can affect the supramolecular expression of
chirality, but could also significantly impact the mechanism of
self-assembly. As a dendritic dipeptide racemized at one amino
acid is comprised of a 50:50 mixture of diastereomeric dendritic
dipeptides, the supramolecular polymerization can proceed
through the incorporation of both dendrons into a single column
or into two distinct columns, one corresponding to the homochiral
dipeptide and the other corresponding to the heterochiral
dipeptide (Figure 8).
Figure 7. Wide-angle XRD patterns collected from the oriented fibers
of the dendritic dipeptide (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-AlaOMe,
where X and Y are indicated (a). Meridional plots of the corresponding
XRD patterns from (a) and (b) indicating that after annealing the
k
homochiral dendritic dipeptide (LꢀL) changes from Φh,g into a Φh
phase, and the heterochiral dendritic dipeptide (LꢀD) changes from Φh,g
into a Φhio phase (c).
monomer addition of ꢀ35 kcal/mol. On the other hand, heterochiral
dendritic dipeptides are found to transition from nucleation to
elongation at higher temperature 28 °C, but exhibit a lower molar
enthalpy of monomer addition, ꢀ30 kcal/mol. While both homochiral
and heterochiral dendritic dipeptides clearly exhibit helical cooperative
growth during solution-phase supramolecular polymerization, these
results indicate a more pronounced nucleation step for the homochiral
dendritic dipeptides, which provides a more enthalpically favorable
elongation process.
Self-assembly and self-organization of the dendritic dipeptides
in the solid state can be viewed as a process analogous to their
solution-phase supramolecular polymerization. However, higher
effective monomer concentration and the effect of neighbor-to-
neighbor column interactions result in a rapid nucleation and
polymerization process at significantly elevated temperature
(94ꢀ96 °C), taking the form of a first-order phase transition
from the isotropic state (Figure 6). For the homochiral dendritic
dipeptides, the transition (TΦꢀI) from the hexagonal columnar
phase (Φh) to the isotropic phase (I) occurs at 96 °C with a
corresponding enthalpy of 5.9 kcal/mol (Figure 6a and Table 1).
For the heterochiral dendritic dipeptide, TΦꢀI occurs at 94 °C
with a lower corresponding enthalpy of 5.5 kcal/mol (Figure 6b
and Table 1). Both homochiral and heterochiral dendritic
dipeptides undergo a glass transition followed by the Φh,g phase
CDꢀUVꢀvis spectroscopy analysis of dendritic dipeptides
comprised of one racemic amino acid (Figure 9aꢀd) reveals that
a single enantiopure Tyr residue maintains an overall net
ellipiticity with a sign determined by the handedness of the
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Figure 8. Self-assembly of dendritic dipeptides where Ala (top) or Tyr (bottom) has been racemized into porous supramolecular columns via a helical
cooperative growth. Schematic and analysis of self-assembly via supramolecular polymerization in solution and the corresponding side-view and cross-
section of the porous columns determined from XRD analysis in solid state. The color code of the dipeptides used in the cross-section of the porous
supramolecular columns is explained in Figure 1b.
Tyr. On the other hand, a single enantiopure Ala residue in the
conjunction with racemized Tyr provides no net ellipticity. If self-
assembly of these singly racemized dendritic dipeptides occurs
through two distinct columns composed of either homochiral or
heterochiral dendritic dipeptides, we would expect both the
temperature of the transition from nucleation to elongation
and the molar enthalpy of monomer addition to be an average
of what was observed for the homochiral and heteorchiral
columns, or Te = 26 °C and he = ꢀ32.5 kcal/mol (Figure 8).
Contrary to this expectation, for dendritic dipeptides composed
of enantiopure Ala and racemized Tyr, (4-3,4-3,5)12G2-CH2-
Boc-D-Tyr-DL-Ala-OMe and (4-3,4-3,5)12G2-CH2-Boc-L-Tyr-
DL-Ala-OMe, a Te of 21 °C and an he of 25 kcal/mol were
observed (Figure 9e). Likewise, for dendritic dipeptides com-
posed of enantiopure Tyr and racemized Ala, (4-3,4-3,5)12G2-
CH2-Boc-DL-Tyr-D-Ala-OMe and (4-3,4-3,5)12G2-CH2-Boc-
DL-Tyr-L-Ala-OMe, a Te of 19 °C and an he of ꢀ26 kcal/mol
were observed (Figure 9f). In both cases, the temperature of the
transition from nucleation to elongation and the molar enthalpy
of monomer addition were lower than expected for a 50/50
blend of homochiral and heterochiral dendritic dipeptides,
suggesting that both homochiral and heterochiral dendritic
dipeptides will coassemble into single columns during the
solution-phase supramolecular polymerization.
