Synthesis, double-helix formation, and higher-assembly formation of chiral polycyclic aromatic compounds: conceptual development of polyketide aldol synthesis.

Personal Account

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Synthesis, Double-Helix Formation, and Higher-Assembly Formation of Chiral Polycyclic Aromatic Compounds: Conceptual Development of Polyketide Aldol Synthesis Masahiko Yamaguchi,*[a] Masanori Shigeno,[a] Nozomi Saito,[b] and Koji Yamamoto[a] Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences Tohoku University, Aoba, Sendai 980-8578 (Japan) E-mail: [email protected] Fax: (+81) 22-795-6811 [b] International Advanced Research and Education Organization Tohoku University, Sendai 980-8578 (Japan)

[a]

Received: July 29, 2013 Published online: December 16, 2013 This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the 40th anniversary of his discovery of the Mukaiyama aldol reaction.

ABSTRACT: Polycyclic aromatic compounds are an important group of substances in chemistry, and the study of their properties is a subject of interest in the development of drugs and materials. We have been conducting studies to develop chiral polycyclic aromatic compounds, i.e., helicenes and equatorenes. These helical molecules showed notable aggregate-forming properties and the capability for chiral recognition exerted by noncovalent bond interactions, which were not observed in compounds with central chirality. Homo- and hetero-double-helix-forming helicene oligomers were developed, and the latter self-assembled to form gels and vesicles. In this article, we describe such hierarchical studies of polycyclic aromatic compounds, which were started from polyketide aldol synthesis. DOI 10.1002/tcr.201300014 Keywords: chirality, helical structures, noncovalent interactions, polyketides, self-assembly

1. Introduction After receiving his PhD under the supervision of Professor Mukaiyama 30 years ago, M. Y., one of the authors of this article, started to study polyketide aldol synthesis, and applied it to the synthesis of several natural products with polycyclic aromatic structures. Then, his study was directed to the synthesis and determination of the properties and functions of a class of polycyclic aromatic compounds with helical chirality, i.e., helicenes and equatorenes. These compounds exhibited various notable properties that compounds with central chirality did not, as shown by M. S., N. S., and K. Y., the other authors of this article. Their strong tendency to form aggregates and their chiral recognition capability were utilized to develop double-helix-forming oligomers and their higher assemblies.

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The dynamic properties of these chiral aromatic compounds also turned out to be interesting. On the occasion of celebrating the 40th anniversary of Mukaiyama’s discovery of the Mukaiyama aldol reaction, in this article we discuss a conceptual development in the synthesis of multifunctionalized polycyclic aromatic compounds.

2. Polyketide Synthesis of Multifunctionalized Polycyclic Aromatic Compounds The aldol reaction of nucleophilic enolates and electrophilic aldehydes/ketones is extensively utilized in biological systems

© 2013 The Chemical Society of Japan and Wiley-VCH, Weinheim

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for C–C bond formation. For example, fructose 1,6bisphosphate aldolase catalyzes the reversible reaction that splits bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which is an important process in the glycolytic pathway (Scheme 1).[1] Another notable enzymatic aldol reaction is the aromatase/cyclase (ARO/CYC)–catalyzed reaction in the biosynthesis of polycyclic aromatic com-

pounds.[2] The synthesis involves the sequential Claisen condensation of acetyl-CoA followed by an intramolecular aldol reaction to form polycyclic aromatic compounds, which is catalyzed by ARO/CYC.[3] This biosynthesis provides various antibiotics including tetracyclines, anthraquinones, flavones, and angucyclines, being an excellent example of how nature utilizes an aldol reaction to produce useful compounds.

Masahiko Yamaguchi is a professor at Tohoku University. He was born in Fukuoka in 1954, and received his BSc (1977) and PhD degrees (1982) from the University of Tokyo under the guidance of Professor Teruaki Mukaiyama. He joined the Department of Industrial Chemistry, Kyushu Institute of Technology, in 1982 as assistant professor and was promoted to associate professor in 1985. He became associate professor of the Department of Chemistry at Tohoku University in 1991. From 1987 to 1988 he worked as a postdoctoral fellow at Yale University with Professor S. Danishefsky. In 1997, he was appointed as a professor in the Faculty of Pharmaceutical Sciences of Tohoku University. He was Professor of the Graduate School of Pharmaceutical Sciences and Graduate School of Science of the same university during 2006–2013, and PI of WPI-AIMR during 2007–2013. During 2007–2013, he was group leader of the GCOE program for chemistry at Tohoku University. Since 2013, he has been Professor of the Graduate School of Pharmaceutical Sciences. He received the Chemical Society of Japan Award for Young Chemists in 1986 and the Synthetic Organic Chemistry Award, Japan, in 2007. His research interests are in the area of synthetic methodology and synthesis/function of helical compounds.

