Disruption of Tumor Cells Using a pH-Activated and Thermosensitive

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Disruption of tumor cells using a pH-activated and thermosensitive antitumor lipopeptide containing a leucine zipper structure Sijia Wang, Tong Wang, Junqi Zhang, Shouhong Xu, and Honglai Liu Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b00474 • Publication Date (Web): 18 Jun 2018 Downloaded from http://pubs.acs.org on June 19, 2018

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Deprotonation Induced Phase Evolutions in CoAssembled Molecular Structures Nan Cao, Jinqiang Ding, Biao Yang, Junjie Zhang, Chencheng Peng, Haiping Lin, Haiming Zhang, Qing Li,* and Lifeng Chi* Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, P. R. China

ABSTRACT: In this work, we systematically studied the co-assembly behavior of 1,3,5-tris(4carboxyphenyl)benzene (TCPB) and 4,4''-diamino-p-terphenyl (DATP) on a silver surface. Due to the thermal instability of the carboxylic acids, the co-assembly structure exhibits temperature dependent evolutions on Ag(111). The level of the deprotonation reactions of TCPB are clarified by the characteristic self-assembled footprints. Aided by these footprints, we are able to identify structures of the complex co-assembly of TCPB and DATP entities at each stage. Finally, the conclusions are further evidenced by density functional theory calculations.

INTRODUCTION One of the most commonly applied techniques for the bottom up fabrication of supramolecular nanostructures is the molecular self-assembly on surfaces.1-6 Generally speaking, self-assembly is driven by non-covalent intermolecular interactions, such as van der Waals interactions,7-11

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hydrogen bonding,12-18 halogen bonding,19-26 π-π stacking,27-29 and electrostatic interactions.30-32 Among the various non-covalent interactions, hydrogen bonding is considered to be one of the most intriguing interactions because of its directionality and ubiquity in bio-systems. While thorough investigations on mono-component self-assembled structures have been performed during the past decades, studies on bi-component systems on surfaces have seen a rise as well.6, 14, 33-36

In particular, many studies have been focused on the self-assembly of carboxyl and amino

derivatives due to their vital importance to the formation of proteins. Previous research found the carboxyl derivatives can self-assemble into multiple architectures via the O-H…O hydrogen bonds on various surfaces, such as Au,37 Ag,16-17 Cu,38-39 Pd40 and graphite.41-42 However, further studies reveal that carboxyl derivatives have poor thermal stability on metal surfaces. They could have their carboxyl hydrogens38,

43

or the entire carboxyl species44 detached at elevated

temperature, which leads to the temperature dependent self-assembled structural evolutions. In this aspect, despite the significant importance, few studies were reported on their co-assembly and the thermal induced structural evolutions on metal surfaces. In the present work, by introducing 1,3,5-tris(4-carboxyphenyl)benzene (TCPB) and 4,4''diamino-p-terphenyl (DATP) as precursors (the structural models are shown in Scheme 1), we studied the co-assembly behavior of carboxyl and amino derivatives on a Ag(111) surface. Carboxyl hydrogens of TCPB monomers would indeed be detached on the Ag(111) surface with the increasing annealing temperature. Depending on the level of the deprotonation reactions, various characteristic self-assembled footprints were obtained. We use these characteristic features to identify the structural evolutions of the complex co-assembly of TCPB and DATP entities on silver surface. Moreover, combining the scanning tunneling microscopy (STM)


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studies and the density functional theory (DFT) calculations, we explained how the DATP monomers be stabilized by co-deposition with TCPB on the silver surface. Scheme 1. Ball-stick models of the employed molecules.

(a) 1,3,5-tris(4-carboxyphenyl)benzene (TCPB), (b) 4,4''-diamino-p-terphenyl (DATP).

