Supramolecular Walls from Cyclic Peptides: Modulating Nature and

Jun 15, 2009 - The units of the former (n = 3) are held together by NH···π/NH···OC interactions, whereas they are glued by a very dense network...
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Supramolecular Walls from Cyclic Peptides: Modulating Nature and Strength of Weak Interactions Pierre Baillargeon and Yves L. Dory* Laboratoire de synthe`se supramole´culaire, De´partement de chimie, Institut de Pharmacologie UniVersite´ de Sherbrooke, 3001, 12e aVenue nord, Sherbrooke Que´bec J1H 5N4, Canada

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 8 3638–3645

ReceiVed April 6, 2009; ReVised Manuscript ReceiVed June 1, 2009

ABSTRACT: Both macrolactams cyclo-[NH-CH2-CtC-CH2-C(Me)2-CO]n (n ) 3 and n ) 2) have been synthesized and crystallized. They have respectively one intramolecular hydrogen bond and no such bond. Both macrocycles self-assemble as parallel supramolecular walls with or without inclusion of solvent between them. The units of the former (n ) 3) are held together by NH · · · π/NH · · · OC interactions, whereas they are glued by a very dense network of classical parallel-oriented hydrogen bonds, involving all the amides of the rings, in the latter (n ) 2). In that case, the bulky C(Me)2 groups are located on the surface of the walls and can be held responsible for the piling process of the layers, by means of attractive van der Waals interactions. This spatial arrangement recalls the 3D structure of cellulose, where all constitutive sheets stack mostly via van der Waals forces. Introduction Many cyclic peptides have so far proven very useful for the supramolecular assembly of nanoobjects such as nanotubes1 or nanospheres.2 These reversibly crafted supramolecules can be endowed with numerous properties and find applications in transport, catalysis, photonics, material science, etc.3 Thus, hollow nanospheres can be used either as nanocontainers in drug delivery systems or as enzyme-like catalytic active sites.4 Nanotubes can ease transport across biological membranes like their natural analogues, gramicidin A or porin;5 they can also be used as drugs.6 The selectivity and potency of these biologically active nanotubes are directly linked to the nature of the side chains used in their ring-shaped units. Since nanotubes made from stacked cyclo-[R-aminoacyl]n (n ) 8) or cyclo-[β-aminoacyl]n (n ) 3, 4) are notoriously insoluble materials, side chains can also be useful to impart solubility. With subunits longer than β-amino acids, the solubilizing moiety can still be a side chain or belong directly to the main ring skeleton. We have successfully introduced E-alkenes in δ-amino acids to generate side-chain-free soluble nanotubes from stacked cyclo-[NH-CH2-CHdCH-CH2-CO]n (n ) 2, 3, 4) macrolactams 1, 2 and 3 (Scheme 1).7 According to plans, 1 and 2 stacked as endless tubes; such was not the case from 3. Although this latter macrocycle is shaped like a bracelet, apparently prone to induce tubular stacking, it prefers to self-assemble as a 2D square grid, a (4,4)net8 which we name a supramolecular wall9 because of its width (Figure 1). There are at least two reasons why 3 might prefer to avoid the tubular arrangement: (i) there would remain too much empty space in the resulting crystal, and (ii) stacking is not favored because of poor van der Waals contacts between badly positioned alkenes, most of their CHdCH constitutive atoms being in the same plane as that of the ring. Such ring geometry would result in a disadvantageous gap between each alkene moiety on stacking driven by hydrogen bonds from amides. In order to test this hypothesis and to be able to create supramolecular walls at will, we replaced alkenes for groups that occupy even less space and for which tubular stacking driven by amides would be equally disfavored. Alkyne bonds were first introduced in δ-amino acids then into ε-amino acids * Corresponding author. E-mail: [email protected].

Scheme 1. Macrolactams 1-3

Scheme 2. Structures of Macrocycles 4 and 6 That Could Be Prepared from Protected δ-Amino Acid 5

to build cyclic peptides self-assembling as supramolecular walls. This is the topic of the work presented in this manuscript. Results and Discussion We designed our first target 4 in a very straightforward manner, simply by replacing all three alkenes of known macrolactam 2 by alkynes (Scheme 2). As 2 self-assembles as endless nanotubes, in which both amides and alkenes contribute favorably to the stacking through hydrogen bonding and van der Waals interactions respectively, we expected that replacement of alkenes for alkynes would disturb significantly the tubular stacking. The protected alkyne δ-amino acid precursor 510 was synthesized in seven steps from but-3-yn-1-ol. All attempts to activate the acid group of 5 before peptide coupling invariably led to the formation of allenes. Although the corresponding trimeric allene macrolactam cyclo-[NHCH2-CHdCdCH-CO]3 6 could obviously lead to interesting crystals, we did not pursue this path for the time being, since it would require full control of allene chirality (Scheme 2). We can easily relate the formation of allenes to the acidity of the R-protons in the δ-amino acid derivatives (Scheme 3).

