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A selection of pyrene-based liquid crystal dimers have been prepared, containing either methylene-ether or diether linked spacers of varying length and parity. All the diether linked materials, CBOnO.Py (n=5, 6, 11, 12), exhibit conventional nematic and smectic A phases, with the exception of CBO11O.Py which is exclusively nematic. The methylene-ether linked dimer, CBnO.Py, with an even-membered spacer (n=5) was solely nematogenic, but odd-members (n=6, 8, 10) exhibited both nematic and twist-bend nematic phases. Replacement of the cyanobiphenyl fragment by cyanoterphenyl giving CT6O.Py, gave elevated melting and nematic-isotropic transition temperatures, and SmA and SmCA phases were observed on cooling the nematic phase. Intermolecular face-to-face associations of the pyrene moieties drive glass formation, and all these materials have a glass transition temperature at or above room temperature. The stability of the glassy twist-bend nematic phase allowed for its study using AFM, and the helical pitch length, PTB , was measured as 6.3 and 6.7 nm for CB6O.Py and CB8O.Py, respectively. These values are comparable to the shortest pitch of a twist-bend nematic phase measured to date.

A number of liquid crystal dimers have been synthesised and characterised containing secondary or tertiary (N-methyl) benzanilide-based mesogenic groups. The secondary amides all form nematic phases, and we present the first example of an amide to show the twist-bend nematic (NTB) phase. Only two of the corresponding N-methylated dimers formed a nematic phase and with greatly reduced nematic-isotropic transition temperatures. Characterisation using 2D ROESY NMR experiments, DFT geometry optimisation and X-ray diffraction reveal that there is a change in the preferred conformation of the benzanilide core on methylation, from Z to E. The rotational barrier around the N-C(O) bond has been measured using variable temperature 1H NMR spectroscopy. This dramatic change in shape accounts for the remarkable difference in liquid crystalline behaviour between these secondary and tertiary amide-based materials.

The synthesis and characterisation of two homologous series of non-symmetric dimers are reported, the 1-(4-methoxybiphenyl-4ʹ-yl)-6-(4-alkylanilinebenzylidene-4ʹ-oxy)hexanes (MeOB6O.m, m = 1–10) an...

The synthesis and characterisation of a new set of azobenzene-based non-symmetric liquid crystal dimers, the 1-(4-substitutedazobenzene-4ʹ-yloxy)-6-(4-methoxybiphenyl-4ʹ-yl)hexanes (MeOB6OABX), that exhibit the twist-bend nematic phase, NTB, is described. The terminal substituents are methyl, methoxy, ethyl, butyl, butoxy, and nitrile. All six dimers exhibit both the NTB and conventional nematic, N, phases. The identification of the NTB phase was performed using polarised light microscopy and confirmed for binary mixtures with a standard twist-bend nematogen 1,7-bis-4-(4ʹ-cyanobiphenyl) heptane (CB7CB). The transitional behaviour of the MeOB6OABX dimers is compared with that of the corresponding ether-linked 1-(4-substitutedazobenzene-4ʹ-yloxy)-6-(4-methoxybiphenyl-4ʹ-yloxy)pentanes, MeOBO5OABX, all of which exhibit a conventional nematic phase. In addition, the nitrile-substituted MeOBO5OABCN shows the NTB phase. The behaviour of these non-symmetric dimers is also compared to that of the corresponding symmetric dimers. Differences in the transitional properties between these sets of new materials are accounted for in terms of not only molecular shape but also other factors including the strength of the mixed mesogen interaction.

Acknowledgements E.G. and D.P. acknowledge the support of the National Science Centre (Poland): (Grant Number 2016/22/A/ST5/00319). R.W. gratefully acknowledges The Carnegie Trust for the Universities of Scotland for funding the award of a PhD scholarship.

The synthesis and characterisation of two series of cyanobiphenyl-based liquid crystal dimers containing sulfur links between the spacer and mesogenic units, the 4ʹ-[1,ω-alkanediylbis(thio)]bis-[1,1ʹ-biphenyl]-4-carbonitriles (CBSnSCB), and 4ʹ-({ω-[(4ʹ-cyano[1,1ʹ-biphenyl]-4-yl)oxy]alkyl}thio)[1,1ʹ-biphenyl]-4-carbonitriles (CBSnOCB) are described. The odd members of both series show twist-bend nematic and nematic phases, whereas the even members exhibit only the nematic phase. An analogous cyanoterphenyl-based dimer, 34-{6-[(4ʹ-cyano[1,1ʹ-biphenyl]-4-yl)thio]-hexyl}[11,21:24,31-terphenyl]-14-carbonitrile (CT6SCB), is also reported and shows enantiotropic NTB and N phases. The transitional properties of these dimers are discussed in terms of molecular curvature, flexibility and biaxiality. The same molecular factors also influence the birefringence of nematic phases. Resonant X-ray scattering studies of the twist-bend nematic phase at both the carbon and sulfur absorption edges were performed, which allowed for the determination of critical behaviour of the helical pitch at the transition to the nematic phase, the behaviour was found to be independent of molecular structure. It was also observed that despite the different molecular bending angle and flexibility, in all compounds the helical pitch length far from the N-NTB transition corresponds to 4 longitudinal molecular distances.