Figure 1. Self-assembly of TCPB on a Ag(111) surface after annealing the sample at different temperatures. (a) STM image after depositing TCPB on a Ag(111) surface held at 200 K. (b) STM image after annealing the sample at 320 K. (c) STM image after annealing the sample at 370 K. The unit cell of each phase is superposed on the STM images. The marked internal angle


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within the unit cell is 60 ± 1º, 81 ± 1º, 60 ± 1º,respectively. Tunneling parameters are It = 20 pA, Vb = -1 V for (a) and (c); It = 100 pA, Vb = -1 V for (b). RESULTS AND DISCUSSION STM Studies. Figure 1a gives a representative STM image after deposition of the TCPB molecules on a Ag(111) surface with the substrate held at 200 K. Two dimensional (2D) hexagonal networks are formed with 3.10 ± 0.02 nm pore-to-pore distance. Subsequent annealing of the sample at 320 K for 20 minutes results in a transformation of the networks from porous to one dimensional (1D) ribbon-like structure (Figure 1b). The ribbons are separated by 2.19 ± 0.02 nm and the periodicity along the ribbon is 1.55 ± 0.02 nm. The self-assembly structure further transforms to a close-packed packing after annealing the sample at 370 K for 20 minutes. As shown in Figure 1c, the close-packed structure exhibits a three-fold symmetry, and the lattice constant is measured to be 1.33 ± 0.02 nm. It is noteworthy that all the three kinds of self-assembly structures can form large and defect-free islands, as shown in Supporting Information Figure S1. All the observed structural transitions are irreversible.


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Figure 2. Structural models of Figure 1(a)-(c). (a)-(c) High resolution STM images of Figure 1(a)-(c). Image sizes are 5.8 nm 5.8 nm, 3.5 nm 3.5 nm and 4.3 nm 4.5 nm, respectively. (d)-(f) Four kinds of basic self-assembly motifs, which are corresponding to different level of deprotonation reactions of TCPB molecules on the Ag(111) surfaces. (g)-(i) DFT optimized structural models of (a)-(c), respectively. Tunneling parameters are It = 20 pA, Vb = -1 V for (a) and (c); It = 100 pA, Vb = -1 V for (b).


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According to previous STM45-46 and XPS47-48 measurements, the observed structural evolutions can be ascribed to the hierarchical deprotonation reactions. At initial adsorption of TCPB with the sample held at 200 K (Figure 2a), the adjacent molecules anchor on the Ag(111) surface with a “head to head” fashion (we refer to as “Type I” configuration). The carboxyl groups of the constitute molecules maintain their pristine configuration and form O-H…O hydrogen bonds with their adjacent carboxyl groups, as shown in Figure 2d. The three-fold symmetry of the TCPB entities then lead to the formation of the porous self-assembly networks (Figure 1a) on silver surface. To confirm the proposed structure, DFT calculations were performed. The optimized structure does exhibit a porous network. The calculated unit cell size is 3.10 × 3.10 nm2 and the internal angle is 59.9º, which agrees nicely with the experimental observations (Figure 2g). Deprotonation reactions of the TCPB entity take place after annealing the sample at 320 K, leading to the formation of the 1D ribbon-like structure. Two types of basic intermolecular interactions can be observed at this stage (Figure 2e). One type exhibits a “Tail to Tail” configuration (as shown in the green dashed line in Figure 2b), in which the pristine carboxyl group of one molecule forms one hydrogen bond with the oxygen atom of the newly formed COO group of the adjacent molecule. As a consequence, the “Tail to Tail” configuration is formed via two O-H…O hydrogen bonds (we refer to as “Type II” configuration). Another type exhibits a “side to side” configuration (as shown in the yellow dashed line in Figure 2b), in which the newly formed carboxylate group of one molecule points to the mid-edge of an adjacent TCPB molecule, via the PARI interaction49-53 (we refer to as “Type III” configuration). Based on this, we obtained the optimized structural model with DFT calculations. As shown in Figure 2h, the ribbons are constructed by TCPB entities, and each TCPB has one hydrogen atom detached. The calculated unit cell of the ribbon-like structure has a size of 2.19 nm 1.55 nm,


