This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 2317--2319 2317 Cite this: Chem. Commun., 2013, 49, 2317 Peptoid nanotubes: an oligomer macrocycle that reversibly sequesters water via single-crystal-to- single-crystal transformations† Sidonie B. L. Vollrath, ab Chunhua Hu, a Stefan Bra ¨se b and Kent Kirshenbaum* a A highly thermostable peptoid cyclo-octamer can reversibly accom- modate and release water molecules from central channels formed by the macrocycles in a crystalline array. We report the first single-crystal- to-single-crystal transformation for a peptidomimetic oligomer. Materials scientists are designing a variety of new crystalline materials capable of sophisticated functions such as selective catalysis and sequestration of gas molecules. These materials now include chemical species that undergo extensive alterations in the solid state while retaining a single crystal form. 1 Early examples of such single-crystal-to-single-crystal (SCSC) transformations included photochemical processes occurring within the crystal lattice. 2 Additional SCSC reactions have been described 3 such as the formation of channel-structures. 4 Metal–organic framework materials, in particular, can undergo SCSC transformations, which are often solvent-mediated processes. 5 Water loading and unloading processes have been demonstrated in crystalline Ni and Co complexes. 6 Solvent exchange has also been performed in Fe–organic crystals. 7 In addition to metal–organic materials, oligomeric compounds can also exhibit SCSC transformations. For example, a peptide macrocycle crystallizes in a tubular arrangement that enables uptake and release of chloroform. 8 The search for new functional materials has concurrently stimu- lated interest in peptidomimetic oligomer systems. A number of so-called ‘‘foldamer’’ compounds have been identified that exhibit conformational ordering, even at short oligomer chain lengths. Among these, N-substituted glycine peptoid oligomers (Fig. 1) show the capability to mimic a range of biomolecular structures and functions, 9 and can accommodate extraordinary chemical diversity while resisting proteolytic degradation. Recent studies have examined peptoid assemblies as highly organized nano- structured materials. 9b,10 Nevertheless, the true potential of peptoids as materials awaits development of reliable strategies to define the conformation of peptoid macromolecules and supramolecular assemblies. Various approaches have been esta- blished to enforce conformational ordering in peptoid oligomers, leading to the description of peptoid secondary structures such as helices and loops. 11 The introduction of long-range structural constraints is particularly important, as peptoids lack the intrinsic capacity to form hydrogen bond networks. We recently demonstrated that the formation of head-to-tail macrocyclic constraints in peptoids enforces a hairpin conformation that allows the predictable placement of diverse side chain groups. 12 The chemical diversity and structural ordering of cyclic peptoids suggests their capability for molecular recognition and supra- molecular assembly. Indeed, the first X-ray crystallographic studies of cyclic peptoids already indicated that the molecules can bind solvent or metal ions within the macrocycle interior. 13 Evaluation of packing in the crystal lattice also revealed a tubular organization of peptoid macrocycles with various ring sizes, in an arrangement similar to those described for peptide ‘‘nanotubes’’. 14 We now present structural investigations of a peptoid macrocycle in solution and the solid state, and demonstrate that the peptoid octamer reversibly sequesters water within a channel formed by stacking of the macrocycles in the crystal lattice. We began our design by noting that cyclic peptoids can establish an interior cavity sufficiently large to accommodate guest molecules. 13a We then selected a peptoid octamer sequence that would enforce a pattern of cis and trans amide bond con- formers (ccttcctt) that has been consistently observed for peptoid macrocycles. 12 In particular, N-aryl glycine peptoid monomers are known to enforce an amide trans geometry, while certain N-alkyl Fig. 1 Structure of a peptoid oligomer depicting cis and trans conformations of the amide bond. Torsion angles are shown at right. R groups indicate the location of highly diverse peptoid side chains. a Dept. of Chemistry, New York University, 100 Washington Sq., New York, NY 10003, USA. E-mail: [email protected]b Institute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany † Electronic supplementary information (ESI) available: Synthetic procedures, NMR, HPLC. CCDC 887682–887690. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc37163h Received 1st October 2012, Accepted 30th January 2013 DOI: 10.1039/c3cc37163h www.rsc.org/chemcomm ChemComm COMMUNICATION Published on 12 February 2013. Downloaded by Harvard University on 27/09/2013 13:10:32. View Article Online View Journal | View Issue
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This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 2317--2319 2317
Cite this: Chem. Commun.,2013,49, 2317
Peptoid nanotubes: an oligomer macrocycle thatreversibly sequesters water via single-crystal-to-single-crystal transformations†
Sidonie B. L. Vollrath,ab Chunhua Hu,a Stefan Braseb and Kent Kirshenbaum*a
A highly thermostable peptoid cyclo-octamer can reversibly accom-
modate and release water molecules from central channels formed by
the macrocycles in a crystalline array. We report the first single-crystal-
to-single-crystal transformation for a peptidomimetic oligomer.