Significance The twist–bend (TB) liquid crystal phase is the newest nematic phase, having only been identified in 2011. Still, there are many outstanding mysteries about the nature of its nanoscale organization and behavior. We elucidate how the number of monomer units in a linear TB oligomer influences the structure of its nanoscale helix, an important TB phase structure–property relationship. While a TB dimer exhibits a temperature-dependent variation of its helix pitch, the analogous trimer features a temperature-independent helix pitch considerably shorter than that of the dimer and other known TB materials. This study illuminates the scope of possible variations that manifest in the TB phase and represents a substantial step in controlling its nanoscale behavior for technological applications., We synthesized the liquid crystal dimer and trimer members of a series of flexible linear oligomers and characterized their microscopic and nanoscopic properties using resonant soft X-ray scattering and a number of other experimental techniques. On the microscopic scale, the twist–bend phases of the dimer and trimer appear essentially identical. However, while the liquid crystal dimer exhibits a temperature-dependent variation of its twist–bend helical pitch varying from 100 to 170 Å on heating, the trimer exhibits an essentially temperature-independent pitch of 66 Å, significantly shorter than those reported for other twist–bend forming materials in the literature. We attribute this to a specific combination of intrinsic conformational bend of the trimer molecules and a sterically favorable intercalation of the trimers over a commensurate fraction (two-thirds) of the molecular length. We develop a geometric model of the twist–bend phase for these materials with the molecules arranging into helical chain structures, and we fully determine their respective geometric parameters.

The syntheses and characterisation of the first ten homologues of the 1-(4-cyanobiphenyl-4'-yl)-6-(4-alkylanilinebenzylidene-4'-oxy)hexanes (CB6O.m) are reported. All ten members of the series exhibit an enantiotropic nematic, N, phase, and a monotropic twist-bend nematic, NTB, phase. Only CB6O.10 shows a smectic phase. The assignment of both nematic phases was confirmed using X-ray diffraction. For short chain lengths (m = 1-6) the local packing in both nematic phases is an intercalated arrangement, for intermediate chain lengths a frustrated local structure is seen and for the longest chain length, a bilayer arrangement is observed. This change in the local structure on increasing m has no apparent effect on the stability of either nematic phase, and TNTBN and TNI show a regular dependence on m. Specifically, TNTBN and TNI decrease on increasing m and superimposed upon this is a weak odd-even effect in which the odd members show the higher values. TNI decreases more rapidly than TNTBN on increasing m such that the ratio TNTBN/TNI increases. The lower temperature liquid crystal phase shown by 1-(4-cyanobiphenyl-4'-yloxy)-5-(4-butylanilinebenzylidene-4'-oxy)pentane (CBO5O.4) is reassigned as a twist-bend nematic phase. The transitional properties of the CB6O.m, CB6O.Om and CBO5O.m series are compared.

Using a photo-responsive dimer exhibiting the transition between nematic (N) and twist-bend nematic (NTB) phases, we prepared spherical cap-shaped droplets on solid substrates exposed to air. The internal director structures of these droplets vary depending on the phase and on the imposed boundary conditions. The structural switching between the N and NTB phases was successfully performed either by temperature control or by UV light-irradiation. The N phase is characterized by an extremely small bend elastic constant K3, and surprisingly, we found that the droplet-air interface induces a planar alignment, in contrast to that seen for typical calamitic liquid crystals. As a consequence, the director configuration was stabilized in a structure substantially different from that normally found in conventional nematic liquid crystalline droplets. In the twist-bend nematic droplets characteristic structures with macroscopic length scales were formed, and they were well controlled by the droplet size. These results indicated that a continuum theory is effective in describing the stabilization mechanism of the macroscopic structure even in the twist-bend nematic liquid crystal droplets exhibiting director modulations on a scale of several molecular lengths.