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and an angle of 78º, which is consistent with the experimental observations. The close-packed structure shown in Figure 2c can be ascribed to further deprotonation reactions after annealing the sample at higher temperature (370 K). All the monomers have unified orientations, and the adjacent molecules exhibit a “head to tail” fashion. According to previous reports, each TCPB molecule has two hydrogen atoms detached34. In our case, considering the close-packed structure remains unaltered up to 440 K annealing, it is reasonable to assume that all the carboxyl groups of TCPB monomers have been transformed to carboxylate groups (Figure 2c). Although the deprotonated TCPB molecules are negatively charged, the charges should be delocalized over the whole molecules due to the large conjugation systems, and may also be transferred to the metal substrates. Therefore, the electrostatic repulsions between negatively charged molecules do not destroy the self-assembly networks. We further performed DFT calculations, revealing that the TCPB monomers aggregate via the interactions between the COO oxygen atoms of one entity and CH group of an adjacent one (we refer to as “Type IV” configuration). The optimized close packed structure in gas phase is given in Figure 2i. The size of the unit cell of the structure is 1.33 nm 1.33 nm with an angle of 60.1º, which agreed nicely with the STM images. In summary, Figure 2 gives the STM images and the corresponding structural models of the selfassembly of TCPB molecules through the well-controlled annealing experiments. Four kinds of characteristic configurations (“Type I-IV”) are extracted, providing the footprints of the respective interactions between the adjacent molecules.


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Figure 3. Co-assembly of TCPB and DATP molecules on a Ag(111) surface. (a) STM image of mixed structure after depositing TCPB and DATP on a Ag(111) surface held at 200 K. (b)-(d) STM images of the co-assembled structure of TCPB and DATP after annealing the sample at 320 K (b), 340 K (c) and 420 K (d), respectively. (e)-(h) The corresponding DFT optimized structural models. Tunneling parameters are It = 20 pA, Vb = -1 V for (a), (b) and (d); It = 100 pA, Vb = -500 mV for (c). In order to study the co-assembly behavior of carboxyl and amino derivatives, DATP molecules are introduced. DATP exhibits two-fold symmetry (Scheme 1b), differs significantly from the three-fold symmetry nature of the TCPB entity. DATP monomers move fastly on the Ag(111) surface at 77 K, suggesting a rather weak molecule-molecule and molecule-substrate interactions (see Supporting Information Figure S2). The DATP monomers, however, can be stabilized and become visible at 77 K on Ag(111) surfaces by interacting with TCPB monomers. Figure 3a gives a representative STM image after co-deposition of DATP and TCPB constituents on the Ag(111) surface held at 200 K. The TCPB monomers tend to form hexagonal networks,


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which is same to that shown in Figure 1a, both in size and shape (the size of the unit cell is 3.10 nm 3.10 nm, and the internal angle is 60 ± 1º). Considering all the adjacent TCPB molecules exhibit a “Type I” fashion, the TCPB monomers maintain their pristine configurations at this stage. The DATP monomers are decorated in the pores and interact with the surrounding TCPB entities via N-H…O hydrogen bonds, as illustrated in Figure 3e. After annealing the sample at 320 K, a new assembly phase emerges. As shown in Figure 3b, the TCPB entities form a 1D backbone structure, in which the TCPB monomers interact with each other in two kinds of configurations: “Type I” and “Type II”. Based on the footprints provided in Figure 2, one can immediately identify that one carboxyl group of each TCPB monomer has transformed to the carboxylate group (Figure 3f). As shown in Figure 3b, the periodicity along the backbone chain (direction b of the unit cell) is measured to be 2.94 ± 0.02 nm. The 1D TCPB chains are separated by the decorated DATP monomers. The separation (direction a of the unit cell) is 3.20 ± 0.02 nm, and the angle within the unit cell is 76 ± 1º. Closer investigations reveal that the DATP monomers have their amino groups point to the C=O bonds of the adjacent TCPB monomers, forming the N-H … O hydrogen bonds. This way, each unit cell of this phase composes of two TCPB and four DATP monomers. Optimized structural model (Figure 3f) suggests the periodicity of the co-assembly structure is a = 3.20 nm and b = 2.94 nm, and the angle between direction a and b is 80.2º, which is consistent with the STM measurement. In this phase, each TCPB monomer has one hydrogen atom detached, which is similar to that shown in Figure 2b. Despite that, the self-assembly structures between those given in Figure 3b and Figure 2b are rather different. This difference can be ascribed to the N-H…O bonds between the newly introduced DATP monomers and the TCPB molecules. Further structural transition takes place after annealing the sample at 340 K for 20 minutes. As shown in Figure 3c, the TCPB entities 9 Environment ACS Paragon Plus