10.1021/cg900379n CCC: $40.75  2009 American Chemical Society Published on Web 06/15/2009

Supramolecular Walls from Alkyne Cyclic Peptides

Crystal Growth & Design, Vol. 9, No. 8, 2009 3639 Scheme 4. Synthesis of Lactams 14-16a

a Reagents and conditions: (a) n-BuLi, THF, -78 °C, 45 min; (b) CH2O, -78 °C to rt, 12 h; (c) Ph3P, NaHCO3, CCl4, reflux, 4 h, rt, 12 h; (d) NH4OH, MeOH, rt, 48 h; (e) Boc2O, K2CO3, H2O, EtOAc, rt, 48 h; (f) PPTS, EtOH, rt, 12 h, 50 °C, 1 h; (g) Jones reagent, AcMe, 0 °C, 1 h, rt, 3 h; (h) DCC, PfpOH, EtOAc, 0 °C to rt, 48 h; (i) TFA, CH2Cl2, rt, 45 min; (j) K2CO3, THF, rt, 72 h.

Scheme 5. Preparation of the Pfp Esters 20 and 21a

Figure 1. Supramolecular wall structure of 3. (a) Periodic tiling of the macrocycles as a square network. (b) Cross-section of the wall (relaxed stereoview) showing the packing of macrocycles.

Scheme 3. β-γ Alkyne δ-Aminoacyl versus γ-δ Alkyne ε-Aminoacyl Residues

One obvious way to bypass or solve that problem is to add an extra sp3 carbon atom between the carbonyl group and the alkyne moiety. The required Boc-protected ε-amino acid 12 was prepared as follows (Scheme 4). The alkyne anion of 7 was allowed to react with formaldehyde to yield the propargylic alcohol 8 (59%),11 which was successively transformed into the corresponding propargylic chloride 9 (39%) and then into propargylic Boc-protected amine 10 (80%). The THP ether was cleaved to produce the alcohol 11 (80%), which was then oxidized to the desired acid 12 (42%). The acid 12 was activated as its pentafluorophenyl (Pfp) ester 13 (53%).12 The Boc protective group was removed with TFA, and the resulting salt was treated under cyclooligomerization conditions to yield three cyclic peptides 14-16. Only the cyclotrimer 15 could be purified by chromatography (24%

a Reagents and conditions: (a) K2CO3, MeCN, rt, 6 days; (b) LDA, THF, -78 °C and rt, 75 min; (c) 17, THF, -78 °C, 110 min; (d) KOH, H2O, EtOH, rt, 12 h; (e) DCC · 3PfpOH, EtOAc, 0 °C to rt, 13 h.

isolated yield), because 14 and 16, the cyclic dimer and tetramer respectively, proved far too insoluble for further manipulation and to be of any use. Even 15 was sparingly soluble in most usual solvents, and failed to crystallize for that reason.1i This contrasts markedly with the cyclotrialkene 2 (Scheme 1) that appears to be much more lipophilic and dissolves readily in moderately polar to polar solvents, despite the fact that it contains three fewer carbon atoms. According to tables of hydrophobicity factors (log P),13 an alkyne is less lipophilic than a trans alkene (∆ log P ≈ 1) and each methyl or methylene group increases the molecule log P value (substituant π factor) by about 0.5. Therefore, 15 is more hydrophilic than 2 by about

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Scheme 6. Synthesis of Macrolactam 26a

lipophilicity has increased by around 3 and 1.5 respectively.13 Consequently, solubility should not be a problem anymore and crystallization should be facilitated. The necessary Boc-protected and Pfp activated amino acids 20 and 21 were obtained in three straightforward steps from Boc2NH,14 1,4-dibromo-2-butyne and methyl isobutyrate (Scheme 5). Boc2NH was deprotonated by means of NaH. The resulting anion was used to desymmetrize 1,4-dibromo-2-butyne and yielded the propargylic bromide 17 (43%).15 The anion of methyl isobutyrate reacted with 17 to give the esters 18 (76%) and 19 (9%).16 Ester 18 was hydrolyzed, and the resulting acid was transformed into the Pfp esters 20 and 21 (65%). 18 was treated with TFA (Scheme 6), and the corresponding amine was coupled with the activated ester 21 to provide the dipeptide 22 (69%). The same two-step sequence was repeated to couple 22 with the activated ester 20 and to obtain the tripeptide 23 (72%). The ester 23 was hydrolyzed with KOH (100%) without loss of one Boc protective group as in similar hydrolysis of 18 (Scheme 5). This surprising result may come from folding of the now much longer chain around the lipophilic NBoc2 region and acting as a shield against hydroxide ions. The resulting acid 24 was activated as its Pfp ester 25 (67%). 25 was subsequently treated with TFA, then macrocyclized by simply adding the resulting TFA salt to a suspension of K2CO3 in acetone and water. The final product 26 (46%) was much less polar than all of our previously synthesized macrolactams, in full agreement with