A selection of novel non-symmetric supramolecular liquid crystal dimers and trimers formed by hydrogen-bonding have been prepared and their phase behaviour characterised by polarised optical microscopy, X-ray diffraction and temperature-dependent Fourier-transform infrared spectroscopy. We mix the bent twist-bend nematogen 4-[6-(4&rsquo, cyanobiphenyl-4-yl) hexyloxy]-benzoic acid (CB6OBA) with a series of small stilbazole-based compounds 4-[(E)-2-(n-alkoxyphenyl)ethenyl]pyridines (nOS) of varying terminal chain length (n) to obtain the CB6OBA:nOS complexes. Complexes with n &le, 7 exhibit nematic and twist-bend nematic behaviour, followed on cooling by a smectic C phase for n = 4&ndash, 7, and finally, a hexatic-type smectic X phase for n = 3&ndash, 7. Mixtures with n = 8&ndash, 10 exhibit a smectic A phase below the conventional nematic phase, and on further cooling, a biaxial smectic Ab phase and the same hexatic-type SmX phase. Supramolecular trimers, CB6OBA:CB6OS and CB6OBA:1OB6OS, formed between CB6OBA and dimeric stilbazoles [(E)-2-(4-{[6-(4&rsquo, methoxy[1,1&rsquo, biphenyl]-4-yl)hexyl]oxy}phenyl)ethenyl]pyridine (1OB6OS) or 4-[(E)-4&rsquo, (6-{4-[(E)-2-(pyridin-4-yl)ethenyl]phenoxy}hexyl)[1,1&rsquo, biphenyl]-4- carbonitrile (CB6OS), exhibit nematic and twist-bend nematic phases, and are the first hydrogen-bonded trimers consisting of unlike donor and acceptor fragments to do so.

The synthesis and characterisation of the first eleven members of the 4′-(alkylthio)[1,1′-biphenyl]-4-carbonitriles series is reported. All eleven members show monotropic liquid crystal behaviour. The first six members are exclusively nematogenic, the seventh member shows nematic and smectic A phases, and the higher homologues only smectic A behaviour. A comparison of their transitional behaviour with that of the corresponding alkyl and alkyloxy-cyanobiphenyls reveals a new pattern of behaviour. Specifically, the nematic-isotropic transition temperatures show a large decrease on passing from the methylthio to ethylthio homologues. This unexpected behaviour is interpreted in terms of chalcogen bonding.

The synthesis and characterisation of an homologous series of bent odd-membered mesogenic dimers, the 4'-(6-{4-[(E)-{[4-(alkylthio)phenyl]imino}-methyl]phenoxy}hexyl)[1,1'-biphenyl]-4-carbonitriles (CB6O.Sm) is reported. This general class of materials, despite being achiral, has a strong tendency to form helical structures, and here, for the first time we report three such chiral phases in a single homologous series. Specifically, the heliconical twist-bend nematic (NTB) phase for short terminal thioalkyl chains, and its smectic equivalent -- the twist-bend smectic C (SmCTB) phase for longer chains. All the dimers showed the helical filament B4 phase, which is typically seen for rigid bent-core mesogens, but has only rarely been reported for flexible dimeric molecules. In addition, on increasing chain length, smectic behaviour emerges including the smectic A and the smectic CTB phases. We also show that these materials have the potential for their morphology to be controlled through surface interactions. The presence of the little-studied thio-linkage in the terminal chain, and the wide range of properties present in this single group of homologues, with promise of broad applicability in optics, photonics, as well as fundamental significance as a case study to achieve a better understanding of chirality and symmetry breaking in liquid crystals, ensures the importance of this new series of mesogens.

Alzheimer's disease (AD) is a tauopathy characterised by pathological fibrillisation of tau protein to form the paired helical filaments (PHFs) which constitute neurofibrillary tangles. The methylthioninium (MT) moiety reverses the proteolytic stability of the PHF core and is in clinical development for treatment of AD in a stable reduced form as leuco-MT (LMT). It has been hypothesised that MT acts via oxidation of cysteine residues which is incompatible with activity in the predominantly reducing environment of living cells. We have shown recently that the PHF-core tau unit assembles spontaneously in vitro to form PHF-like filaments. Here we describe studies using circular dichroism, SDS-polyacrylamide gel electrophoresis, transmission electron microscopy and site-directed mutagenesis to elucidate the mechanism of action of the MT moiety. We show that MT inhibitory activity is optimal in reducing conditions, that the active moiety is the reduced LMT form of the molecule, and that its mechanism of action is cysteine-independent.