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retain the 1D backbone structure. However, the TCPB monomers interact with each other in alternative two kinds of motifs: “Type II” and “Type III”. We then obtain the structural model of the TCPB backbone based on the footprints given in Figure 2. As shown in Figure 3g, each TCPB entity has two hydrogen atoms detached. The newly formed carboxylate group interacts with the pristine carboxyl group of an adjacent TCPB molecule via the O-H…O bonds. Two TCPB backbones are separated along b direction by the DATP monomers. The DATP and TCPB molecules interact with each other via N-H…O hydrogen bonds. The unit cell of the co-assembly structure composes of two TCPB and two DATP monomers. The calculated size of the unit cell is a = 2.25 nm and b = 3.25 nm, and the angle is 64.4º, both of which are close to the STM observations (a = 2.25 ± 0.02 nm, b = 3.20 ± 0.02 nm, 65 ± 1º). After further annealing the sample at 420 K for 20 minutes, zigzag shaped TCPB rows are formed. The TCPB entities interact with each other with “Type III” motif (Figure 3d), suggesting all the carboxyl groups have been transformed to the carboxylate groups. This agrees well with that complete deprotonation reactions of the carboxyl groups of the TCPB molecules take place after 370 K annealing (Figure 2c). The structural model of the mixed phase is provided in Figure 3h. Within the ordered rows, two carboxylate groups of the TCPB monomers interact with the CH group of the adjacent molecule by the PARI interactions. The COO groups at the border of the rows interact with DATP monomers via the N-H…O hydrogen bonds. The size of the unit cell is calculated to be 2.0 nm 3.55 nm, and the angle is 43º, which is in good agreement with experimental observations (a = 2.05 ± 0.02 nm, b = 3.55 ± 0.02 nm and the angle is 45 ± 1º).


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Figure 4. (a) DFT optimized structural model of Figure 2c. (b) A model showing the randomly dispersed DATP molecules on a Ag(111) surface. (c) DFT optimized model of Figure 3d. DFT Calculations. The structural evolutions from Figure 3a to 3d not only provide the evidence for the successive deprotonations, but also show how the introduced amino derivatives influence the self-assembly of TCPB entities. For example, after all the carboxyl terminals of TCPB monomers transform into COO species, the self-assembly of sole TCPB molecule shows a three-fold symmetric close packed structure (Figure 2c), whereas the TCPB entities exhibit a 1D backbone when co-deposition with DATP constituents (Figure 3d). Intuitively speaking, the net hydrogen bonds between the TCPB and DATP constituents reduce the total free energy of the system, so that the DATP monomers can be stabilized on the silver surface and influence the self-assembly behavior of the TCPB. To quantitatively rationalize the formation of the coassembly structures, DFT calculations were carried out. All the calculations were performed in gas phase, and the calculation details can be found in the “Methods” part of this article. For simplicity, we only take the condition that all the carboxyl species have converted to COO terminals for example. To determine the self-assembly nature of the co-deposition of TCPB and DATP monomers, we calculated the free energy difference of two candidate conditions: (1) TCPB shows no obvious interactions with DATP molecules, so that they form separated phases