Further evidence for the coassembly of all stereoisomeric
dendritic dipeptites into a single-column is provided by the
self-assembly and self-organization of singly racemized dendritic
dipeptides in the solid state. XRD analysis provides no indication
of dissimilar supramolecular objects co-organized to form a
superlattice. All of the partially racemized dendritic dipeptides
self-organize into Φh lattices composed of columns with similar
pore sizes (13.4ꢀ13.8 Å), but differing configurations of the
dendritic dipeptides (Figure 8). Dendritic dipeptides with en-
antiopure Tyr but racemic Ala arrange into helical columns
(Figure 8, top), whereas dendritic dipeptides with racemic Tyr
but enantiopure Ala arrange into less ordered columns without
demonstrable helicity over extended length scale (Figure 8,
bottom). Interestingly, the racemization of either the Tyr or
the Ala residue eliminates the effect of annealing on dendritic
dipeptides in the bulk state (Figure 10 and Table 1). Both
dendritic dipeptides racemized at Tyr or Ala exhibit TΦꢀI at
94 °C with associated transition enthalpy changes of 5.3 and 5.9
kcal/mol, respectively. Annealing at 80 °C for 60ꢀ180 min did
not result in the emergence of a higher temperature phase or a
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Figure 9. CD (blue) and UVꢀvis (red) of dendritic dipeptides with racemized Ala (a,b) or racemized Tyr (c,d) (1.6 ꢁ 10ꢀ4 M in cyclohexane). Degree
of aggregation as a function of temperature for dendritic dipeptides containing racemic Ala (e) or racemic Tyr (f) calculated from UVꢀvis spectra.
significant increase in the enthalpy change of isotropization
corresponding to an intracolumnar crystallization. Likewise,
WAXS of the oriented fibers of the singly racemized dendritic
dipeptides showed little change following the annealing process,
indicating no major amplification of intracolumnar order
(Figure 11).
Dendritic Dipeptides Composed of Racemized Tyr and
Ala. The dendritic dipeptide (4-3,4-3,5)12G2-CH2-Boc-DL-Tyr-
DL-Ala-OMe containing racemic Tyr and racemic Ala was
prepared. As described in Figure 2, this dendritic dipeptide is
in fact a 25:25:25:25 mixture of enantiomeric and diastereomeric
pairs of all of the stereochemical permutations of the dendritic
dipeptides:
(4-3,4-3,5)12G2-CH2-Boc-D-Tyr-D-Ala-OMe, (4-3,4-3,5)12G2-
CH2-Boc-D-Tyr-L-Ala-OMe, (4-3,4-3,5)12G2-CH2-Boc-L-Tyr-
D-Ala-OMe, and (4-3,4-3,5)12G2-CH2-Boc-L-Tyr-L-Ala-OMe.
Consequently, the solution -phase supramolecular polymeriza-
tion of the dendritic dipeptides could proceed in one of three
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Figure 10. DSC traces upon heating of (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-AlaOMe containing racemized Ala (DꢀDL) (a) or racemized Tyr (DLꢀD) (b)
with various annealing times prior to isotropization. The associated enthalpy changes are indicated in parentheses (kcal/mol).
possible fashions: (a) into four enantiomerically and diastereo-
merically pure columns, (b) into 2ꢀ4 distinct columns com-
posed of mixed diastereomers, or (c) coassembly of all four
dendritic dipeptides into a single column (Figure 12).
For the dendritic dipeptides composed of a single racemic
amino acid, the discrimination between the various modes of self-
assembly can be made through the analysis of the temperature
dependence on the degree of supramolecular polymerization.