We apply UV light to control the stability of twist-bend nematic phases, NTB, and conventional nematic phases, N, in three new liquid crystalline nonsymmetric dimers containing cyanobiphenyl and light-responsive azobenzene fragments connected by a hexyloxy spacer. The dynamic and static (5 kHz) dielectric responses of (E)-4′-(6-(4-((4-(ethoxy)phenyl)diazenyl)phenoxy)hexyl)-[1,1′-biphenyl]-4-carbonitrile, CB6OAzO2, (E)-4′-(6-(4-((4-(hexyloxy)phenyl)diazenyl)phenoxy)hexyl)-[1,1′-biphenyl]-4-carbonitrile, CB6OAzO6, and (E)-4′-(6-(4-((4-hexylphenyl)diazenyl)phenoxy)hexyl)-[1,1′-biphenyl]-4-carbonitrile, CB6OAz6, are measured at different temperatures, in planar and homeotropic alignments, by the application of bias and alternating electrical fields. The three CB6OAz(O)n dimers show high values of the dielectric mean, e ¯ , and dielectric anisotropy, Δ e , due to the dipole moment associated with the cyanobiphenyl groups. The absence of the ether linkage to the terminal chain in CB6OAz6 reduces the NTB - N transition temperature and increases the bend elastic constant, K3, compared to those seen for CB6OAzO6. Isothermal phase transitions are promoted by light-irradiation, via trans-to-cis photoisomerisation of the azobenzene units, resulting in the disruption of the liquid crystal order and appearance of re-entrant nematic and isotropic phases at low temperatures. It is possible to control the dynamics and reversibility of these transitions by varying the chemical structure of the new dimers, the temperature and UV light dosage. This may be exploited in devices using multiple external stimuli.

Dynamic electro-optic response of the liquid crystal (LC) director shows a backflow effect that is manifested as an optical bounce in chiral nematic LCs (N*LC) during field-induced homeotropic-twis...

Zigzag patterns were successfully generated in the twist-bend nematic (NTB) phase of 1-(4-cyanobiphenyl-4′-yl)-6-(4-cyanobiphenyl-4′-yloxy)hexane (CB6OCB) via simple surface treatment. A de...

The synthesis and characterisation of a range of non-symmetric liquid crystal dimers designed to exhibit the twist-bend nematic phase is reported. Beginning with 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-cyanobiphenyl-4′-yl) hexane, each nitrile group is exchanged systematically for a methoxy group. The behaviour of these dimers is interpreted in terms of their bent shape being the predominant driving force for the formation of the twist-bend nematic phase, and the small differences between the twist-bend nematic–nematic transition temperatures are attributed to the differences between the interaction strength parameters of the mesogenic units. The 4-alkyloxyphenyl 4-[6-(4′-cyanobiphenyl-4-yl)hexyloxy]benzoates with ethyl, butyl, hexyl and octyl chains show the twist-bend nematic phase, whereas the corresponding 4-alkyloxyphenyl 4-[5-(4′-cyanobiphenyl-4-yloxy)pentyloxy]benzoates do not. This difference in behaviour is attributed to the more bent structure of the former. Increasing the terminal chain length initially decreases the twist-bend nematic–nematic transition temperature and this suggests that the chain disrupts the interactions between the mesogenic units. Subsequent increases in chain length have a smaller effect suggesting that the chain can be accommodated within an intercalated arrangement. The transitional behaviour of 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-butyloxybiphenyl-4′-yl) hexane is compared to that of 1-(4-cyanobiphenyl-4′-yloxy)-6-(4-((S)-2-methyl)butyloxybiphenyl-4′-yl) hexane, and it is shown that chain branching strongly destabilises the twist-bend nematic phase. This is attributed to difficulties associated with packing the dimers.

The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer’s disease (AD) and other tauopathies. Full‐length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297‐391 known as ‘dGAE’, spontaneously forms cross‐β‐containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation., Truncated tau (297‐391) is the principal component of the core of paired helical filaments (PHFs) in neurofibrillary tangles isolated from Alzheimer’s brain tissue. Truncated tau forms filaments in vitro that share macromolecular characteristics with PHFs found in vivo. Truncated tau, without modification, is sufficient for the assembly of PHFs.

Complex materials often exhibit a hierarchical structure with an intriguing mechanism responsible for the ‘propagation’ of order from the molecular to the nano- or micro-scale level. In particular, the chirality of biological molecules such as nucleic acids and amino acids is responsible for the helical structure of DNA and proteins, which in turn leads to the lack of mirror symmetry of macro-bio-objects. To fully understand mechanisms of cross-level order transfer there is an intensive search for simpler artificial structures exhibiting hierarchical arrangement. Here we present complex systems built of achiral molecules that show four levels of structural chirality: layer chirality, helicity of a basic repeating unit, mesoscopic helix and helical filaments. The structures are identified by a combination of hard and soft x-ray diffraction measurements, optical studies and theoretical modelling. Similarly to many biological systems, the studied materials exhibit a coupling between chirality at different levels., It was previously shown that chiral structures can be formed from achiral bent-shaped mesogens. Here the authors observe hierarchical chiral structures with coupling of chirality at different levels in a system with achiral constituents.