Nozomi Saito is an assistant professor at Tohoku University. She was born in Yamagata in 1984, and received her BSc (2007) and PhD degrees (2012) from Tohoku University under the guidance of Professor Masahiko Yamaguchi. She was a JSPS fellow under the Japanese Junior Scientists Program from 2009 to 2012. She had the opportunity to work under the direction of Professor Deqing Zhang at the Institute of Chemistry, Chinese Academy of Sciences, for one month in 2010. In 2012, she was appointed as an assistant professor at Tohoku Universtity. She received the Springer Theses Prize in 2013. Her research interest is in the development of hierarchical self-assembly systems with motional functions using chiral molecules.

Masanori Shigeno is an assistant professor at Tohoku University. He was born in Shiga in 1983, and received his BSc (2005) and PhD degrees (2009) from Kyoto University under the guidance of Professor Masahiro Murakami. He was a JSPS fellow under the Japanese Junior Scientists Program from 2008 to 2009. In 2009, he joined Professor Masahiko Yamaguchi’s group at Tohoku University as an assistant professor. He had the opportunity to work under the direction of Professor Ivan Huc at Université de Bordeaux, as a visiting assistant professor for two months in 2012. His research interests are the discovery/development of novel phenomena and functions using chiral molecules.

Koji Yamamoto is a JSPS Postdoctoral Research Fellow at Tohoku University. He was born in Ishikawa in 1985, and received his BSc (2008) and PhD degrees (2013) from Tohoku University under the guidance of Professor Masahiko Yamaguchi. He was a JSPS fellow under the Japanese Junior Scientists Program from 2012 to 2013. He had the opportunity to work under the direction of Professor Kyo Han Ahn at Pohang University of Science and Technology for one month in 2011. He has been a JSPS Postdoctoral Research Fellow at Tohoku University since 2013. His research interests are in the development of new functional solid-surface-grafting chiral molecules and the synthesis of novel helical compounds.

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C h i r a l Po l yc yc l i c A ro m a t i c C o m p o u n d s : He l i c e n e s a n d Eq u a t o re n e s

Scheme 1. Aldol reactions in biosynthesis.

Owing to the unique structure and reactivity of polyketides, a synthetic approach was studied in the mid-1980s by M. Y. This approach utilized a repetitive method of extending β-polycarbonyl chains by the Claisen condensation of acetoacetate dianions.[4,5] Employing the two-step manipulation of the Claisen condensation and Ca(OAc)2–promoted aldol reaction, various diesters were converted to aromatized compounds with a glutarate moiety. For example, the reaction of β-hydroxyglutarate 1 gave 1,8-naphthalenediol 2 (R=H). The dimethylated derivative 2 (R=Me) could be used as the substrate in the next aromatization, and the tetracyclic naphthacene 3 was obtained. Since this method provides multifunctionalized polycyclic aromatic compounds with structures related to natural products, the synthesis of relatively complex natural products was attained.[5a] Employing a C-glycosidic polyketide derived from C-glycosidic glutarate (4), the Claisen condensation and aromatization gave 1,8-naphthalenediol 5 with the 7-C-glycoside moiety (Scheme 2). Functional manipulations then provided (–)-urdamycinone B (–)-6.[5a] These studies showed the potential of aldol reaction for the synthesis of multifunctionalized polycyclic aromatic compounds of natural origin. On the basis of his experiences and knowledge accumulated during these works, M. Y. directed his interest to the synthesis and study of the function of polycyclic aromatic compounds with chiral structures.[6]

3. Synthesis and Function of Helicenes The [6]helicene 7 with a six o-condensed aromatic ring system was first synthesized and resolved by Newman in the 1950s (Figure 1).[7] Because of the steric repulsion between the terminal benzene rings, 7 formed a nonplanar distorted structure. Since then, a number of helicenes were synthesized and characterized.[8] Unfortunately, they could not be prepared in large quantities and their properties were not elucidated. Although

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Scheme 2. Polyketide aldol synthesis.