Materials scientists are designing a variety of new crystallinematerials capable of sophisticated functions such as selectivecatalysis and sequestration of gas molecules. These materialsnow include chemical species that undergo extensive alterations inthe solid state while retaining a single crystal form.1 Early examplesof such single-crystal-to-single-crystal (SCSC) transformationsincluded photochemical processes occurring within the crystallattice.2 Additional SCSC reactions have been described3 such asthe formation of channel-structures.4 Metal–organic frameworkmaterials, in particular, can undergo SCSC transformations,which are often solvent-mediated processes.5 Water loadingand unloading processes have been demonstrated in crystallineNi and Co complexes.6 Solvent exchange has also been performedin Fe–organic crystals.7 In addition to metal–organic materials,oligomeric compounds can also exhibit SCSC transformations.For example, a peptide macrocycle crystallizes in a tubulararrangement that enables uptake and release of chloroform.8
The search for new functional materials has concurrently stimu-lated interest in peptidomimetic oligomer systems. A number ofso-called ‘‘foldamer’’ compounds have been identified that exhibitconformational ordering, even at short oligomer chain lengths.Among these, N-substituted glycine peptoid oligomers (Fig. 1) showthe capability to mimic a range of biomolecular structures andfunctions,9 and can accommodate extraordinary chemicaldiversity while resisting proteolytic degradation. Recent studieshave examined peptoid assemblies as highly organized nano-structured materials.9b,10 Nevertheless, the true potential of
peptoids as materials awaits development of reliable strategiesto define the conformation of peptoid macromolecules andsupramolecular assemblies. Various approaches have been esta-blished to enforce conformational ordering in peptoid oligomers,leading to the description of peptoid secondary structures suchas helices and loops.11 The introduction of long-range structuralconstraints is particularly important, as peptoids lack theintrinsic capacity to form hydrogen bond networks. We recentlydemonstrated that the formation of head-to-tail macrocyclicconstraints in peptoids enforces a hairpin conformation thatallows the predictable placement of diverse side chain groups.12
The chemical diversity and structural ordering of cyclic peptoidssuggests their capability for molecular recognition and supra-molecular assembly. Indeed, the first X-ray crystallographic studiesof cyclic peptoids already indicated that the molecules can bindsolvent or metal ions within the macrocycle interior.13 Evaluation ofpacking in the crystal lattice also revealed a tubular organization ofpeptoid macrocycles with various ring sizes, in an arrangementsimilar to those described for peptide ‘‘nanotubes’’.14 We nowpresent structural investigations of a peptoid macrocycle insolution and the solid state, and demonstrate that the peptoidoctamer reversibly sequesters water within a channel formed bystacking of the macrocycles in the crystal lattice.
We began our design by noting that cyclic peptoids canestablish an interior cavity sufficiently large to accommodateguest molecules.13a We then selected a peptoid octamer sequencethat would enforce a pattern of cis and trans amide bond con-formers (ccttcctt) that has been consistently observed for peptoidmacrocycles.12 In particular, N-aryl glycine peptoid monomers areknown to enforce an amide trans geometry, while certain N-alkyl
Fig. 1 Structure of a peptoid oligomer depicting cis and trans conformations ofthe amide bond. Torsion angles are shown at right. R groups indicate the locationof highly diverse peptoid side chains.