The liquid crystal nonsymmetric dimer, 1-(4-butoxyazobenzene-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl) hexane (CB6OABOBu), shows enantiotropic twist-bend nematic, NTB, and nematic, N, phases. The NTB phase has been confirmed using polarized light microscopy, freeze fracture transmission electron microscopy, and X-ray diffraction. The helicoidal pitch in the NTB phase is 18 nm. The NTB-N (TNTBN) and N-I (TNI) transition temperatures are reduced upon UV light irradiation, with the reduction in TNTBN being much larger than that in TNI. An isothermal, reversible NTB-N transition may be driven photochemically. These observations are attributed to a trans-cis photoisomerization of the azobenzene fragment on UV irradiation, with the cis isomers stabilizing the standard nematic phase and the trans isomers stabilizing the NTB phase. The dramatic changes in TNTBN provide evidence that the transition between the normal nematic and twist-bend nematic with spontaneous breaking of chiral symmetry is crucially dependent on the shape of molecular dimers, which changes greatly during the trans-cis isomerization.

The most important inter­molecular inter­actions in the two indole derivatives described here are N—H⋯π bonds, which lead to chains in one case and inversion dimers in the other; C—H⋯π inter­actions appear to reinforce the N—H⋯π bonds in each case., We describe the syntheses and crystal structures of two indole derivatives, namely 6-isopropyl-3-(2-nitro-1-phenyl­eth­yl)-1H-indole, C19H20N2O2, (I), and 2-(4-meth­oxy­phen­yl)-3-(2-nitro-1-phenyl­eth­yl)-1H-indole, C23H20N2O3, (II); the latter crystallizes with two mol­ecules (A and B) with similar conformations (r.m.s. overlay fit = 0.139 Å) in the asymmetric unit. Despite the presence of O atoms as potential acceptors for classical hydrogen bonds, the dominant inter­molecular inter­action in each crystal is an N—H⋯π bond, which generates chains in (I) and A+A and B+B inversion dimers in (II). A different aromatic ring acts as the acceptor in each case. The packing is consolidated by C—H⋯π inter­actions in each case but aromatic π–π stacking inter­actions are absent.

Four related indole derivatives crystallize with a consistent C(6) N—H⋯O chain motif, but in each case the reinforcing inter­actions and crystal symmetries are different., We describe the crystal structures of four indole derivatives with a phenyl ring at the 2-position and different carbonyl-linked substituents at the 3-position, namely 1-(2-phenyl-1H-indol-3-yl)ethanone, C16H13NO, (I), 2-cyclo­hexyl-1-(2-phenyl-1H-indol-3-yl)ethanone, C22H23NO, (II), 3,3-dimethyl-1-(2-phenyl-1H-indol-3-yl)butan-1-one, C20H21NO, (III), and 3-benzoyl-2-phenyl-1H-indole, C21H15NO, (IV). In each case, the carbonyl-group O atom lies close to the indole-ring plane and points towards the benzene ring. The dihedral angles between the indole ring system and 2-phenyl ring for these structures are clustered in a narrow range around 65°. The dominant inter­molecular inter­action in each case is an N—H⋯O hydrogen bond, which generates a C(6) chain, although each structure possesses a different crystal symmetry. The C(6) chains are consolidated by different (C—H⋯O, C—H⋯π and π–π stacking) weak inter­actions, with little consistency between the structures.

The mol­ecular conformations of three highly substituted cyclo­penta­[c]furans appear to correlate strongly with different intra­molecular O—H⋯O and C—H⋯O inter­actions., The crystal structures of three cyclo­penta­[c]furans with various substituents at the 4-, 5- and 6-positions of the ring system are reported, namely, (±)-(3aR,4S,5S,6aS)-4-methyl-5-phenyl­hexa­hydro-1H-cyclo­penta­[c]furan-4,5-diol, C14H18O3, (I), (±)-(3aR,4S,5S,6aS)-4-benz­yloxy-4-methyl-5-phenyl­hexa­hydro-1H-cyclo­penta­[c]furan-5-ol, C21H24O3, (II), and (±)-(1aR,1bS,4aR,5S,5aR)-5-benz­yloxy-5-methyl-5a-phenyl­hexa­hydro-2H-oxireno[2′,3′:3,4]cyclopenta­[1,2-c]furan, C21H22O3, (III). The dominant inter­action in (I) and (II) is an O—H⋯O hydrogen bond across the bicyclic 5,5-ring system between the non-functionalized hy­droxy group and the tetra­hydro­furan O atom, which appears to influence the envelope conformations of the fused five-membered rings, whereas in (III), the rings have different conformations. A weak intra­molecular C—H⋯O inter­action appears to influence the degree of tilt of the phenyl ring attached to the 5-position and is different in (I) compared to (II) and (III).