Fig. 1. Chiral helicenes and naphthalenes.

the central chirality of molecules is very important in chemistry, it was considered that another chiral molecular world containing helical chirality is equally important, since many natural substances have helical structures. This work was started in the mid-1990s by examining 1,8-disubstituted naphthalenes (Figure 1), inspired by a structural analogy to 1,8-naphthalenediols obtained by polyketide aldol synthesis. The introduction of bulky groups at the peri position is known to distort a naphthalene ring exhibiting chirality. It was, however, reported that 1,8-bis(t-butyl) naphthalene (8) readily racemized at room temperature.[9] Derivatives of 1,8-bis(trimethylsilyl)naphthalene (9) were then examined in order to increase the bulkiness and the height of the energy barrier for racemization. The silicon derivative 9, however, showed no sign of resolution, and this attempt suggested that the long length of the C–Si bond at the peri position compared with that of the C–C bond decreases the racemization energy barrier height, and that C–C bond derivatives must be considered. Recently, this has turned out to be



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Scheme 3. Synthesis of (M)-5,8-dicarboxylic acid (M)-11.

correct, and chiral 1,8-bis(1-adamantyl)naphthalene (10) was synthesized and resolved (see Section 4).[10] On the basis of the unsuccessful study of the naphthalene derivatives, compounds based on the 1,12-dimethylbenzo [c]phenanthrene nucleus were examined, since the structures of these compounds could be regarded as equivalent to those of 1,8-disubstituted naphthalenes. We developed a method of synthesizing racemic 5,8-dicarboxylic acid (±)-11 in hundredgram quantities and optically pure (P/M)-11 in ten-gram quantities (Figure 1).[11,12] The diketone 12,[7a,7c] reported by Newman, was converted to (±)-11, which was resolved using quinine salts (Scheme 3). Thus, we were able to study the properties and function of chiral polycyclic aromatic compounds systematically.[6] In this article, 11 and its functionalized derivatives are referred to as “helicenes”. The studies conducted on helicenes at the molecular level since the late 1990s include those of oligosaccharide binding, DNA binding, asymmetric catalysis, asymmetric synthesis,[13] charge-transfer (CT) complexation,[13] self-assembly gel formation,[14] and switchable diodes[15] (Figure 2). Noncovalent bond interactions and chiral recognition are characteristic features of chiral aromatic molecules; a recent example is provided below. Self-assembly gels were obtained by the helicenemethylamine (M)-13 at the interface of two miscible organic solvents (Figure 3).[14] To a solution of (M)-13 in chloroform in a test tube, hexane was slowly added. When the two-layer system was sonicated, the upper hexane layer gelated and the lower chloroform layer remained in the sol state. By turning the test tube upside down, the liquid layer could be confined in the gel. This phenomenon utilizes the diffusion of (M)-13 and chloroform from the lower layer to the upper layer. The gelation was initiated at the interface of the organic solvents, and the gel phase grew upward. The corresponding achiral naphthalene derivative, possessing a naphthalene moiety in place of the helicene, did not form a gel, and racemic (±)-13 showed less tendency to form a gel than optically pure (M)-13. The chiral helicene structure played an important role in self-assembly gel formation.


Fig. 2. A variety of helicene derivatives.

Fig. 3. Gel-sol two-layer formation by a self-assembly organogel of (M)-13.

Noncovalent bond interactions by the helical π-face are an important feature of helicenes, and therefore chiral recognition becomes substantial; that is, different properties of (P)/(P) interactions and (P)/(M) interactions were observed. A preference to form stronger complexes was generally observed between the same absolute configuration of the helicenes: (P)/ (P) or (M)/(M) combinations are favored over diastereomeric (P)/(M) combinations. The preference named the right/right and left/left rule stands for helicenes of small molecules.[6a] However, it is not always applicable to oligomeric compounds, which have a number of helicene moieties. This may be because the relative thermodynamic stability balances in oligomeric compounds between preferences at the small molecular level and macromolecular level.

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4. Development of Equatorenes

compounds were named equatorenes, because of the distorted structures at their equatorial plane. The method can in principle be applied to all polycyclic aromatic compounds. The UV-vis properties of chiral equatorenes exhibited a redshift of absorption maxima of up to 60 nm compared to achiral arenes. Equatorenes are polycyclic aromatic compounds with a chiral distorted naphthalene moiety and a flat polycyclic moiety; the latter may be manipulated by conventional aromatic synthetic methods. Thus, equatorenes can be a chiral version of functional polycyclic aromatic compounds.