a Dept. of Chemistry, New York University, 100 Washington Sq., New York,
NY 10003, USA. E-mail: [email protected] Institute of Organic Chemistry, Karlsruhe Institute of Technology,
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
† Electronic supplementary information (ESI) available: Synthetic procedures,NMR, HPLC. CCDC 887682–887690. For ESI and crystallographic data in CIF orother electronic format see DOI: 10.1039/c3cc37163h
Received 1st October 2012,Accepted 30th January 2013
2318 Chem. Commun., 2013, 49, 2317--2319 This journal is c The Royal Society of Chemistry 2013
monomers can favor the cis conformation.15 Thus, phenyl sidechain groups were selected for positions 2, 3, 6 and 7 (Scheme 1).Similarly, either methoxyethyl or propargyl side chains wereselected for positions 1, 4, 5 and 8. The propargyl groups wereincluded in order to facilitate conjugation reactions for modifyingthe macrocycle in future studies.16 The overall linear sequence wasthen [N-(propargyl) glycine; N-(phenyl) glycine; N-(phenyl) glycine;N-(2-methoxyethyl) glycine]2.
Macrocycle synthesis was initiated by solid phase assembly ofthe linear oligomer precursor (Scheme 1). A submonomer synthesisprotocol was used, which iterates sequential bromoacetylation of aresin bound amine followed by nucleophilic displacement by aselection of diverse primary amines.17 In this case, aniline,2-methoxyethylamine and propargylamine were used as sub-monomer reagents to create the desired peptoid sequence. Thelinear peptoid precursor was cleaved from solid support andwas readily cyclized by head-to-tail amide bond formation.12
The peptoid macrocycle was purified by High PerformanceLiquid Chromatography (to B99% purity). A 1H-NMR spectrumobtained in CDCl3 indicated the presence of a unique conformer,consistent with enhanced ordering established by macrocycliza-tion. Additional 2D HSQC, NOESY and COSY spectra enabled peakassignments and established the presence of the anticipatedpattern of cis and trans amide bonds (see Fig. 2 and ESI†).Colorless, plate-like crystals were grown by evaporation frommethanol. Single crystal X-ray structure determination revealedthat the compound crystallized in the monoclinic space groupC2/c, with four peptoid molecules in the unit cell. The oligomermonomer sequence enables the C2 symmetry. The backbone isrelatively planar and forms a hairpin-type structure,12 leaving acavity in the interior of the macrocycle. The N-propargyl sidechains and two N-phenyl side chains are projected perpendicularto the macrocycle plane, thus extending the central cavity. Theobserved backbone amide dihedral angles (see ESI†) were consis-tent with both the solution phase studies and with previous solid-state structures of other peptoid oligomers15 � the N-phenyl sidechains dictate a trans amide conformation whereas the N-alkyl
peptoid residues form cis amides. This result illustrates the emer-ging capability to establish a predictable relationship betweenpeptoid monomer sequence and the oligomer structure.15,18 Otherpeptoid dihedral angles were as expected from previous modelingstudies (j E 751; c E 1801).18 The only unanticipated dihedralangles were the w1 angles for the two N-phenyl side chains at posi-tions 3 and 7, which vary considerably from the usually favoredorientation perpendicular to the backbone amide (w1 E 901).15
Both side chains point along the crystal b axis, leaving the cavityinside the macrocycle accessible for guest molecules.
In the crystal lattice, the individual macrocycles stack alongthe b axis. This organization of the backbone atoms orients theinterior macrocycle cavities to form a tubular array. The X-raydiffraction data indicated electron density corresponding towater molecules within the central channel. The oxygen atom ofthe crystal water sits on a twofold axis and the water moleculeis stabilized via two hydrogen bonds to peptoid backbonecarbonyl oxygen atoms, with an H-bond length of 2.03(8) Å andan O–H� � �O angle of 172(6)1 (Fig. 3 and Table S2, ESI†).
