Self-Assembly of C3 Symmetric Rigid Macrolactams into Very Polar and Porous Trigonal Crystals

Article abstract of DOI:10.1002/chem.201900802

Cyclohexane and cyclotri-β-alanyl have been used as scaffolds for the design of new C₃-symmetric rings incorporating conjugated alkenes and dienes. All three C₃-symmetric lactams share the same triangular shape and their crystal system is trigonal. They all belong to the R3 space group, R3m, R3 and R3c, for the increasingly large 12-, 18- and 24-membered rigid rings, respectively. All lactams stack on top of each other, through H-bonds and van der Waals noncovalent interactions, leading to endless supramolecular cylinders and tubes. The largest member of the family leads to tubes, the central pores of which is wide enough to let water in. A common feature of all the lactams is their very large dipole, of around 9 D, according to DFT calculations. Surprisingly, all the resulting cylinders and tubes pack side by side in the crystals, with all the dipoles pointing to the same direction. As a result, all three crystals are anisotropic and appear to be the first members of a new kind of highly polar crystals.

Full text of DOI:10.1002/chem.201900802

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Accepted Article
Title: Self-Assembly of C3 Symmetric Rigid Macrolactams into Very
Polar and Porous Trigonal Crystals
Authors: Yves Luc Dory and Thomas Marmin
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Self-Assembly of C3 Symmetric Rigid Macrolactams into Very
Polar and Porous Trigonal Crystals
Thomas Marmin,[a] and Yves L. Dory*[a]
Abstract: Cyclohexane and cyclotri-b-alanyl have been used as
scaffolds for the design of novel C3-symetric rings incorporating
conjugated alkenes and dienes. All three C3-symmetric lactams share
the same triangular shape and their crystal system is trigonal. They
all belong to the R3 space group, R3m, R3 and R3c respectively for
the increasingly large 12-, 18- and 24-membered rigid rings. All
lactams stack on top of each other, through H-bonds and van der
Waals non-covalent interactions, leading to endless supramolecular
cylinders and tubes. The largest member of the family leads to tubes,
whose central pore is wide enough to let water in. A common feature
of all the lactams is their very large dipole, of around 9 D according to
DFT calculations. Surprisingly, all the resulting cylinders and tubes
pack side by side in the crystals, with all the dipoles pointing to the
same direction. As a result, all three crystals are anisotropic and
appear to be the first members of a new kind of highly polar crystals.
dipole of the monomers to the infinite nanotubes of which they are
composed. [10,15] We have even continued this phenomenon of
amplification of the dipoles to monocrystals, in principle
ferroelectric. [16,17]
Several works have sought to clarify whether the strong electric
dipole of a-helices influences their arrangement inside the
proteins. [1,2] The question is legitimate when one observes a
ribonuclease inhibitor (Fig. 1a), whose all sixteen a-helices see
their dipoles aligned in the same direction. [3] Beside these
fundamental considerations, it would be highly desirable to pack
a-helices, or related objects, in the same way to create crystals or
materials with strong permanent dipoles. [4-7] The helical
structure is also very interesting since it can be used as a base
for the synthesis of nanotubes, while mimicking gramicidin A. [8,9]
However, this approach lacks the modular characteristic of
supramolecular chemistry. [10] Nevertheless, some chemists
took up the challenge by creating nanotubes by stacking
macrolactams (Fig. 1b). [11] This approach is truly versatile and
many cyclo-octapeptides constituted of residues of alternating
chirality have shown the ability to form trans-membrane channels.
[12,13] These cyclo-octapeptides are comparable to cyclic b-
sheets, whose amides orient their dipoles perpendicularly to the
plane of the macrocycle (Fig. 1c). [14] Of course, this geometry is
ideal to allow the formation of the hydrogen bridges responsible
for the tubular stack. It is however notable that the tubes formed
are devoid of electric dipole unlike a-helices.
Figure 1. From
a
-helices to supramolecular polar nanotubes. a. The 16
parallel a-helices of the ribonuclease inhibitor. b. A helix and an equivalent
supramolecular nanotube obtained through a modular self-assembly process.
c. Section of a non-polar supramolecular tube constituted of cyclo-octapeptides
(side chains and non-polar hydrogen removed for clarity). d. Design of a polar
C3-symmetric macrolactam destined to self-assemble as endless very polar
nanotubes, through backbone–backbone H-bond interactions and van der
Waals contacts. The sausage-like regions are meant to impart rigidity to the ring
and to hold the amides in the adequate parallel crown conformation.