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over the surface; (2) TCPB and DATP monomers form a co-assembled mixed phase. The free energy difference was defined as: Edif = ETCPB-DATP ― 2 × (ETCPB + EDATP) Where ETCPB-DATP, ETCPB and EDATP are the DFT total energy for each unit cell of the mixed phase and separated phase in gas phase. For separated phase, the TCPB molecules aggregate into a close packed structure (Figure 4a). In this structure, each unit cell composes of one TCPB entity and the ETCPB is calculated to be -335.51 eV. Since the interactions between amines are rather weak (see Supporting Information Figure S2), the DATP monomers can be considered to disperse on the surface randomly (Figure 4b). Accordingly, the EDATP of each DATP molecule is calculated to be -238.41 eV. For mixed phase (shown in Figure 4c), each unit cell of the coassembly structure contains two TCPB and two DATP monomers, and the ETCPB-DATP is calculated to be -1155.26 eV. As a consequence, if considering two TCPB and two DATP monomers, the free energy difference Edif is -7.42 eV which means that the total energy of the mixed phase is 7.42 eV lower than that of separated phase. This indicates that the 12 hydrogen bonds in the mixed phase are stronger than the 12 hydrogen bonds in the separate phased (when same number of molecules are considered) by 7.42 eV. For each hydrogen bond, the energy drop is only 0.62 eV. It should be noted here that the molecular-substrate interaction is not considered in this calculation, so that the total energies for each phase do not reflect the real situation. The calculations thus qualitatively explain why a mixed phase is preferred. Taking into account that the N-H bonds are more polarized than the C-H bonds, the hydrogen bonds in N-H…O should be stronger than the C-H…O interactions. We have noticed that in our DFT calculations, the length of hydrogen bonds in N-H…O of the mixed phase (2.62 Å) is smaller than that of the C-H…O (2.95 Å) in the separated phase, this may account for the increased stability of mixed phase.


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The calculation suggested that the mixed phase is prefer to be formed when depositing both TCPB and DATP onto the Ag(111) surface. CONCLUSIONS We have systematically studied the co-assembly behavior of carboxyl and amino derivatives on a silver surface. Successive structural evolutions are observed upon the well-controlled annealing experiments, which can be ascribed to the stepwise deprotonation reactions of the TCPB monomers on the Ag(111) surface. The structural model of the co-assembly phase is revealed by both the characteristic backbone structure of TCPB packing and the DFT calculations. Moreover, combining the thorough STM observations and DFT calculations, we clarify that co-assembled structures were easier to be formed with the deprotonation of TCPB monomers, and further preferably understand the evolution of the co-assembled structures. Except the deprotonation, increased complexity of self-assembled structures of bi-component or even multi-component systems might be achieved by adjusting the electronic state, the geometry or functional groups of one component. METHODS STM measurements: All experiments were performed with a commercial low temperature scanning tunneling microscopy (Unisoku LT-STM 1500S) at a base pressure better than 1 1010

Torr. The Ag(111) surface was prepared by several cycles of sputtering with argon ions and

subsequent annealing at 750 K. A tungsten tip was used for the STM imaging. All images were processed and analyzed by WSxM.54 TCPB molecules (purity higher than 98%) were purchased from J&K Company, and DATP molecules (purity higher than 98%) were purchased from TCI Company.


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Theoretical Calculations: First-principles DFT calculations were performed on 2D networks of TCPB self-assembly structures and co-assembly structures of TCPB and DATP. The substrate is not considered in DFT calculations. All calculations were carried out in gas phase. The periodicity boundary conditions (PBC) were used to describe the self-assembled structures. The calculations were conducted with the Vienna Ab-initio Simulation Package (VASP, version 5.3.5)55-56 using the gradient-corrected Perdew-Burke-Ernzerhof (PBE) functional,57 and the projector augmented wave (PAW) method55 with a plane-wave basis set with energy cutoff of 400 eV. The self-assembled structures were optimized by PBE in combination with the D3 dispersion correction proposed by Grimme.58-59 The Brillouin zone was sampled by a 4 4 1 k-point mesh. ASSOCIATED CONTENT Supporting Information The following files are available free of charge. STM images of TCPB and DATP and its co-assembly structure on the Ag(111) surface; Evidence of the presence of DATP. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected] Author contributions L.F.C. and Q.L. designed the experiments. N.C. and B.Y. performed the STM measurements. J.Q.D and H.P.L. carried out the DFT calculations. All of the authors contribute in the data analysis and the manuscript writing. All of the authors approve to the submission of the final version. 14 Environment ACS Paragon Plus