The chirality of [6]helicenes and related compounds is generated by the steric repulsions between the terminal benzene rings in o-condensed polycyclic aromatic systems, and therefore has limitations in structure. For example, it was not possible to obtain chiral naphthalene and pyrene; therefore, another methodology was required to obtain chiral versions of these compounds (Scheme 4). Although several chiral naphthalenes are known, their racemization barriers are not sufficiently high to allow the isolation of enantiomers.[9] Then, naphthalenes with bulky 1,8-substituents were re-examined in the 2010s, and bis(1-adamantyl)naphthalene turned out to have a high racemization barrier.[10] The aryne Diels-Alder reaction was used to construct the 1,8-disubstituted naphthalene nucleus 14, followed by aromatization; the resulting naphthol 15 was resolved using ketopinic acid esters (Scheme 4). The energy barrier for racemization was approximately 29 kcal/mol, and (P)-15 did not racemize under ambient conditions. The optically pure naphthol (P)-15 was converted to naphthalene (P)-10, phenanthrene (P)-16, chrysene (P)-17, and pyrene (P)-18 without racemization (Scheme 4).[16] The chirality of these polycyclic aromatic compounds originated from the bis(1-adamantyl) groups at the peri position, and the

Noncovalent bond interactions and the chiral recognition of helicenes occur on solid surfaces as well as in solution, the study of which was started in the late 2000s. Nanoparticles grafted with a helicene on their surface were synthesized and analyzed in terms of their aggregate-forming properties. Silica nanoparticles of 70 nm average diameter with aminopropylated surfaces were treated with (P)-helicenecarbonyl chloride (P)-19 (Figure 4).[17] The resulting chiral nanoparticles reversibly precipitated in trifluoromethylbenzene and dispersed in iodobenzene. As will be noted later in the double-helix

Scheme 4. Synthesis of chiral naphthalenes and equatorenes.

Fig. 4. Optical resolution of 1-phenylethanol (20) using helicene-grafted silica nanoparticles.

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5. Aggregation of Helicene-Grafted Nanoparticles



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formation of ethynylhelicene oligomers, the results were ascribed to the stronger interactions between helicenes in hard aromatic solvents.[18] Chiral recognition occurred in the interactions between small molecules and silica nanoparticles (Figure 4).[17,19] The 70 nm silica nanoparticles grafted with (P)-helicene were dispersed in m-bis(trifluoromethyl)benzene. When 1-phenylethanol (20) was added, (P)-nanoparticles started to precipitate. Notably, the (P)nanoparticles precipitated faster with (S)-20 than with (R)-20, which indicated chiral recognition in the aggregation (Figure 4). Accordingly, when racemic (±)-20 was treated with the (P)nanoparticles, a 47% ee of (S)-20 was recovered from the precipitate. This is a novel optical resolution method for racemic compounds, whose advantage is that nonpolar liquid compounds can be resolved by precipitation. Chiral recognition also occurred between nanoparticles.[20] Gold nanoparticles of 10 nm diameter were grafted with (P)-, (M)-, and (±)-helicene thiols 21, giving derivatized nanoparticles that were named (P)-balls, (M)-balls, and (±)balls, respectively (Figure 5). The rate of precipitation in bromobenzene was as follows: 1:1 mixture of (P)-balls and (M)-balls > (M)-balls > (±)-balls. These results indicated chiral recognition in the interactions between isomeric nanoparticles, and the interactions between (P)-balls and (M)-balls were stronger than those between (P)-balls. Also note that (±)-balls and the (P)-balls/(M)-balls mixture, being diastereomeric, exhibited different aggregation behaviors. Various derivatives of chiral nanoparticles can be obtained by controlled synthesis, and novel properties may emerge from these substances of nanometer size.

6. Homo-Double-Helix Formation of Helicene Oligomers Synthetic oligomers for forming double-helix structures without employing metal coordination were reported by Lehn et al. in 2000,[21] and the development of double-helix-forming molecules has attracted much interest.[22] In 2004, we reported that the helicene oligomers 22 containing an acetylene linker, an m-phenylene moiety, and a decyloxycarbonyl side chain form double helices in solution (Figure 6).[23] The structure was determined from the following: 1) very strong Cotton effect up to Δε 3000 cm-1 M-1 showing the formation of the three-dimensional helical structure;[23] 2) 1H-NMR broadening and high-field shift showing aromatic π-stacking;[23] 3) bathochromic shifts and a hypochromic effect examined by UV-vis analysis, showing π-stacking;[23] 4) dimer formation detected by vapor pressure osmometry (VPO) analysis;[23] 5) dependence of the number of helicenes in the oligomers, showing the necessity of the minimum length of the oligomers for aggregate formation;[23] 6) calculated structures showing the


Fig. 5. Chiral recognition between helicene-grafted gold nanoparticles.