We present here how we have succeeded in synthesizing cyclic
peptides of a novel genus and presenting strong dipoles (Fig. 1d).
By a hierarchical process, we have been able to transfer the
a-Helices have 3.6 residues per turn and the amides are all
oriented in the same direction. It is of course impracticable to
respect this arrangement with cyclo-peptides, since they
necessarily consist of an integer number of residues. On the other
hand, cyclotri-b-alanyl, formed of three b-amino acid residues,
[18,19,20] can mimic the 310-helix (three residues per turn). [20]
This simple molecule, 1, has already been created and it stacks
in the form of infinite nanotubes (Fig. 2a). [21-23] Its three amides
are oriented parallel to one another, so that the dipole moment (µ)
of macrocycle 1 should approach 10 D, corresponding to three
amides (Table 1). [24] Indeed, the dipole moment calculated by
DFT method is 9.3 D. [25-27] Thus, the supramolecular
[a]
T. Marmin, Prof. Y.L. Dory
Département de Biochimie, Institut de Pharmacologie de
Sherbrooke and Centre Québécois sur les Matériaux
Fonctionnels/Quebec Centre for Advanced Materials
Université de Sherbrooke, 3001, 12e avenue nord
Sherbrooke, Québec J1H 5N4 (Canada)
E-mail: Yves.Dory@USherbrooke.ca
Supporting information for this article is given via a link at the end of
the document.
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nanotubes of which they are formed also possess a permanent
macro-dipole like 310- and a-helices. [19]
Figure 2. A family of rigid triangular lactams of increasing size and crystallizing in the trigonal system as ferroelectrics. a. The medium ring lactam 1
crystallizes in the R3m space group. Its three gauche ethanes (like in chair cyclohexane) control the entire conformation of the 12-membered triangle. There is no
space for guests. b. The 18-membered lactam 2, obtained by adding three rigid conjugated E-alkenes to 1, crystallizes in the R3 space group. Although there is
now some available free space (3.7%), it is likely not sufficient to accommodate large guests. c. Addition of three conjugated E-alkenes to ring 2 leads to the 24-
membered large triangular macrolactam 3, that crystallizes in the R3c space group. The void space, as parallel channels, reaches 14.4% of the whole solid and is
large enough to incorporate water molecules (bottom right picture).
The stack is directed by three hydrogen bridges between each
pair of macrolactams and by a very favorable dipole alignment,
which optimizes the Keesom interactions. [28] It is also very
Table 1. Dipole moments of Rings 1-3 and AcNHMe.
probable that the stability of the tubular edifice is further increased
Method
Ring 1
9.31 D
9.33 D
/
Ring 2
9.03 D
8.77 D
/
Ring 3
8.81 D
8.57 D
/
AcNHMe
3.77 D
3.78 D
3.71 D
by the cooperativity which usually develops when several peptide
bonds form tapes of hydrogen bonds. [29,30] On the other hand,
what is very surprising and counterintuitive is the packing of the
nanotubes in the crystal, since all the tubes are parallel. [2,4,5] As
a result, all the dipoles are aligned and lead to a polar crystal
having an enormous macro-dipole.
DFT B3LYP
DFT M06-2X
Experimental
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The resulting crystal has all the characteristics of a ferroelectric
material. [16,17,31] It is remarkable that all the information stored
in each molecule 1 is transferred into the crystal. The crystal
system is trigonal and the space group is R3m, perfectly reflecting
the C3-symmetry of 1.
In order to achieve a sufficient cavity size, another conjugated
double bond was added. The new macrolactam 3 of C3-symmetry
now contains three flat dienamide systems which stiffen the sides
(Fig. 2c). [36] The size of the cycle has increased to 24 atoms and
its calculated dipole moment is still high with 8.8 D. Having more
or less the same characteristics as macrolactam 2, if not of the
size, one could therefore suppose that the behavior could be
similar. The synthesis, adapted from the preceding ones, [34]
confirmed how easy the macrocyclization of this kind of molecule
is (Scheme 1). It should be mentioned that macrolactams 2 and 3
are totally devoid of transannular interactions, which are often
serious impediments during ring closure reactions. [37,38] The
synthesis of the linear tripeptide 11 follows a straightforward six-
step sequence starting from the alcohol 4 (overall yield: 27%). [39]
The aldehyde 5, obtained by Swern oxidation of the alcohol 4,
was reacted with the phosphonate 6 [40] in a Wadsworth-
Emmons reaction to produce the diene 7 (56% yield from 4). [41]
Its hydrolysis gave the corresponding acid 8 (87%), that was
subsequently activated as its pentaflurophenyl (Pfp) ester 9 (97%).