a Reagents and conditions: (a) TFA, CH2Cl2, rt, 45 min; (b) 21, K2CO3, AcMe, H2O, rt, 60 h, 35 °C, 12 h; (c) 20, K2CO3, AcMe, H2O, rt, 60 h; (d) KOH, H2O, MeOH, rt, 12 h, diox, 45 °C, 3 h; (e) DCC · 3PfpOH, EtOAc, 0 °C to rt, 12 h; (f) K2CO3, AcMe, H2O, rt, 72 h, 45 °C, 12 h.

1.5 (∆ log P). A few methyl side chains were then added to 15 to increase its lipophilicity and also to inhibit intermolecular hydrogen bonding sterically. The resulting macrolactam 26 (synthesis shown in Schemes 5 and 6) contains an extra six bulky methyl groups located next to the three amide carbonyls. By comparison with its parent macrocycles 15 and 2, its

Table 1. Crystallographic Parameters for 26 Grown in Different Solvents and 29 Formula MW temp (K) wavelength (Å) diffractometer Detector distance Crystal system space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z density (Mg/m3) absorption coefficient (mm-1) F(000) crystal size (mm3) θ range (deg) index ranges reflections collected independent reflections completeness to θ absorption correction max and min transmission refinement method data/restraints/parameters goodness-of-fit on F2 final R indices [I > 2σ(I)] R indices (all data) scan type exposure time largest diff. peak and hole a

26 · AcMea

26 · AcOHb

C27H39N3O4 469.61 213(1) 0.71073 Bruker AXS P4/ SMART 1000 5 cm Monoclinic P21/n 16.6187(13) 10.1985(8) 16.7613(13) 90 106.534(1) 90 2723.3(4) 4 1.145 0.077 1016 0.50 × 0.40 × 0.40 1.52 to 27.50 -21 e h e 19, -12 e k e 13, -21 e l e 19 18206 6089 [R(int) ) 0.0182] 96.4% (θ ) 27.50°) SADABS 0.783 full-matrix least-squares on F2 6089/0/470 1.068 R1 ) 0.0427, wR2 ) 0.1168 R1 ) 0.0563, wR2 ) 0.1244 ω and φ 20s 0.278, -0.155 e · Å-3

C26H37N3O5 471.59 198(1) 0.71073 Bruker AXS P4/ SMART 1000 5 cm Orthorhombic Pbca 10.5167(9) 19.4581(16) 26.198(2) 90 90 90 5361.1(8) 8 1.169 0.081 2032 0.70 × 0.40 × 0.40 1.55 to 27.50 -13 e h e 13, -24 e k e 25, -31 e l e 33 27315 6074 [R(int) ) 0.0308] 98.5% (θ ) 27.50°) SADABS 0.836 full-matrix least-squares on F2 6074/3/315 1.145 R1 ) 0.0724, wR2 ) 0.2357 R1 ) 0.1127, wR2 ) 0.2702 ω and φ 10s 0.897, -0.523 e · Å-3

26 · CH2Cl2c

26 · t-BuOAcd

C25H35Cl2N3O3 496.46 218(2) 1.54056 Enraf-Nonius CAD-4

C30H45N3O5 527.69 293(2) 1.54176 Enraf-Nonius CAD-4

NA Monoclinic P21/n 15.995(7) 10.034(3) 17.137(9) 90 106.26(4) 90 2640(2) 4 1.249 2.451 1056 0.60 × 0.50 × 0.50 3.34 to 69.81 -19 e h e 18, 0 e k e 12, 0 e l e 20 4882 4882 [R(int) ) 0.0000] 97.5% (θ ) 69.81°) ψ-scan 0.8005 and 0.5736 full-matrix least-squares on F2 4882/21/330 1.094 R1 ) 0.0772, wR2 ) 0.2214 R1 ) 0.1024, wR2 ) 0.2469 ω/2θ NA 0.469, -0.280 e · Å-3

NA Monoclinic P21/c 15.764(4) 10.205(4) 19.874(16) 90 99.69(4) 90 3152(3) 4 1.112 0.605 1144 0.70 × 0.50 × 0.20 2.84 to 69.81 -19 e h e 18, 0 e k e 12, 0 e l e 24 5782 5782 [R(int) ) 0.0000] 97.0% (θ ) 69.81°) ψ-scan 0.9958 and 0.8544 full-matrix least-squares on F2 5782/3/354 1.024 R1 ) 0.0803, wR2 ) 0.2393 R1 ) 0.1357, wR2 ) 0.2764 ω/2θ NA 0.198, -0.184 e · Å-3