CDꢀUV/vis spectroscopy reveals that, as expected, the com-
pletely racemized dendritic dipeptide shows no net ellipticity
(Figure 13a). For a mixture of all four enantiomerically and
diastereomerically pure columns, a molar enthalpy of monomer
addition of ꢀ30 to 35 kcal/mol is expected, while a mixture of
2ꢀ4 distinct columns composed of diastereomeric pairs is
expected to result in a molar enthalpy of monomer addition of
approximately ꢀ25 kcal/mol. Application of the model for
helical cooperative self-assembly to the UV/vis spectra of the
temperature-dependent solution-phase supramolecular polym-
erization of the completely racemized dendritic dipeptide pro-
vided a molar enthalpy of monomer addition of ꢀ19 kcal/mol
(Figure 13b). This low molar enthalpy of monomer addition
suggests the exclusion of all models of self-assembly except for
self-assembly into a single mixed column. The mixed column
forms because the self-assembly process is mediated by the
dendritic part of the dendritic dipeptide. Once the column is
generated, its intracolumnar order starts to form and is stabilized
by H-bonding that is determined by the stereochemistry of the
dipeptide. This mechanism is similar to the hydrophobic effect
that mediates the folding of proteins. Once the folding occurs, its
Figure 11. WAXS patterns collected from the oriented fibers of the
dendritic dipeptide (4-3,4-3,5)12G2-CH2-Boc-X-Tyr-Y-Ala-OMe,
where X and Y are indicated (a,b). Meridional plots of the corresponding
XRD patterns from (a) and (b) indicating that after annealing the
structure is stabilized via H-bonding.
The assertion of a single mixed column is supported in the
solid state by XRD analysis suggesting a Φh lattice self-
organized from a single supramolecular object, exhibiting a
dendritic dipeptides with either Tyr or Ala peptide racemized did not
somewhat smaller pore diameter of 12.8 Å (Figure 12). As with
the partially racemized dendritic dipeptides, the doubly race-
mized dendritic dipeptide does not exhibit significant enhance-
ment of the isotropization enthalpy upon annealing (Figure 14
and Table 1). Likewise, no evidence of increased intracolumnar
order was observed via XRD analysis after the annealing
period.
change their Φh,g phases (c).
Dendritic Dipeptides with Racemized Tyrosine and Chiral
Alkyl Groups on the Periphery. It was shown in the previous
sections that the fully racemized dendritic dipeptides self-as-
sembled with lower enthalpy of monomer addition in the
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Figure 12. Self-assembly of racemic dendritic dipeptides into porous supramolecular columns via a helical cooperative growth. Schematic and analysis
of self-assembly via supramolecular polymerization in solution and the corresponding side-view and cross-section of the supramolecular porous columns
determined from XRD analysis in solid state. The color code of the dipeptides used in the cross-section of the porous supramolecular columns is
explained in Figure 1b.
Figure 13. CD (blue) and UVꢀvis (red) of racemic dendritic dipeptides (a) (1.6 ꢁ 10ꢀ4 M in cyclohexane). Degree of aggregation as a function of
temperature for racemic dendritic dipeptides (b).
supramolecular polymerization process and did not exhibit
intracolumnar order in the solid state. This was the result of
coassembly of all stereoisomers into mixed columns that did not
express any helicity. The higher enthalpies and greater degree-of-
order associated with the supramolecular polymerization of
homochiral and to a lesser extent heterochiral and partially
racemized dendritic dipeptides hint at a mechanism of amplifica-
tion and selection of enantiomerically and diasteriomerically
enriched oligopeptide-containing systems. However, aside from
statistical spontaneous deracemization,53,54 these results do not
offer a pathway by which the helical handedness of an otherwise
racemic system could be selected.
One strategy to achieve the selection of the helix-sense would
be to place a chiral unit at the periphery of dendritic dipeptide in
the form of a chiral alkyl tail. As a first test of this approach, a
chiral-tailed analogue of the fully racemized dendritic dipeptide
was prepared using (S)-3,7-dimethyloctyl (dm8*) periphery
units. This dendritic dipeptide (4-3,4-3,5)dm8*G2-CH2-Boc-
DL-Tyr-DL-Ala-OMe was prepared but did not exhibit helical
cooperative self-assembly. The presence of the branched tail
likely reduced the temperature of nucleation below what could be
observed in cyclohexane solution experiments. Two analogous
dendritic dipetides with stereocenters in their alkyl periphery
groups were prepared, (6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-
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Tyr-DL-Ala-OMe and (6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-
L-Ala-OMe (Scheme 2), where the 4-substituted benzyl periph-
ery unit was replaced with a 6-naphthyl periphery. The presence
of the naphthyl groups2f,33g,33h was expected to increase the
temperature of the nucleation to elongation transition in solution.