double helix of (P)-22 with three units of helicene and m-phenylene per turn, a diameter of 3.0 nm, a helix pitch of 0.38 nm, and right-handed screw sense;[24,25] 7) presence of enantiomeric structures detected by CD analysis showing the presence of both right- and left-handed helical structures;[26] 8) thickness of the self-assembled monolayer (SAM) on the gold surface in accordance with that of the calculated structure;[27] 9) substantial dimer–monomer structural changes consistent with double-helix formation;[23] 10) homo-/hetero-dimer formation consistent with double-helix formation;[23,25,26,28] 11) chiral recognition with regard to the helical moiety in dimeric aggregate formation;[25,26] 12) involvement of the hard-soft acid-base (HSAB) principle and π−π interactions;[23,29] 13) insensitivity to side chain bulkiness, showing the important role of main

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Fig. 6. Homo-double-helix formation of ethynylhelicene oligomers (P)-22 and derivatives of ethynylhelicene oligomers (M)-27 and (M)-28 at the side chain.

chain structure in forming the helical structure;[28] and 14) very large entropy loss in aggregate formation showing the formation of a highly ordered structure.[24] The driving force for double-helix formation was ascribed to the π−π interactions between the nonplanar π-systems of helicenes. An insight into such interactions was obtained from the solvent effects in the double-helix and random-coil structural changes. The heptamer (P)-22 (n = 7) changed its structure from double helix to random coil at ambient temperature. The rates of unfolding in aromatic solvents were largely affected by the aromatic substituent; unfolding was very slow in fluorinated benzenes with a half-life on the order of weeks to months, but very fast in iodobenzene with a half-life on the order of seconds.[23] The π−π interactions, therefore, were related to softness on the basis of the HSAB principle:[18] the interactions needed to form double helices have a soft nature and are prevented by soft aromatic solvents such as iodobenzene.

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Electronic properties of the side chains could affect the homo-double-helix formation, where steric effects were minimal. In addition to the decyloxycarbonyl compound (P)22, the side chain derivatives of 4-methyl-2-(2-methylpropyl) pentyloxycarbonyl (P)-23, perfluorooctyl (P)-24, decylthio (P)-25, and alternating decyloxycarbonyl/perfluorooctyl (P)-26 were synthesized (Figure 6).[26,28] The stability of the homodouble-helix formed by the perfluorooctyl derivative was higher than those formed by the decyloxycarbonyl and 4methyl-2-(2-methylpropyl)pentyloxycarbonyl derivatives,[26] and the stability lowered with the decylthio and alternating decyloxycarbonyl/perfluorooctyl derivatives. In analogy to the solvent effect, this order was interpreted by the capability of the hard m-phenylene moiety to increase the stability of the homo-double-helix. The bis(ethynylhelicene) oligomers (M)-27 and (M)-28 (Figure 6), which formed the double helix in an intramolecular manner, were synthesized.[24] The intramolecular complex was more stable than the intermolecular complex of (P)-22, and different dynamisms in double-helix formation appeared between the intermolecular and intramolecular complexes. An apparent negative activation energy, in which the double-helix formation was faster at lower temperatures, was observed for (M)-27. Despite the apparent monomolecular nature of the intramolecular double-helix formation of (M)-27, the reaction rate exhibited a concentration dependence, i.e., it was greater at higher concentrations. These observations suggested selfcatalysis; accordingly, hysteresis was observed by UV-vis analysis during heating and cooling in the intramolecular complex formation of (M)-27, but not in the intermolecular complex formation of (P)-22. The acetylene linker of ethynylhelicene oligomers could be replaced with other two-atom linkers without losing the ability to form dimeric aggregates (Figure 7).[30–32] The amidohelicene oligomers (P)-29, in which the helicene and m-phenylene moieties were connected by an amide linker, formed helix dimers in nonpolar solvents.[30] Since the structures of the amide derivatives are not yet well elucidated, they were denoted as helix dimers instead of double helices. The structural change of (P)-29 was insensitive to temperature changes, which contrasted to the high sensitivity of the ethynylhelicene oligomers (P)-22.[23,29] The orthogonal properties of (P)-22 and (P)-29 were utilized to develop functional multidomain oligomers.[33] The reverse amidohelicene tetramer (P)-30 (n = 4), in which the carbonyl and amine groups were exchanged compared to the amidohelicene oligomer (P)-29, also formed a helix dimer.[31] The sulfonamidohelicene tetramer (M)-31 (n = 4) formed a helix dimer in m-difluorobenzene.[32] This is notable because sulfonamides were considered not suitable for forming an organized structure, which was ascribed to the facile rotation of the N–S bond. The tetramer (M)-31 (n = 4) changed its



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Fig. 7. Structures of helicene oligomers connected by two-atom linkers.