29e C16H22N2O2 274.36 213(2) 0.71073 Bruker AXS P4/ SMART 1000 5 cm Triclinic P1j 9.825(4) 11.792(5) 21.229(10) 99.350(5) 95.583(7) 105.412(5) 2314.0(16) 6 1.181 0.078 888 0.60 × 0.15 × 0.03 1.83 to 28.16 -12 e h e 12, -13 e k e 14, -27 e l e 27 13489 9565 [R(int) ) 0.0509] 96.4% (θ ) 25.00°) SADABS 0.9977 and 0.9545 full-matrix least-squares on F2 9565/2/524 0.959 R1 ) 0.1239, wR2 ) 0.2874 R1 ) 0.2625, wR2 ) 0.3696 ω and θ 60s 0.872, -0.854 e · Å-3

Crystals obtained by slow evaporation in AcMe. b Crystals obtained by slow evaporation in AcOH/H2O. c Crystals obtained by slow evaporation in CH2Cl2. d Crystals obtained by slow evaporation in t-BuOAc. e Crystals obtained by slow evaporation in CHCl3.

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Figure 2. Conformation of macrolactam 26 in all four crystals.

the log P calculated trends. Indeed, 26 could be purified by chromatography using mixtures of ethyl acetate and hexane as eluants. As anticipated, crystals could be grown readily by slow evaporation from solutions of acetone, acetic acid, dichloromethane and tert-butyl acetate (Table 1). In all cases solvent molecules were included in the crystal lattice. Moreover, 26 always assumed the same conformation governed by the presence of an intramolecular hydrogen bond into an 11membered ring and somewhat reminiscent of a β-turn (Figure 2). Since the intramolecular hydrogen bond warps the ring, 26 cannot form supramolecular tubes. Besides the intramolecular hydrogen bond that directs the folding of the macrolactam ring, 26 self-assembles as dimers held together by means of two intermolecular hydrogen bonds (Figures 3a, 4b). There remain two apparently unfulfilled hydrogen bonding sites: one carbonyl acceptor and one amide NH group donor. Close examination of the crystal suggests that these two vacant sites might in fact take part in another kind of weak interaction (Figure 3b). The remaining unmatched carbonyl is in the remote vicinity (2.65 Å) of an “orphan” hydrogen atom from another amide. In addition, the O-HsN angle, which is very far away from a straight line (125°), indicates that this interaction is not really a “normal” hydrogen bond. The same amide hydrogen atom is also located at very similar distances to two alkyne carbon atoms (2.69 Å and 2.66 Å). This type of NH · · · π interaction17 is mostly known for systems where the amide hydrogen interacts with aromatic π systems (calculated stabilization of 4 kcal/mol).18 It is of paramount importance in the biology realm for inducing secondary structures in proteins19 or for stabilizing enzymesubstrate complexes.20 Pairs of macrolactams can be compared to supramolecular bricks that are further glued together by NH · · · π/NH · · · OC interactions to create a supramolecular wall with the connectivity and arrangement found in honeycomb (6,3)-net.8,21 The thick sheets pile up with insertion of solvent molecules in grooves located on the surface (Figures 4a, 5). The structure of the wall remains the same independently of the crystallization conditions that were used. The only difference between the four crystals comes from the distance between consecutive wall planes (Figure 5). This distance appears to correlate nicely with the volume of the solvent molecules (Table 2). It is rather small when acetone, acetic acid and dichloromethane were used, and it becomes wider for the much bulkier tert-butyl acetate solvent molecule. In the former three solvents two consecutive walls can still have

Figure 3. Packing of macrolactam 26 in all four crystals. (a) Description (relaxed stereoview) of all weak interactions experienced by one unit (apart from van der Waals). (b) Details of the NH · · · π/NH · · · OC interaction.