Rewardingly, both the naphthyl-containing dendritic dipeptide
with racemized tyrosine and enantipure alanine, (6 Np-3,4-
3,5)dm8*G2-CH2-Boc-DL-Tyr-L-Ala-OMe, and the naphthyl-
containing dendritic dipeptide with fully racemized dendritic
dipeptides exhibited a selection of helical handeness (Figure 15a,
b) and helical cooperative self-assembly (Figure 15c,d). Further-
more, the temperature at which nucleation transitions into
elongation and the enthalpy of supramolecular polymerization
process are similar but slightly higher for the dendritic dipeptide
containing racemized tyrosine but enantiopure alanine than for
the dendron with a fully racemic dipeptide. These results indicate
that the selection of helical handedness can occurs from either
the periphery of the alkyl groups or the apex-dipeptide and that
all stereoisomers of the dipeptide can be accommodated in the
same helical column. Furthermore, it appears that the presence of
a single enantiopure stereocenter in the dipeptide can be
reinforced by the external chiral selection resulting in modest
increase in the elongation transition temperature and enthalpy of
monomer addition.
Perspectives on the Self-Assembly Mechanism. Applica-
tion of temperature-dependent CD/UVꢀvis spectroscopy, mod-
eling of the supramolecular structures resulting from the
supramolecular polymerization in solution, and the examination
of the self-organization and enhancement of intracolumnar order
through annealing in solid state through DSC and XRD analysis
to all stereochemical permutations of the dendritic dipeptide
(4-3,4-3,5)12G2-Boc-X-Tyr-Y-Ala-OMe suggested a mechanism
for the self-assembly of dendritic dipeptides. It is evident that
these dendritic dipeptides self-assemble in solution through a
process of helical cooperative supramolecular polymerization.
Figure 14. DSC traces upon heating of (4-3,4-3,5)12G2-CH2-Boc-DL-
Tyr-DL-Ala-OMe with various annealing times prior to isotropization. The
assosciated enthalpy changes are indicated in parentheses (kcal/mol).
Figure 15. CD (blue) and UVꢀvis (red) of napthyl-based dendritic dipeptides with chiral alkyl periphery groups, and a dipeptide containing racemic
Tyr, (6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-L-Ala-OMe, (a) or a fully racemic dipeptide, (6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-DL-Ala-OMe, (b)
(1.6 ꢁ 10ꢀ4 M in cyclohexanes). Degree of aggregation as a function of temperature for (6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-L-Ala-OMe (c) and
(6 Np-3,4-3,5)dm8*G2-CH2-Boc-DL-Tyr-DL-Ala-OMe (d).
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Table 2. Thermodynamic Data Calculated from the Fits of the UV Data Collected in Cyclohexane for (4-3,4-3,5)12G2-CH2-Boc-
X-Tyr-Y-Ala-OMe and from the DSC Data Collected with 10 °C/min after Annealing
dipeptide stereochemistry XꢀY =
Te (°C) a,b,c
Tm (°C) a,b,c
he (kcal/mol) a,b,c
Tiso (°C) d
ΔH (kcal/mol) d
LꢀL, DꢀD
LꢀD, DꢀL
LꢀDL, DꢀDL
DLꢀL, DLꢀD
DLꢀDL
24 ( 1 [28 ( 1]e
25 ( 1 [28 ( 1]e
21 ( 1
21 ( 1 [24 ( 1]e
21 ( 1 [24 ( 1]e
18 ( 1
ꢀ35 ( 3
ꢀ30 ( 3
ꢀ25 ( 3
ꢀ26 ( 3
ꢀ19 ( 3
105
100
94
13.3 ( 0.4
10.2 ( 0.4
5.6 ( 0.3
6.1 ( 0.3
5.9 ( 0.3
19 ( 1
16 ( 1
94
20 ( 1
16 ( 1
93
a,b,c Te, Tm, and he calculated from the fit of the temperature dependence of the UV maxima from 226 nm using eq 1. d Isotropization transition
temperature Tiso and associated enthalpy change ΔH measured by DSC after annealing in the Φh phase (Table 2). e For the homochiral and heterochiral
dendritic dipeptides, a small hysteresis of ∼4 °C was observed between heating and cooling data; the values in the square brackets were calculated from
the fits of the UV data collected upon heating. Note: A possible hysteresis of ∼1 °C was observed for all the racemized dendritic dipeptides, but the
difference between heating and cooling cycles was comparable with the experimental error.
For enantio- and diasteriomerically pure dendritic dipeptides, the
stereochemistry of the Tyr residue dictates the handedness of the
supramolecular helical column, while the Ala residue allosteri-
cally regulates the structure of the column and the thermody-
namics of the self-assembly process (Table 2). Homochiral
dendritic dipeptides self-assemble with a higher molar enthalpy
of monomer addition than heterochiral dendritic dipeptides.