structure between a helix dimer and a random coil on cooling and heating, and thermal hysteresis was observed in the structural change: the structural change occurred differently during cooling and heating (see Section 9). Thus, the oligomers obtained by connecting the helicene and m-phenylene with two-atom linkers of acetylene, amide, reverse amide, and sulfonamide formed dimeric aggregates in solution. This is a general method of obtaining double-helixforming molecules, and a diversity of such aggregates with different properties can be obtained. The driving force of the aggregation of the oligomers may be ascribed to the strong and stereospecific π−π interactions exerted by the nonplanar π-system and hydrogen bonding for amido- and sulfonamidohelicene oligomers.

by the function of DNA. Hetero-double-helix formation, however, is more difficult than homo-double-helix formation: two oligomers with different structures must form a complex. The complexation must be much stronger than the homocomplexation of each oligomer; otherwise, mixtures of heteroand homo-double-helices form. Several hetero-double-helices of synthetic oligomers were reported, but their properties and functions remain unclarified.[34] Since various homo-double-helix-forming helicene oligomers were obtained in the present study, it was expected that a hetero-double-helix would be formed by choosing an appropriate combination from the library. Ethynylhelicene oligomers with different side chains, chiralities, and numbers of helicenes were examined for this purpose. It was found that the oligomers containing the enantiomeric helicene formed a strong hetero-double-helix under conditions in which a homodouble-helix did not form. Such combinations were named pseudoenantiomeric. When a (P)-ethynylhelicene pentamer (P)-22 (n = 5) with decyloxycarbonyl side chains and an (M)-ethynylhelicene tetramer (M)-23 (n = 4) with 4-methyl-2-(2-methylpropyl) pentyloxycarbonyl side chains were mixed in m-difluorobenzene, a hetero-double-helix was formed (Figure 8), which was determined from the following: 1) very strong Cotton effect up to Δε 1000 cm-1 1 M ; 2) bathochromic shifts and a hypochromic effect examined by UV-vis analysis; 3) dimer formation detected by VPO analysis; 4) 1:1 complexation determined from Job plots; 5) dependence on the number of helicenes in the oligomers; 6) calculated structure of the (P)-22 (n = 5)/(M)-23 (n = 4) complex showing three units of helicene and m-phenylene per turn, a diameter of 3.2 nm, a helix pitch of 0.39 nm, and a right-handed screw sense; and 7) MS analysis.[25] The homo- and hetero-double-helices exhibited similar aggregation properties: they reversibly changed their structure between a random coil and a double helix on heating and cooling, showed similar solvent effects, stabilized in fluorinated aromatic solvents,[35] and showed similar cylindrical structures in calculations.[25] Substantial differences, however, were also observed between the homoand hetero-double-helices. The hetero-double-helix formed a much stronger complex than the homo-double-helix, which indicated significant chiral recognition in the double-helix formation.[25] Also note that the hetero-double-helix showed a high tendency to form higher assemblies but the homo-double-helix did not, as discussed in the next section.

7. Hetero-Double-Helix Formation of Ethynylhelicene Oligomers

8. Higher-Assembly Formation of Hetero-Double-Helices of Ethynylhelicene Oligomers: Intercomplex Interactions

A hetero-double-helix can be used to develop functional materials still different from a homo-double-helix, as indicated

The hetero-double-helices formed from the pseudoenantiomeric oligomers showed a tendency to form higher


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Fig. 8. Hetero-double-helix formation by pseudoenantiomeric (P)- and (M)-ethynylhelicene oligomers.

aggregates. This is probably due to their cylindrical structures, which have a large surface area. In addition, the cylindrical structure likely has helical grooves, which can strengthen the lateral interactions. The interactions occur in only the heterodouble-helix and not the homo-double-helix nor random coils; they were named intercomplex interactions.[25] Slight differences in the structures of hetero-double-helices and homodouble-helices obtained by calculations cause quite different intercomplex interactions. When pseudoenantiomeric (P)- and (M)-ethynylhelicene oligomers possessing different number of helicenes were mixed in toluene, a hetero-double-helix was formed, which further aggregated to form a fiber and gelated the solvent (Figure 8).[25,36] Self-assembly gels of small molecules, particularly two-component gels, have attracted much attention, because of the potential diversity of materials that can be obtained by changing the combination.[37] Since it is often observed that slight changes in the molecular structure of the components result in the loss of gelation ability, it was not facile to systematically fine-tune the gel properties. In contrast, the present method employs oligomeric compounds, and the number of helicenes, side chain structure, and chirality can be varied without losing gelation ability. For example, both (P)-22 (n = 4)/(M)-22 (n = 5) and (P)-22 (n = 3)/(M)-22 (n = 7) combinations formed gels, but exhibited different properties with regard to their appearance, CD, fluorescence, fiber structure, and viscosity.[36] The presence of two types of gel was ascribed to the differences in the number of helicenes (n) between the two components, and therefore to the difference in the stoichiometry of the complex: a 1:1 complex in the former and 1:2 to 1:3 complex in the latter.[36b] This is an