some van der Waals contacts between surface methyl groups. In the latter, the walls do not “see” each other. This indicates that the hydrogen bond network is sufficiently strong to impart rigidity to the wall, whose structure is not the only result of crystal packing effects. Although 26 self-assembles as a supramolecular wall as expected, its wrinkled surface is an obstacle to a good piling up process, like that found for 3 (Figure 1) or for a natural supramolecular wall like cellulose.22 Their surfaces being smooth, each resulting supramolecular layer can easily pile up without insertion of foreign molecules. On the contrary, 26 must compensate for its ridged surface with the insertion of solvent molecules between each piled up layer. Logically, this drawback can be attributed to the intramolecular hydrogen bond that warps the ring (Figure 2). A way to obtain units with more controllable shapes is simply to remove one amide group (peptide unit) from 26. The resulting 14membered macrolactam dimer 29 (Scheme 7) cannot form intermolecular hydrogen bonds anymore, exactly like the 12membered ring 1 could not.7 Although 1 self-assembled as endless tubes, it could be expected that 29 would not because the gem-dimethyl groups would interfere with the proper alignment of hydrogen bonds. The target 29 was prepared from the ester 22 (Scheme 7) that was hydrolyzed to the acid 27 (77% yield), then activated as the Pfp ester 28 (68% yield). Cyclization occurred (54% yield) when the TFA salt obtained from 28 was treated with K2CO3. The resulting macrolactam 29 was crystallized in chloroform (Table 1). Contrary to the trimeric ring 26, the dimeric macrolactam 29 crystallizes without the inclusion of solvent molecules. As many as six conformers (including two pairs of enantiomers) of 29 are present in the crystal (Figure 6). Each ring shaped molecule, comparable to a brick, is a part of a

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Figure 4. Supramolecular wall structure (relaxed stereoview) of 26 in all four crystals. (a) Periodic tiling of the macrocycles in the wall showing grooves where solvent molecules insert. (b) Display of hydrogen bonds holding a portion of the wall made of seven dimers (normal hydrogen bonds are red, and distorted hydrogen bonds are yellow); intramolecular hydrogen bonds not shown. The honeycomb (6,3)-network is clearly visible.

Scheme 7. Synthesis of Macrolactam 29a

a Reagents and conditions: (a) KOH, H2O, MeOH, rt, 12 h; (b) DCC · 3PfpOH, EtOAc, 0 °C to rt, 12 h; (c) TFA, CH2Cl2, rt, 30 min; (d) K2CO3, AcMe, H2O, rt, 48 h.

Figure 5. Cross-section of two consecutive walls (relaxed stereoview) showing the packing of macrocycles and the hydrophobic surfaces for 26 · t-BuOAc (solvent molecules are omitted for clarity). Table 2. Distances between Two Consecutive Wall Planes for 3, 26 (Grown in Different Solvents), 29 and Cellulose I22a 3 26 · AcOH 26 · CH2Cl2 26 · AcMe 26 · t-BuOAc 29 cellulose I

10.40 Å 13.10 Å 13.22 Å 13.38 Å 15.54 Å 8.35 Å 3.91 Å

supramolecular wall, whose cement is a tight hydrogen bonding network (Figure 7a) shaped like a square grid (2,2)net.8 There are no NH · · · π/NH · · · OC interactions, and all possibilities for hydrogen bonding are completely fulfilled. Nanotubes are not favored because the gem-dimethyl groups prevent the constitutive rings from stacking properly. As a

consequence, the hydrogen bonds would become elongated in such a cylindrical object. In the wall, things are different because the gem-dimethyl parts can occupy positions where they do not bump into each other, and the hydrogen bonds can remain short and therefore strong. (2.00 to 2.17 Å range). The 11.5 Å thick wall (much thicker than many known infinite sheets)8d,23 is covered with hydrophobic groups, methyls and alkynes (Figure 7b). These now govern piling of the thick hydrogen bonded layers through orthogonally oriented van der Waals interactions (Figures 7c, 8). As a whole, this new layered material can be compared to cellulose.22 Each flat layer is maintained by means of interwoven moderate to strong hydrogen bonds.24 In cellulose the resulting thin sheets attract each other by numerous van der Waals interactions and a few potential intersheet weak hydrogen bonds.22a,24 In the same way the much thicker layers

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Figure 6. Shapes of the six conformers of macrolactam 29 present in the crystal. Conformers a, a′, c and c′ are C1 symmetric, whereas b and d are Ci symmetric.

(comparable to blankets rather than sheets) formed by peptide 29 stick to each other through van der Waals interactions (Table 2). Conclusions The supramolecular assembly of symmetrical cyclic peptides may in principle lead to the formation of infinite nanotubes. Since this process requires alignment of all macrocycles along the axis of the nanotubes, several factors must be controlled. In particular, the shape of the constitutive macrocycles, the nature and the direction of the weak forces dictate the type of supramolecules that will ultimately be obtained. The solubility of the macrolactams, which can be associated with their hydrophobicity, is also important in controlling the kinetics of the stacking.1i This latter aspect was clearly demonstrated in this study where none of the cyclo-[NH-CH2-CtC-CH2-CH2-CO]n (n ) 2-4) lactams could be of any use for low solubility reasons, their log P values (Molinspiration)25 being 0.66, 0.91, and 1.15 for 14 (n ) 2), 15 (n ) 3) and 16 (n ) 4) respectively. Adding gem-dimethyl groups at the R position led to the corresponding lactams cyclo-[NH-CH2-CtC-CH2-C (Me)2-CO]n (n ) 2,3) that were all freely soluble in nonpolar solvents. 29 (n ) 2) and 26 (n ) 3) could even be crystallized with ease. The log P values of these more lipophilic macrolactams have drastically increased to 3.10 and 4.56 for 29 and 26 respectively. The shape of the cyclic peptide ring can be controlled by the absence or presence of intramolecular hydrogen bonds. Tubular