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Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We acknowledge the Collaborative Innovation Center of Suzhou Nano Science & Technology and the Priority Academic Program Development of Jiangsu Higher Education Institutions. This work was supported by National Science Foundation of China (21790053, 21622306, 91545127, 21403149), National Major State Basic Research Development Program of China (2017YFA0205002, 2014CB932600) and Natural Science Foundation of Jiangsu Province (BK20140305). REFERENCES (1) De Feyter, S.; De Schryver, F. C. Two-Dimensional Supramolecular Self-Assembly Probed by Scanning Tunneling Microscopy. Chem. Soc. Rev. 2003, 32, 139-150. (2) Barth, J. V.; Weckesser, J.; Lin, N.; Dmitriev, A.; Kern, K. Supramolecular Architectures and Nanostructures at Metal Surfaces. Appl. Phys. A 2003, 76, 645-652. (3) Kudernac, T.; Lei, S.; Elemans, J. A. A. W.; De Feyter, S. Two-Dimensional Supramolecular Self-Assembly: Nanoporous Networks on Surfaces. Chem. Soc. Rev. 2009, 38, 402-421. (4) Elemans, J. A. A. W.; Lei, S.; De Feyter, S. Molecular and Supramolecular Networks on Surfaces: From Two-Dimensional Crystal Engineering to Reactivity. Angew. Chem. Int. Ed. 2009, 48, 7298-7332. (5) Kuehnle, A. Self-Assembly of Organic Molecules at Metal Surfaces. Curr. Opin. Colloid In. 2009, 14, 157-168.


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(6) Bouju, X.; Mattioli, C.; Franc, G.; Pujol, A.; Gourdon, A. Bicomponent Supramolecular Architectures at the Vacuum-Solid Interface. Chem. Rev. 2017, 117, 1407-1444. (7) Zambelli, T.; Goudeau, S.; Lagoute, J.; Gourdon, A.; Bouju, X.; Gauthier, S. Molecular Self-Assembly of Jointed Molecules on a Metallic Substrate: From Single Molecule to Monolayer. Chem. Phys. Chem. 2006, 7, 1917-1920. (8) Guillermet, O.; Niemi, E.; Nagarajan, S.; Bouju, X.; Martrou, D.; Gourdon, A.; Gauthier, S. Self-Assembly of Five fold-Symmetric Molecules on a Three fold-Symmetric Surface. Angew. Chem. Int. Ed. 2009, 48, 1970-1973. (9) Ghijsens, E.; Ivasenko, O.; Tahara, K.; Yamaga, H.; Itano, S.; Balandina, T.; Tobe, Y.; De Feyter, S. A Tale of Tails: Alkyl Chain Directed Formation of 2D Porous Networks Reveals Odd-Even Effects and Unexpected Bicomponent Phase Behavior. ACS Nano 2013, 7, 80318042. (10) Chen, Q.; Chen, T.; Pan, G. B.; Yan, H. J.; Song, W. G.; Wan, L. J.; Li, Z. T.; Wang, Z. H.; Shang, B.; Yuan, L. F.; Yang, J. L. Structural Selection of Graphene Supramolecular Assembly Oriented by Molecular Conformation and Alkyl Chain. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 16849-16854. (11) Gong, J. R.; Wan, L. J.; Yuan, Q. H.; Bai, C. L.; Jude, H.; Stang, P. J. Mesoscopic SelfOrganization of a Self-Assembled Supramolecular Rectangle on Highly Oriented Pyrolytic Graphite and Au(111) Surfaces. Proc. Natl. Acad. Sci. U. S. A. 2005, 102, 971-974. (12) Slater, A. G.; Perdigao, L. M.; Beton, P. H.; Champness, N. R. Surface-Based Supramolecular Chemistry Using Hydrogen Bonds. Acc. Chem. Res. 2014, 47, 3417-3427.


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