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example of a two-component self-assembly gel, in which the combination of two components can be varied in a systematic manner. In diethyl ether, vesicles were formed from the pseudoenantiomeric ethynylhelicene oligomers (Figure 8).[25,35] The combinations of (P)-22 (n = 5)/(M)-23 (n = 4), (P)-23 (n = 5)/(M)-23 (n = 4), and (P)-26 (n = 4)/(M)-22 (n = 5) produced vesicles with different sizes and shapes, which indicated the tunability of aggregates by the combination. Note that the 2 nm thickness of the vesicle membrane derived from (P)-23 (n = 5)/(M)-23 (n = 4) coincided with the height of the hetero-double-helix obtained by the calculations. The results are consistent with the vesicle membrane constructed using a single monolayer of double helices, likely by the lateral interactions between the hetero-double-helix. Since gels and vesicles showed similar CD spectra to the hetero-double-helix, a higher assembly should be formed by the assembly of the double helix. That the vesicles were converted to fibers by solvent exchange was consistent with the interpretation. The pseudoenantiomeric ethynylhelicene oligomers grafted on gold nanoparticles exhibited notable properties of stimulus response.[38] Composite materials of disulfidecontaining two-component gels derived from (P)-28 (n = 3)/ (M)-28 (n = 4) and gold nanoparticles of 10 nm average diameter were synthesized (Figure 9). The materials exhibited fluorescence at 600–800 nm, which was not observed in the original gels or isolated gold nanoparticles grafted with (P)-28 (n = 3)/(M)-28 (n = 4). Confocal microscopy showed emission from the gold nanoparticles. The fluorescence reversibly disappeared on heating and cooling with sol and gel formation. It was proposed that the pseudoenantiomeric ethynylhelicene



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Fig. 10. Reversal of relative thermodynamic stability in the transition between double helix and random coil upon temperature change.

9. Dynamic Properties of Transition between Double Helix and Random Coil

Fig. 9. Fluorescence of composite materials of pseudoenantiomeric ethynylhelicene oligomers (P)-28 (n=3)/(M)-28 (n=4) and gold nanoparticles.

fibers were activated by light and transferred energy to the gold nanoparticles, which then emitted light. The fluorescence of gold nanoparticles is quite unusual because gold nanoparticles are well known to quench fluorescence, and the present fluorescence is characteristic of the composite materials of gold nanoparticles and two-component gels. Thus, the synthetic double helix molecules are a novel type of compound possessing a previously unknown chiral cylindrical structure, and exhibit notable aggregation behavior and stimulus-responsive properties. This is a bottom-up methodology for substances from the helical molecules of helicenes to oligomeric macromolecules, double helices, and higher aggregates. The properties of centimeter-sized substances can be fine-tuned by the structural modification of oligomers, and various stimulus-responsive substances based on molecular structural changes could be obtained by appropriate design.


Dynamism is another important feature of double-helix formation, which was observed in the present study. The ethynylhelicene[23,24,29] and sulfonamidohelicene[32] oligomers thermoreversibly changed their structure between a double helix and a random coil on cooling and heating, which was shown by the large changes in the binding constants K = [double helix]/[random coil]2 (Figure 10). This is an equilibrium system, in which the double helix is exclusively formed at a low temperature, T1, and the random coil at a high temperature, T2. The structural change proceeds via the temperature Teq, where [double helix] = [random coil]. The relative thermodynamic stability expressed by the Gibbs free energy ΔG of the two states reverted with the temperature change. The structural change was sensitive to temperature and often occurred within temperature changes of less than 30°C. The phenomenon of the structural change being sensitive to temperature changes can be expressed by the thermodynamic property of a large enthalpy gain ΔH in the formation of a double helix and an extremely large entropy loss ΔS (Table 1, Figure 11). From the relationship between the equilibrium constant K and the Gibbs free energy RTlnK = –ΔG, the equation RlnK = –(ΔH/T) + ΔS is obtained. The large negative ΔH indicates a strong binding comparable to covalent bond formation and a strong temperature dependence of lnK or K between T1 and T2. When ΔH is small, a small change occurs in lnK or K. The thermal structural change between a double helix and a random coil can also be described as follows taking ΔS into account: K takes values above and below [double helix] = [random coil] at temperatures lower and higher than Teq, which means that ΔS balances with ΔH/T between T1 and T2. Since ΔH takes a very large negative value, ΔS must also take a very large negative value, which is derived from the loss of freedom in the structural change from a random coil to a double helix. When ΔS is small, Teq is outside the range between T1 and T2, which does not provide an interconvertible system. Both the large negative ΔH and ΔS are the origin of the sharp transition between a double helix and a random coil induced by temperature change. This is an interesting reversible reaction system that is not common in small organic molecules.