Figure 7. Crystal packing of macrolactam 29 as a supramolecular wall. (a) Hydrogen bonding network between the 6 conformers a-a′ (enantiomers), b, c-c′ (enantiomers) and d. (b) CPK picture of the wall showing the square grid (2,2)-net. (c) Hydrogen bonding packing and orthogonal van der Waal piling of the walls.

stacking requires ideally intermolecular hydrogen bonds from amides oriented perpendicularly to the ring.7 For that reason, intramolecular hydrogen bonds, which tend to induce in-ring plane orientation of the amides, are conceptually detrimental. 26 preferred to adopt such a β-turn-like structure and proved not to be a proper tube inducer; rather, it developed a composite weak force: a NH · · · π/NH · · · OC interaction. Although these noncovalent interactions are interesting, they can be difficult to use efficiently to design supramolecular synthesis of specific targets. A flat ring with amides perpendicular to the ring is likely to form supramolecular architectures driven by perpendicular hydrogen bonds; these include tubes or walls. If stacking occurs without hindrance, tubes become possible (as with 1 and 2); whereas, they become virtually impossible when hydrogen bonds become too long from repulsive factors. For 29, repulsive effects arise from steric interactions between bulky groups on the rings undergoing stacking and unfavorable van der Waals interactions between too remote alkynes. The resulting final supramolecular framework is still controlled by the hydrogen bonds, but each ring shifts to avoid steric hindrance and to restore correct bond length for the hydrogen bonds. A supramo-

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Figure 8. Cross-section of two consecutive walls (relaxed stereoview) showing the packing of 29.

lecular wall, an artificial cellulose-like material, is created in the process (Figures 7 and 8). This superstructure is even facilitated when units like 29 have faces with different affinities like multipolar magnets.

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Acknowledgment. We thank NSERC Canada for financial support and Andreas Decken (University of New Brunswick at Fredericton) and Daniel Fortin (Universite´ de Sherbrooke) for collecting and processing the crystal data. Supporting Information Available: Experimental procedures and spectral characterization data for all compounds and crystallographic information files (CIF) corresponding to Table 1. Movie files (avi) of 26 (dimeric brick) and 29 (wall). This material is available free of charge via the Internet at http://pubs.acs.org.

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References (1) (a) Patzke, G. R.; Krumeich, F.; Nesper, R. Angew. Chem., Int. Ed. 2002, 41, 2446–2461. (b) Xiong, Y.; Mayers, B. T.; Xia, Y. Chem. Commun. 2005, 5013–5022. (c) Remskar, M. AdV. Mater. 2004, 16, 1497–1504. (d) Goldberger, J.; Fan, R.; Yang, P. Acc. Chem. Res. 2006, 39, 239–248. (e) Xia, Y.; Yang, P.; Sun, Y.; Wu, Y.; Mayers, B.; Gates, B.; Yin, Y.; Kim, F.; Yan, H. AdV. Mater. 2003, 15, 353– 389. (f) Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M. R. Angew. Chem., Int. Ed. 2001, 40, 988–1011. (g) Balbo Block, M. A.; Kaiser, A.; Khan, A.; Hecht, S. Top. Curr. Chem. 2005, 245, 89–150. (h) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N. Nature 1993, 366, 324–327. (i) Seebach, D.; Matthews, J.; Meden, A.; Wessels, T.; Baerlocher, C.; McCusker, L. B. HelV. Chim. Acta 1997, 80, 173–182. (j) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVersity 2004, 1, 1111–1239. (k) Fujimura, F.; Hirata, T.; Morita, T.; Kimura, S. Biomacromolecules 2006, 7, 2394–2400. (l) Jagannadh, B.; Reddy, M. S.; Rao, C. L.; Prabhakar, A.; Jagadeesh, B.; Chandrasekhar, S. Chem. Commun. 2006, 4847– 4849. (m) Fujimura, F.; Horikawa, Y.; Morita, T.; Sugiyama, J.; Kimura, S. Biomacromolecules 2007, 8, 611–616. (n) Fujimura, F.; Fukuda, M.; Sugiyama, J.; Morita, T.; Kimura, S. Org. Biomol. Chem. 2006, 4, 1896–1901. (o) Gauthier, D.; Baillargeon, P.; Drouin, M.; Dory, Y. L. Angew. Chem., Int. Ed. 2001, 40, 4635–4638. (p) Leclair, S.; Baillargeon, P.; Skouta, R.; Gauthier, D.; Zhao, Y.; Dory, Y. L. Angew. Chem., Int. Ed. 2004, 43, 349–353. (2) Baillargeon, P.; Dory, Y. L. J. Am. Chem. Soc. 2008, 130, 5640–5641. (3) (a) Horne, W. S.; Ashkenasy, N.; Ghadiri, M. R. Chem.sEur. J. 2005, 11, 1137–1144. (b) Ashkenasy, N.; Horne, W. S.; Ghadiri, M. R. Small 2006, 2, 99–102. (c) Motesharei, K.; Ghadiri, M. R. J. Am. Chem. Soc. 1997, 119, 11306–11312. (4) (a) Lu¨tzen, A. Angew. Chem., Int. Ed. 2005, 44, 1000–1002. (b) Johnston, M. R.; Latter, M. J. Supramol. Chem. 2005, 17, 595–607.