[34,42] Coupling of the free amine, resulting from Boc
(butoxycarbonyl) cleavage of 8, with the Pfp ester 9 afforded the
dimer 10 (75%). In the same way, the linear trimer 11 was
obtained by coupling the dimeric amine (after Boc cleavage of 10)
to the same activated ester 9 (76%).
Properly speaking, cyclotri-b-alanyl 1 does not really form a
nanotube, because there is no space available inside to
accommodate any molecule whatsoever (Fig. 2a). [32] We have
sought to design molecules that would have all the characteristics
of 1, while offering the possibility of assembling as tubes rather
than cylinders. It was therefore necessary to increase the size of
the sides of molecule 1, while preserving its rigid triangular shape.
We have found that the addition of alkenes conjugated with the
carbonyl group can keep the linearity of the sides. The idea was
to retain three gauche ethane bridges at the corners, as in
cyclohexane and 1, to lock the desired threefold-symmetry (Fig.
3).
Figure 3. Structural relationships between cyclohexane, 1, 2 and 3. From
center to periphery, cyclohexane, 1, 2 then 3 are shown in wall-eye stereo.
Successive symmetrical insertions of three amides, three conjugated alkenes
then another three conjugated alkenes to chair cyclohexane, lead to lactams 1,
2 then 3 respectively.
All these constraints naturally led us to molecule 2, which we
synthesized efficiently (Fig. 2b). [33,34] Molecule 1 is a small 12-
membered macrocycle, while its larger counterpart 2 has 18
heavy atoms in the ring. This new macrolactam is perfectly
triangular, its three flat sides, described by the seven heavy atoms
of each CH2-CH=CH-CO-NH-CH2 region, are practically
orthogonal to the mean plane of the macrocycle, ensuring the
correct orientation of the amides for their stacking by hydrogen
bonds. Macrolactam 2 has the same characteristics as its parent
1 and it also stacks as an infinite triangular prism. The dipole of
each nanotube must also be very strong because the calculated
dipole for monomer 2 is still 9.0 D. In the crystal, all the nanotubes
are parallel, although this arrangement is theoretically
unfavorable. [2,4,5,28] A notable difference appears with respect
to chirality. Of course, neither 1 nor 2 are chiral, on the other hand
each monocrystal formed from 2 is endowed with supramolecular
chirality (Fig. 3b). [35] All macrolactams have exactly the same
shape and orientation in the crystal. This is not the case for 1;
each triangular prism is homochiral as expected, but their packing
is then random, leading to a globally racemic crystal. The crystal
system for 2 is still trigonal and with the space group R3. As
regards the space available inside the nanotubes, it is still very
small, being only 3.7% (solvent accessible volume calculated with
a spherical probe, 1.4 Å in radius), [32] which is not sufficient to
incorporate guest molecules.
Scheme 1. Synthesis of the macrolactam 3.
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Activation of the acid of 11 (Pfp ester), then cleavage of the Boc
protecting group yielded the corresponding TFA (trifluoroacetate)
salt, which cyclized readily (78%) upon addition of DIPEA
(diisopropylethylamine). [34]
pores, occupying as much as 14.4% of the total volume (Fig. 3c).
[32] The nanotubes are therefore truly hollow and, like Gramicidin
A, [9] they can accommodate molecules such as water, of which
a certain quantity is found in the crystal. Each channel passes
through the crystal from edge to edge, along the polar axis c. [6]
In an attempt to explain the reason why all the nanotubes formed
from compounds 1-3 naturally aligned, we paid particular
attention to the geometric characteristics of the three crystals. The
resemblances are really striking (Figs. 2-4). For example, the
crystals are all trigonal (R3m, R3 and R3c respectively for 1, 2
and 3), with increasing lengths for the side a of the unit cell (13.74
Å, 17.30 Å, and 20.33 Å). With respect to the polar axis, the
characteristics of the three crystals are nearly identical. [6] In fact,
along each nanotube, there is a macrolactam every 4.81 Å on
average (1 and 2: c = 4.82 Å, 3: c / 2 = 4.80 Å, its unit cell contains
two macrocycles stacked along c, rather than one for 1 and 2).