Therefore, it seems that the process of elongation/polymeriza-
tion is more favorable for the homochiral stereoisomer. DSC and
XRD analysis suggests that this process may be similar to the self-
assembly and self-organization processs in the solid state. DSC
and XRD analysis show enhanced intracolumnar ordering and an
increase in isotropization enthalpy change after annealing prior
to TΦꢀI. Because the supramolecular polymerization of homo-
chiral dendritic dipeptides was enthalpically more favorable than
that of heterochiral dendritic dipeptides, it is expected that
homochiral dendritic dipeptides will form aggregates with higher
degree of polymerization. Not only do we expect longer aggre-
gates for the homochiral dendritic dipeptides, but it was also
observed that there was more significant intracolumnar ordering
following annealing to form a Φhk phase (Figures 6a and 7a,c).
This effect upon annealing was less dramatic for the heterochiral
dendritic dipeptide, indicating a less pronounced intracolumnar
order or crystallization (Figures 6b and 7b,c).
Helical selection was still possible when the Ala residue was
racemized, but not if the Tyr residue or both residues were
racemized. Whenever one or more of the residues was racemized,
a continual decrease in the enthalpy of monomer addition was
observed (Figure 16a), indicating that the different stereoisomers
in the racemized mixture coassemble into a single column,
diminishing the cooperativity and the degree of order within
the columns. The mixing of stereoisomers into a single column
Figure 16. Degree of aggregation as a function of temperature calculated
and the resulting decrease in order was evidenced in XRD
from the UVꢀvis: comparison between homochiral ((4-3,4-3,5)12G2-
analysis. The increase in intracolumnar order upon annealing
CH2-Boc-L-Tyr-L-Ala-OMe) and partially ((4-3,4-3,5)12G2-CH2-Boc-L-
for homochiral and heterochiral dendritic dipeptides was absent
in the case of partially and completely racemized dendritic
dipeptides. Interestingly, hysteresis in the CDꢀUV/vis spectra
between heating and cooling cycles was observed (Figure 16b,
Supporting Information Figures SF2ꢀ5) for enantiopure den-
dritic dipeptides. However, this hysteresis was absent when one
or both of the amino acids were racemized (Figure 16c).
Hysteresis in cooperative supramolecular polymerization has
been attributed to a kinetic barrier toward nucleation.55 In some
cases, such hysteresis can distinguish between homogoenous
nucleation and heterogeneous nucleations, wherein nucleation is
triggered by a seed particle, defect, or impurity.55 It is possible
Tyr-DL-Ala-OMe) and fully ((4-3,4-3,5)12G2-CH2-Boc-DL-Tyr-DL-Ala-
OMe) racemized dendritic dipeptides (a), hysteresis between assembly
and disassembly present in chiral dipeptides (b), and absent in the racemic
Tyr or Ala (c).
that in the case of dendritic dipeptides containing one or more
racemized amino acids, the dendritic dipeptide with mismatched
stereochemistry can serve as a defect or “as impurity” in the presence
of the other dendritic dipeptide and acts as a seed to initiate the
heterogeneous nucleation.
To further elucidate the effect of incorporating dendritic
dipeptides of mismatched chirality into a single column, a
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Figure 17. CD spectra collected from mixtures of LꢀL and DꢀD at 10 °C in cyclohexane (1.6 ꢁ 10ꢀ4 M) (a) and net helicity dependence (majority rule)
of the enantiomeric excess (b).
majority-rules56 experiment was performed (Figure 17). In the
absence of majority-rules behavior, net helicity will increase
linearly with enantiomeric excess. In typical majority-rules phe-
nomena, net helicity will increase nonlinearly, outpacing the
enantiomeric excess. The extent of majority rules is generally
governed by the balance between monomer mismatch penalty
(MMP), the cost of placing the incorrect stereoisomer in a
suprastructure of the opposite handedness, and the helix reversal
penalty (HRP), the energetic cost of inverting the helicity of a
column. Mixtures of LL and DD dendritic dipeptides were
prepared, and their CD spectra were measured as a function of
composition (Figure 17). Here, the relationship between en-
antiomeric excess and net helicity is complex: 100% net helicity is
only observed for 100% ee and falls off rapidly until 50% ee,
where the net helicity decreases more slowly.
deracemization53,54 for dendrons built from dipeptides contain-
ing one or more racemic R-amino acids. Analysis in the solid state
demonstrated that the kinetics of intracolumnar crystallization
was slow and decreased with diminished stereochemical purity.