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(18) (19)

(20) (21) (22)

(c) Rebek, J., Jr. Angew. Chem., Int. Ed. 2005, 44, 2068–2078. (d) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2002, 41, 1488–1508. (e) Rebek, J., Jr. Acc. Chem. Res. 1999, 32, 278–286. (f) de Mendoza, J. Chem.sEur. J. 1998, 4, 1373–1377. (g) Conn, M. M.; Rebek, J., Jr. Chem. ReV. 1997, 97, 1647–1668. (h) Rebek, J., Jr. Chem. Soc. ReV. 1996, 4, 255–264. (i) Rebek, J., Jr. Pure Appl. Chem. 1996, 68, 1261–1266. (i) Wyler, R.; de Mendoza, J.; Rebek, J., Jr. Angew. Chem., Int. Ed. 1993, 32, 1699–1701. (j) Szabo, T.; OxLeary, B. M.; Rebek, J., Jr. Angew. Chem., Int. Ed. 1998, 37, 3410–3413. (k) Meissner, R. S.; Rebek, J., Jr.; de Mendoza, J. Science 1995, 270, 1485–1488. (l) Grotzfeld, R. M.; Branda, N.; Rebek, J., Jr. Science 1996, 271, 487–489. (m) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394, 764–766. (n) Arduini, A.; Domiano, L.; Ogliosi, L.; Pochini, A.; Secchi, A.; Ungaro, R. J. Org. Chem. 1997, 62, 7866–7868. (o) Shimizu, K. D.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 12403–12407. (p) Koh, K.; Araki, K.; Shinkai, S. Tetrahedron Lett. 1994, 35, 8255–8258. (q) Rose, K. N.; Barbour, L. J.; Orr, G. W.; Atwood, J. L. Chem. Commun. 1998, 407– 408. (r) Huerta, E.; Metselaar, G. A.; Fragoso, A.; Santos, E.; Bo, C.; Mendoza, J. Angew. Chem., Int. Ed. 2007, 46, 202–205. (a) Granja, J. R.; Ghadiri, M. R. J. Am. Chem. Soc. 1994, 116, 10785– 10786. (b) Sanchez-Quesada, J.; Kim, H. S.; Ghadiri, M. R. Angew. Chem., Int. Ed. 2001, 40, 2503–2506. (c) Gibson, S. E.; Lecci, C. Angew. Chem., Int. Ed. 2006, 45, 1364–1377. (a) Fernandez-Lopez, S.; Kim, H. S.; Choi, E. C.; Delgado, M.; Granja, J. R.; Khasanov, A.; Kraehenbvehl, K.; Long, G.; Weinberger, D. A.; Wilcoxen, K. M.; Ghadiri, M. R. Nature 2001, 412, 452–455. (b) Redman, J. E.; Wilcoxen, K. M.; Ghadiri, M. R. J. Comb. Chem. 2003, 5, 33–40. Baillargeon, P.; Bernard, S.; Gauthier, D.; Skouta, R.; Dory, Y. L. Chem.sEur. J. 2007, 13, 9223–9235. (a) Wells, A. F. Three-dimensional Nets and Polyhedra; WileyInterscience: New York, 1977. (b) Batten, S. T.; Robson, R. Angew. Chem., Int. Ed. 1998, 37, 1460–1494. (c) Moulton, B.; Zaworotko, M. J. Chem. ReV. 2001, 101, 1629–1658. (d) Thallapally, P. K.; Basavoju, S.; Desiraju, G. R.; Bagieu-Beucher, M.; Masse, R.; Nicoud, J.-F. Curr. Sci. 2003, 85, 995–1001. (e) Zaworotko, M. J. Chem. Commun. 2001, 1-9. Natarajan, S.; Mahata, P. J. Indian Inst. Sci. 2008, 88, 179-195. (f) Bhogala, B. R.; Vishweshwar, P.; Nangia, A. Cryst. Growth Des. 2005, 5, 1271–1281. Lyssenko, K. A.; Lenev, D. A.; Kostyanovsky, R. G. Tetrahedron 2002, 58, 8525–8537. Hartzoulakis, B.; Rutherford, T. J.; Ryan, M. D.; Gani, D. Tetrahedron Lett. 1996, 37, 6911–6914. (a) Girard, S.; Deslongchamp, P. Can. J. Chem. 1992, 70, 1265–1273. (b) Hubschwerlen, C.; Angehrn, P.; Gubernator, K.; Page, M. G. P.; Specklin, J.-L. J. Med. Chem. 1998, 41, 3972–3975. (a) Schmidt, U.; Lieberknecht, A.; Griesser, H.; Talbiersky, J. J. Org. Chem. 1982, 47, 3261–3264. (b) Dory, Y. L.; Mellor, J. M.; McAleer, J. F. Tetrahedron 1996, 52, 1343–1360. (a) Sangster, J. J. Phys. Chem. Ref. Data 1989, 18, 1111–1227. (b) Chuman, H.; Mori, A.; Tanaka, H.; Yamagami, C.; Fujita, T. J. Pharm. Sci. 2004, 93, 2681–2697. Grehn, L.; Ragnarsson, U. Synthesis 1987, 3, 275–276. Haberhauer, G.; Rominger, F.; Gleiter, R. J. Chem. Soc., Perkin Trans. 2 1999, 5, 947–950. Jacobi, P. A.; Liu, H. J. Org. Chem. 1999, 64, 1778–1779. (a) Viswamitra, M. A.; Radhakrishnan, R.; Bandekar, J.; Desiraju, G. R. J. Am. Chem. Soc. 1993, 115, 4868–4869. (b) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K. J. Am. Chem. Soc. 2000, 122, 11450–11458. Duan, G.; Smith, V. H., Jr.; Weaver, D. F. J. Phys. Chem. A 2000, 104, 4521–4532. (a) Steiner, T.; Koellner, G. J. Mol. Biol. 2001, 305, 535–557. (b) Wlodawer, A.; Walter, J.; Huber, R.; Sjo¨lin, L. J. Mol. Biol. 1984, 180, 301–329. Perutz, M. F.; Fermi, G.; Abraham, D. J.; Poyart, C.; Bursaux, E. J. Am. Chem. Soc. 1986, 108, 1064–1078. Desiraju, G. R. Acc. Chem. Res. 2002, 35, 565–573. (a) Nishiyama, Y.; Sugiyama, J.; Chanzy, H.; Langan, P. J. Am. Chem. Soc. 2003, 125, 14300–14306. (b) Bergenstråhle, M.; Berglund, L. A.; Mazeau, K. J. Phys. Chem. B 2007, 111, 9138–9145. (c) Klechkovskaya, V. V.; Baklagina, Y. G.; Stepina, N. D.; Khripunov, A. K.; Buffat, P. A.; Suvorova, E. I.; Zanaveskina, I. S.; Tkachenko, A. A.; Gladchenko, S. V. Crystallogr. Rep. 2003, 48, 755–762. (d) Yui, T.; Nishimura, S.; Akiba, S.; Hayashi, S. Carbohydr. Res. 2006, 341, 2521–2530. (e) Vie¨tor, R. J.; Mazeau, K.; Lakin, M.; Pe´rez, S. Biopolymers 2000, 54, 342–354.