[19,45,46]
The crystallization, carried out by slow evaporation of the solvent
from a solution of 3 in n-butanol, gave several crystals favorable
to the resolution by X-rays. [43] The crystal system is once again
trigonal and the space group is R3c. The stacking by hydrogen
bridges and by alignment of dipoles is present, but the form of
infinite triangular prism, as observed for 1 and 2, is lost. Seen
along the C3-axis of the macrolactams, the stack appears in the
form of a perfect David star (Fig. 2c). [44] Since this is an
alternating stack of enantiomers, there is therefore no
supramolecular chirality. [35] This time again, all the nanotubes
are oriented in the same direction; the resulting crystal is therefore
highly anisotropic. The voids in the crystal are best described as
Figure 4. Electrostatic potentials maps and relative positions of rings 1-3 in their crystals. a. Electrostatic potentials displayed on 0.002 au isodensity surfaces
of rings 1-3. The maximum values (darkest blue) correspond to 0.050 au. The top views are seen from the d-negative face where the carbonyl oxygen atoms stand,
while the bottom views are seen from the d-positive face where the NH amide groups are located. The strong polarization of the molecules is also supported by
their calculated dipoles (DFT). b. All polar molecules 1-3 (red, green and blue colors are for d–, neutral and d+ regions respectively) adopt exactly the same relative
spatial geometry. The middle reference column shows the three H-bonds between all pairs of polar macrocycles within the same stacks. The six satellite rings,
belonging to neighbouring stacks, are shifted along the polar axis, such that all polar regions, within the crystal, sit next to oppositely charged or neutral regions.
Each nanotube is surrounded by six parallel nanotubes placed at
the six corners of a hexagon (the distances between axes of
adjacent nanotubes are 7.93 Å, 9.99 Å, and 11.74 Å for 1, 2 and
3 respectively). These peripheral nanotubes can be divided into
two families classified according to the translation they undergo
along the c axis. The first family comprises the nanotubes placed
at the arbitrary angles 0°, 120° and 240° and which are offset by
1.60 Å, according to c, with respect to the central reference
nanotube. For the second family, the nanotubes placed at the
angles of 60°, 180° and 300° are offset by -1.60 Å. It is thus
observed that there are in fact three families of nanotubes in each
crystal, which are simply offset from one another. [5,19,45]
Consequently, no macrolactam is perfectly opposite to another
directly adjacent in the a-b plane of the crystal. It is understood
that this would be unfavorable since it corresponds to a
destabilizing Keesom interaction. [28] Of course, Keesom
interactions, whether stabilizing or not, can quickly become
insignificant compared to other non-covalent stronger interactions.
However, it seems clear in these cases that they have been able
to act in synergy with other weak bonds.
In order to better understand the distribution of the partial charges
of each monomer, their electrostatic potential maps were
calculated (DFT). [29,47] It appears that the poles carry opposite
charges, while the equator is neutral (Fig. 4a). Each molecule can
be naively described as the sandwich of a neutral slice between
two slices of opposite charges. All these observations lead to a
plausible and simple explanation of this surprising crystalline
arrangement. Each charged region is surrounded by six lateral
direct neighbors and one oppositely charged neighbor directly
bound by three hydrogen bridges within the same nanotube (Fig.
4b). This latter neighbor exerts a much greater influence than the
lateral neighbors. However, due to the shifting of the nanotubes
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Waals interactions. Overall, the 3D crystal lattice, with all the
parallel nanotubes, perfectly fulfills all the possibilities of weak
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and van der Waals interactions.
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This research was supported by grants from the Natural Sciences
and Engineering Research Council of Canada. We thank Canada
Foundation for Innovation, the Ministère de l'Économie et de
l'innovation du Québec and the Fonds de recherche du Québec
for providing computational facilities and time on the
supercomputer mp2 from the Université de Sherbrooke, managed
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Keywords: Macrolactam • Supramolecular nanotube • Dipole •
Porous crystals • Hydrogen bonds
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Very polar and rigid macrolactams 2
(9.03 D) and 3 (8.81 D), obtained by
adding three alkenes and three
dienes respectively to cyclotri-b-
alanyl 1 (9.31 D) aggregate as
“endless” stacks through backbone-
backbone H-bond interactions and
van der Waals contacts. All three
triangular lactams crystallize in the
trigonal system, all tubular
Thomas Marmin, Yves L. Dory*
Page No. – Page No.
Self-Assembly of C3 Symmetric
Rigid Macrolactams into Very Polar
and Porous Trigonal Crystals
macrodipoles being oriented in the
same direction. Moreover, 3 forms
channels capable of hosting guests.
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