The water content of the crystal was initially determined to beapproximately 19 mol%, relative to the peptoid, based on the occu-pancy refinement of water molecules in the structure. This partialoccupancy suggested the possibility of diffusion of water moleculesthrough the crystal lattice. The peptoid crystal was placedunder ambient conditions for 4 h, and X-ray diffraction wasrepeated by the same techniques. The crystal was observed to befully dehydrated with retention of the single crystalline morphology(Table 1). To further verify the SCSC transformation, the samplewas put into a humid environment for 2 h, following which rehydra-tion to 22 mol% could be obtained. After an additional 20 h in ahumid chamber, the water content could be raised to 44 mol%.
Scheme 1 Synthesis of the cyclic peptoid (a) bromoacetic acid (5.4 equiv.), DIPEA(5.4 equiv.), 0.7 M in CH2Cl2, 40 min, rt; (b) 1 M propargylamine, DMF, rt; (c) bromo-acetic acid (10 equiv.), DIC (10 equiv.), 1.2 M in DMF, rt; (d) 1 M amine solution inDMF, rt; (e) repeat steps (c) and (d) until desired chain length; (f) 20% HFIP in CH2Cl2,30 min; (g) 6 equiv. DIPEA, 3 equiv. PyBOP, 2.4 mM DMF, 30 min, rt.
Fig. 2 Chemical structure of the macrocycle. Red arrows depict the observedNOE-signals. For clarity, the signals are only shown for four residues of the C2
symmetric molecule.
Fig. 3 View along the different axes of the crystal lattice. Left: along a; middle:along b; and right along the c axis. Three peptoid oligomers are shown. Hydrogenatoms of peptoid molecules are omitted for clarity.
This journal is c The Royal Society of Chemistry 2013 Chem. Commun., 2013, 49, 2317--2319 2319
Increased temperature did not enhance water uptake. In fact,exposure of the crystal to water vapor at 95 1C resulted indiminishing the water content to 14 mol%. Leaving the samecrystal in a humid environment for 4 weeks did not furtherenhance the amount of water in the crystal lattice, resulting in amaximal occupancy of 45 mol% (Table 1).
Superposition of the water-associated crystal structure (45 mol%)and the dehydrated crystal structure gives a RMSD (root meansquare deviation of backbone C-a atoms) of only 0.079 Å,indicating that the peptoid undergoes almost no rearrangementduring the water uptake process. The peptoid torsion anglesundergo subtle perturbations in a range of one to two degrees,with the largest changes occurring at the w1-torsion angles of theN-phenyl side chains proximal to the sequestered water mole-cule. These results suggest that peptoid conformations can bedesigned that pre-organize diverse side chain groups for selectivebinding interactions with guest molecules. Heating to 300 1C didnot decompose the crystals, which were also unaltered followingstorage under ambient conditions for several months, indicatingthat the peptoid tubular arrays are highly stable.
Peptoid supramolecular assemblies may prove to be generallyrobust, enabling a range of materials applications.9b,10 Thepeptoid macrocycle structure exhibits extensive similarities withthe family of peptide nanotubes,14 in which the supramolecularbuilding blocks are composed of alternating D,L-amino acids toform tubular structures.14 For peptide nanotubes, assembly isoriented by the formation of a b-sheet type arrangement in whichthe amino acid side chains point outwards to create an interiorchannel in which the amide NH and carbonyl groups are orientedperpendicular to the macrocycle. Our results show that a tubularassembly is also possible for peptidomimetic molecules that areincapable of forming intermolecular hydrogen bonds.
In conclusion, we describe a macrocyclic peptoid crystal-lizing in a tube-like array, permitting reversible sequestration ofco-crystallized water molecules through a single-crystal-to-single-crystal transformation. The formation of the porousnanotube assemblies is enforced by the predictable conforma-tional organization of the oligomer backbone, in the absence ofhydrogen bond or metal coordination interactions. Theseadvances will enable the design of ordered peptoid assemblies
in which the chemical features that establish molecular recog-nition can be controlled through variations in the monomersequences of diverse oligomer macrocycles, enabling a range ofapplications for storage, separation, and catalysis.
This work was supported by the Deutscher AkademischerAustausch Dienst (DAAD, to SBLV), and the US National ScienceFoundation (CHE-1152317 to KK).
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Table 1 Water loading and unloading cycles using the same crystal sample. Threedehydration cycles were conducted to demonstrate reversible solvent loading