Supramolecular Walls from Alkyne Cyclic Peptides (23) (a) Srivatsan, S. G.; Kingsley, S.; Verma, S. Chem. Lett. 2002, 240– 241. (b) Dale, S. H.; Elsegood, M. R.; Coombs, A. E. L. CrystEngComm 2004, 6, 328–335. (c) Zhou, J.; Liu, X.; Dai, J.; Li, D.-Q.; Huang, Z.-W.; Chen, Z.-F.; Liang, H. J. Coord. Chem. 2006, 59, 1711– 1717. (d) Shan, N.; Bond, A. D.; Jones, W. New J. Chem. 2003, 27, 365–371. (e) Pedireddi, V. R.; Belhekar, D. Tetrahedron 2002, 58, 2937–2941. (f) Saha, B. K.; Aitipamula, S.; Banerjee, R.; Nangia, A.; Jetti, R. K. R.; Boese, R.; Lam, C.-K.; Mak, T. C. W. Mol. Cryst. Liq. Cryst. 2005, 440, 295–316.

Crystal Growth & Design, Vol. 9, No. 8, 2009 3645 (24) (a) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford University Press: Oxford, U.K., 1997. (b) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond; Oxford University Press: New York, 1999. (25) (a) Irwin, J. J.; Shoichet, B. K. J. Chem. Inf. Model. 2005, 45, 177– 182. (b) Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43, 3714–3717.

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