We have studied the relationships between liquid crystallinity and hydrogen bonding in mixtures containing 4-pentoxybenzoic acid, 5OBA, and five bipyridines, XBiPy, with spacers having different flexibilities, namely: 4,4′-bipyridine (BiPy), 1,2-bis(4-pyridyl)ethane (EthaBiPy), trans-1,2-bis(4-pyridyl)ethylene (EthylBiPy), 4,4′-trimethylene-dipyridine (PropBiPy), and 4,4′-tetramethylene-dipyridine (ButBiPy). The XBiPy/5OBA mixtures exhibit liquid crystal behaviour for a range of acid concentrations, and predominantly smectic behaviour. The 1 : 2 mixtures have been studied using temperature-dependent Fourier transform infrared spectroscopy, FT-IR, with particular focus on the Fermi bands associated with the hydroxyl groups and on the carbonyl stretching regions. The latter has been interpreted in terms of contributions arising from a number of species, namely the heterocomplex, and free, dimeric and oligomeric acid species. This analysis reveals that the heterocomplexes formed by hydrogen bonding between the unlike species tend to be the dominant species but at all temperatures coexist in equilibria with acid monomers, dimers and oligomers. The hydrogen bond strength in the heterocomplexes is predicted by molecular modelling to be stronger than that in the acid dimers. The smectic behaviour of these mixtures is accounted for in terms of the stabilisation of the layered structures arising from hydrogen bonded catemer strands. The liquid crystal behaviour of these and similar hydrogen bonded liquid crystals, HBLCs, cannot be explained solely by the formation of the heterocomplex between the unlike species, but instead a more realistic view must take into account the presence and concentrations of various different supramolecular species and the interactions between them.

The synthesis and characterisation of four series of liquid crystal dimers based on benzylideneaniline mesogenic units, and in which the lengths of terminal alkyloxy chains are varied are reported. The series differ in terms of their flexible spacers, namely, heptamethylene, nonamethylene, hexyloxy, and oxypentyloxy chains. The heptamethylene- and nonamethylene-linked dimers both show conventional nematic, N, and twist-bend nematic, NTB, phases with short terminal chains, and smectic behaviour emerges on increasing terminal chain length. This is attributed to increased molecular inhomogeneity driving microphase separation. The dimers containing the shorter heptamethylene spacer show a smectic A phase whereas those with the longer nonamethylene spacer exhibit an anticlinic smectic C phase. Smectic behaviour is not observed for the dimers containing either a hexyloxy spacer which exhibit nematic and twist-bend nematic phases, or with an oxypentyloxy spacer which show only a conventional nematic phase. A general observation is that TNTBN and TNI alternate in the same sense in a homologous series on varying the length of the terminal alkyl chains suggesting that the spatial uniformity of the molecular curvature is an important factor in stabilising the NTB phase. The transitional properties of the four corresponding dimers possessing nitrile terminal substituents are also described. These show enantiotropic nematic phases, and in addition, for those containing either polymethylene or hexyloxy spacers, a twist-bend nematic phase is observed. Differences in the thermal behaviour of the dimers may be attributed largely to changes in molecular shape arising from the nature of the link between the spacer and mesogenic units.

The syntheses and characterisation of the first 10 homologues of the 1-(4-cyanobiphenyl-4′-yl)-6-(4-alkyloxyanilinebenzylidene-4′-oxy)hexanes (CB6O.Om) are reported. All 10 homologues exhibit nematic, N, and twist-bend nematic, NTB, phases. In addition, an intercalated, anticlinic smectic C, SmCA, phase is observed for m = 3–5. A second smectic phase is seen for m = 4,5 but for which no structural information was obtained. For short chain lengths, the local packing in the nematic phases is an intercalated arrangement. As the chain length increases monolayer fluctuations are observed in both nematic phases. The NTB-N and N-isotropic transition temperatures exhibit a weak odd-even effect as m is increased in which even members show the higher values. This behaviour is accounted for in terms of the change in shape anisotropy and the dilution of the interactions between the mesogenic units on increasing m. The N-I transition temperature falls faster than the NTB-N temperature on increasing m suggesting that the dilution of the interactions between the mesogenic groups has a smaller effect on the shape-driven NTB-N transition than on N-I. Increasing the terminal chain length does not strongly promote smectic behaviour for the CB6O.Om series. This is attributed to the difficulties associated with packing these bent molecules into smectic arrangements.

Background: Tau aggregation inhibitors could treat Alzheimer disease. Results: Stable reduced forms of leucomethylthioninium (LMTX®) are active in blocking prion-like Tau aggregation in novel cellular models. Conclusion: The intracellular Ki (0.12 μm) is comparable with brain levels required for clinical benefit. Significance: LMTX® could treat Alzheimer disease., Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 μm. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 μm. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 μm) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 μm) required to reverse behavioral deficits and pathology in Tau transgenic mice.