Chem. Rec. 2014, 14, 15–27



Table 1. Comparison of ΔH and ΔS values in the double-helix formation of (P)-22 (n = 7), (P)-27 (n = 6), and (M)-31 (n = 4). (P)-22 (n = 7)[24] toluene (5 μM) ΔH (kJ mol−1) ΔS (kJ mol−1 K−1)

−98 −0.33

(P)-27 (n = 6)[24] toluene (5 μM)

(M)-31 (n = 4)[32] 1,3-difluorobenzene (500 μM)

−194 −0.61

−267 −0.75

Fig. 11. Diagram of RlnK = –(ΔH/T) + ΔS of the structural change between T1 and T2, assuming constant ΔH and ΔS.

Thermal hysteresis was also observed in the sulfonamidohelicene tetramer (M)-31 (n = 4) during its structural change between a helix dimer and a random coil (Figure 12).[32] Although the thermal hysteresis of bulk materials is well known, molecular-level hysteresis in solution is quite rare. The examination of this phenomenon revealed the presence of an induction period in the double-helix formation during cooling from the high-temperature state A to the low-temperature state D. A mechanistic model was provided to explain the molecular phenomena, and hysteresis was explained by the delay in the response of the molecular population to the temperature change: in the states B and C during cooling, the molecules remained in a random-coil structure Y, despite the higher thermodynamic stability of the double-helix structure X. Selfcatalysis was suggested in the double-helix formation. Hysteresis is related to the “memory effect”, which arises from the bistability at the same temperature. The states B and C occur only during cooling but not during heating. Note that the cooling states B and C contain information on the thermal history of the molecule, previously being at high temperatures.

Chem. Rec. 2014, 14, 15–27

Fig. 12. Model of molecular thermal hysteresis and “memory effect” of (M)-31.

Since molecular events are considered to be reversible (microscopic reversibility), the emergence of the memory effect at the molecular level seems unusual. The above model explains the memory effect by the memory of the population in states X/Y expressed by Δε, but not by that of a single molecule. On solid surfaces, double helices exhibit dynamic behaviors different from those in solution. The disulfide derivative (M)-28 (n = 6) of the ethynylhelicene oligomers formed selfassembled monolayers on gold surfaces with the homo-doublehelix structure, when the gold plate was immersed in the solution containing the double helix (Figure 13).[27] A notable observation was that the random-coil solution also gave the homo-double-helix SAM, which indicated that the aggregation occurred on the gold surface during SAM formation. It is likely



THE CHEMICAL RECORD

originates from the unique properties of helicenes with helical π-systems. For the authors, the present work is a study of

polycyclic aromatic compounds, which entails a conceptual development starting from the polyketide aldol reaction.

Acknowledgements This work was financially supported by a Grant-in-Aid for Scientific Research (No. 21229001, No. 23790003, and No. 25860003) from the Japan Society for the Promotion of Science (JSPS). K. Y. thanks the JSPS for a Fellowship for Young Japanese Scientists. Fig. 13. Ethynylhelicene oligomers (M)-28 (n = 6) on a solid surface.

that the homo-double-helix was formed in the vicinity of the homo-double-helix SAM. This is a novel reactivity of the double helix at the solid surface not observed in solution. Also note that the structures of the helicene oligomers in SAM were successfully monitored by CD, which was unprecedented. This is due to the extremely strong CD of the homo-double-helix of the ethynylhelicene oligomers. Various homo- and hetero-double-helix-forming oligomers, which change their structures in response to external stimuli, were obtained. Such synthetic compounds have been considered interesting because of the following: 1) they show structural similarity to biological macromolecules such as DNA, RNA, and proteins; 2) helical cylindrical structures are not obtained using other molecules; and 3) the bistability of double-helix and random-coil states. The present study added the following characteristic properties to the double-helixforming compounds: 4) higher-assembly formation; 5) sharp response to temperature; 6) sensitivity to solvent media; 7) thermal hysteresis; 8) self-catalysis; and 9) different responses to stimuli in solution and on a solid surface. Such properties of double-helix-forming oligomers will find many applications in the development of biologically active substances and functional materials.

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