Therefore, it is evident that the dendritic part of the supramo-
lecular column dominates the self-organization process, while the
transfer of chirality from the dipeptidic apexes was slow, being
observed only after annealing. Therefore, these results provide a
possible explanation for the absence of spontaneous deracemiza-
tion demonstrated by the CD/UVꢀvis experiments, which can
only occur if the self-assembly is driven by the dipeptide. It is
most probable that in solution, as suggested by the majority rules
experiments, once the supramolecular assemblies are formed, the
rate of exchange is very slow, due to the dominant role of the
dendritic part.
Although first observed in poly(isocyanates),56 the theory
developed for the analysis of majority-rules phenomena in
supramolecular systems is based on discotic molecules, where a
single molecule forms a stratum of the column.51 The supramo-
lecular polymerization of dendritic dipeptides represents an
entirely different class of supramolecular polymer that more
closely resembles the capsid suprastructure of TMV,24,25 wherein
each molecular monomer must contort its own preferred con-
formation to form a fraction of the stratum, than the columnar
assemblies generated from discotic molecules. Here, not only can
the dendritic monomer adapt its conformation to facilitate
incorporation into a mismatched column, but as the concentra-
tion of minority monomer changes the entire structure of the
columnar stratum can change producing an entirely different
structure. The complex behavior found in the majority-rules
experiment highlights the two distinct modes of self-assembly.
For the enantiopure homochiral dendritic dipeptides LL and DD,
highly enthalpically favorable helical cooperative self-assembly is
observed. In this domain, the minority dendritic dipeptides with
mismatched handedness begin to disrupt the long-range helical
order (Supporting Information Figures SF1 and SF6). As the
enantiomeric excess decreases, the columnar stratum begins to
lose its helicity and the mechanism for the amplification and
expression of chirality of majority dendritic dipeptides.
’ CONCLUSIONS
In nature, homochirality and heterochirality is evident in a
more grandious scale. Biological systems have evolved to pro-
duce single enantiomers of most classes of building blocks (e.g.,
amino acids, carbohydrates, nucleotides). Biological macromo-
lecules prepared from these enantiopure building blocks are,
therefore, typically entirely homochiral, composed of lengthy
sequences of perfectly repeated stereochemistry. The conse-
quences of stereopurity in the natural world are both marvelous
and easily understood. Life could have also evolved as the mirror
image of its contemporary form, but this Article demonstrates
that a racemic or heterochiral world would bear no resemblence
to the one in which we inhabit (e.g., the structural motifs of
proteins are not stable for heterochiral arrangements of amino-
acids). However, the origin of that chirality from the prebiotic
mileu is more elusive and ultimately very challenging to prove.
Nevertheless, few would disagree that the path toward biological
homochirality must have involved the processes of both sponta-
neous deracemization and chiral amplification.57
It is now apparent that in the supramolecular polymerization
of dendritic dipeptides, there is a thermodynamic preference for
homochiral dipeptides over heterochiral or racemized dipep-
tides. The thermodynamic favorability of supramolecular polym-
erization and the long-range helical order that provides the
Surprisingly, CD/UV analysis in solution and XRD and DSC
analysis in the solid state revealed no spontaneous
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Journal of the American Chemical Society
ARTICLE
emergent function of the supramolecular porous columns is
diminished by heterochirality and destroyed by racemization.
Therefore, these dendritic dipeptides serve as a primitive model
for the amplification of homochirality and its role to the origins of
structure and function in nature, but also can elucidate the role of
chirality on the function in biomolecular materials. Future work will
explore the longer-range amplification of homochirality beyond
dipeptides and the effect of external chiral influence on the
spontaneous desymmetrization of racemic dendritic dipeptides.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures with
b
complete spectral analysis and complete refs 34b and 54e. This
material is available free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Corresponding Author
percec@sas.upenn.edu
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’ ACKNOWLEDGMENT
Financial support by the National Science Foundation
(Grants DMR-0548559, DMR-0520020, and DMR-1066116)
and the P. Roy Vagelos Chair at the University of Pennsylvania is
gratefully acknowledged. B.M.R. gratefully acknowledges fund-
ing from an NSF Graduate Research Fellowship and an ACS
Division of Organic Chemistry Graduate Fellowship (Roche).
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