The phase behaviour of equimolar mixtures of 6-(4'-cyanobiphenyl-4-yl)hexyloxybenzoic acid (CB6OBA) with either 1-(4-butylazobenzene-4'-oxy)-5-(4-oxypyridine)pentane (BuABO5OPyr) or 1-(4-butylazobenzene-4'-oxy)-6-(4-oxypyridine)hexane (BuABO6OPyr) is reported. CB6OBA shows a monotropic twist-bend nematic phase and an enantiotropic nematic phase whereas the two pyridyl-based components do not exhibit liquid crystallinity. Both equimolar mixtures (CB6OBA/BuABOnOPyr) show enantiotropic nematic phases. The nematic-isotropic transition temperature and associated entropy change are higher for the CB6OBA/BuABO6OPyr mixture than for the CB6OBA/BuABO5OPyr mixture. This may be accounted for in terms of the average shapes of the hydrogen-bonded 1:1 complexes formed between the two differing components in the mixtures. However, Fourier transform infrared spectroscopy reveals that this complex is not formed quantitatively, but instead a complex mixture exists over the complete temperature range studied, involving the 1:1 complex, both cyclic and open acid dimers, free acid and hence, free BuABOnOPyr molecules.

Alzheimer's disease is characterised by the self-assembly of tau and amyloid I² proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into {PHFs} is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a {C322A} substitution. We show that disulphide bond formation inhibits assembly and that the {C322A} variant rapidly forms long and highly ordered PHFs.

The synthesis and characterisation of several members of the 1,ω-bis(4-cyanobiphenyl-4′-yl) alkane (CBnCB) and the 1-(4-cyanobiphenyl-4′-yloxy)-ω-(4-cyanobiphenyl-4′-yl) alkane (CBnOCB) homologous series are reported. The new odd members described CB5CB, CB13CB, CB4OCB, CB8OCB and CB10OCB all exhibit twist-bend nematic and nematic phases. The members of these series already reported in literature, CB7CB, CB9CB, CB11CB and CB6OCB, were also prepared in order to allow for a direct comparison of their transitional properties. The properties of these dimers are also compared to those of the corresponding members of the 1,ω-bis(4-cyanobiphenyl-4,-yloxy) alkanes (CBOnOCB). For any given total spacer length, for odd members of these series, the nematic–isotropic transition temperatures and associated entropy changes are greatest for the CBOnOCB dimer and lowest for the CBnCB dimer. These trends are understood in terms of molecular shape. For short spacer lengths, the twist-bend nematic–nematic transition temperature (TNTBN) is higher for the CBnOCB series than for the CBnCB series but this is reversed as the spacer length increases. Of the CBOnOCB dimers, a virtual value of TNTBN was estimated for CBO3OCB and TNTBN was measured for CBO5OCB. These values are considerably lower than those observed for the corresponding members of the CBnCB or CBnOCB series. The dependence of TNTBN on molecular structure is discussed not only in terms of the molecular curvature but also in the ability of the molecules to pack efficiently. As the temperature range of the preceding nematic phase increases, so the twist-bend nematic–nematic transition entropy change decreases and the transition approaches second order for the longer spacers. For comparative purposes, the transitional behaviour of the even-membered dimers CB6CB, CB5OCB and CBO4OCB is reported and differences accounted for in terms of molecular shape.

The synthesis and characterisation of two new sets of non-symmetric liquid crystal dimers is reported, the 1-(4-substitutedazobenzene-4′-yloxy)-6-(4-cyanobiphenyl-4′-yl)hexanes (CB6OABX) and 1-(4-substitutedazobenzene-4′-yloxy)-6-(4-cyanobiphenyl-4′-yloxy)pentanes (CBO5OABX). The terminal substituents are methyl, methoxy, butyl, butyloxy, nitrile and nitro. All the CB6OABX dimers exhibit twist-bend nematic (NTB) and nematic (N) phases. The CBO5OABX dimers also all show an N phase but only the butyl and butyloxy homologues exhibit the NTB phase. The transitional behaviour of the non-symmetric dimers is compared to that of the corresponding symmetric dimers, the 1,5-bis(4-substitutedazobenzene-4′-yloxy)pentanes (XABO5OABX) and either 1,7-bis(4-cyanobiphenyl-4′-yl)heptane or 1,5-bis(4-cyanobiphenyl-4′-yloxy)pentane. The XABO5OABX dimers all show a nematic phase and in addition, the butyl homologue exhibits a smectic A phase. The difference in transitional behaviour between the CB6OABX and CBO5OABX dimers is attributed to the difference in their molecular shapes arising from different bond angles between the para axis of the cyanobiphenyl unit and the first bond in the spacer. Specifically, the all-trans conformation of a CBO5OABX dimer is more linear than that of the corresponding CB6OABX dimer. Differences within each set of dimers are attributed to changes in the average molecular shape and the strength of the mixed mesogen interaction on varying the terminal group. Crystal structures are reported for CB6OABOMe, CBO5OABNO2 and MeOABO5OABOMe.

Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms. The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45. The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau–tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal–lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal–lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers. Methylthioninium chloride (MTC), the first identified tau aggregation inhibitor (TAI), offers an alternative to the amyloid approach. Phase 3 trials are underway with a novel stabilized reduced form of methylthioninium (LMTX) that has improved tolerability and absorption.

The synthesis and characterisation of the nonsymmetric liquid crystal dimer, 1-(4-cyanobiphenyl-4'-yloxy)-6-(4-cyanobiphenyl-4'-yl)hexane (CB6OCB) is reported. An enantiotropic nematic (N)-twist-bend nematic (NTB) phase transition is observed at 109 °C and a nematic-isotropic phase transition at 153 °C. The NTB phase assignment has been confirmed using polarised light microscopy, freeze fracture transmission electron microscopy (FFTEM), (2)H-NMR spectroscopy, and X-ray diffraction. The effective molecular length in both the NTB and N phases indicates a locally intercalated arrangement of the molecules, and the helicoidal pitch length in the NTB phase is estimated to be 8.9 nm. The surface anchoring properties of CB6OCB on a number of aligning layers is reported. A Landau model is applied to describe high-resolution heat capacity measurements in the vicinity of the NTB-N phase transition. Both the theory and heat capacity measurements agree with a very weak first-order phase transition. A complementary extended molecular field theory was found to be in suggestive accord with the (2)H-NMR studies of CB6OCB-d2, and those already known for CB7CB-d4. These include the reduced transition temperature, TNTBN/TNI, the order parameter of the mesogenic arms in the N phase close to the NTB-N transition, and the order parameter with respect to the helix axis which is related to the conical angle for the NTB phase.

The weak inter­molecular inter­actions in two indole derivatives are described., We describe the syntheses and crystal structures of two indole derivatives, namely a second monoclinic polymorph of ethyl 5-chloro-1H-indole-2-carboxyl­ate C11H10ClNO2, (I), and ethyl 5-chloro-3-iodo-1H-indole-2-carboxyl­ate, C11H9ClINO2, (II). In their crystal structures, both compounds form inversion dimers linked by pairs of N—H⋯O hydrogen bonds, which generate R 2 2(10) loops. The dimers are linked into double chains in (I) and sheets in (II) by a variety of weak inter­actions, including π–π stacking, C—I⋯π, C—Cl—π inter­actions and I⋯Cl halogen bonds.

In situ EPR spectroscopy at cryogenic temperatures is used to observe paramagnetic products formed when titania photocatalysts are irradiated with UV–visible light in the presence of reactant molecules. Irradiation in vacuo, in the absence of reactants, produces weak EPR signals of trapped holes (O−) and trapped electrons (Ti3+). When high photon fluxes are used, the intensities of the trapped electron signals are enhanced dramatically when irradiation is stopped. This process is completely reversible on restoring the irradiation, and is attributed to a trapping of EPR invisible conduction band electrons once irradiation is stopped. The trapped electrons are excited back into the conduction band when irradiation is resumed. In the presence of adsorbed organic compounds, products of valence band hole trapping by the organic molecules are detected. Methyl radicals are formed by attack of valence band holes on adsorbed acetic acid. The valence band holes are also able to cleave carbon–silicon bonds, forming methyl radicals from tetramethylsilane. Benzyltrimethylsilane derivatives form both methyl radicals and benzyl radicals through cleavage of all four carbon–silicon bonds. The relevance of these observations to photocatalysed organic reactions in which carbon–carbon bond formation occurs via radical intermediates is discussed.

In vitro measurements of particle filtration were made for nasal geometries of 11 infants aged 3–18 months. The geometries were obtained from computed tomography (CT) scans of seven males and four female infants and replicas were built using rapid prototyping. Particles ranging in aerodynamic diameter from 0.8 to 5.3 μ m were passed through these replicas with simulated tidal breathing. Filtration was determined from particle counts upstream and downstream of the models using an electrical low pressure impactor (ELPI). Mathematical fits were constructed to predict the measured deposition based on the relevant parameters. The fractional deposition, η , is found to depend on the Reynolds number of the flow ( Re ), the particle Stokes number ( Stk ), and an airway dimension D defined as airway volume divided by airway surface area. This dependence is well captured by the formula η = 1 - ( 2.164 * 10 5 / ( 2.164 * 10 5 + ( Re 1.118 Stk 1.057 ( D / D avg ) - 2.840 ) ) ) 0.8510 . Here, D avg is the average value of the dimension D for the group studied and is equal to 1.20 mm. Re and Stk also use the dimension D as the length scale in their definitions.

The crystal structures of four indole derivatives with various substituents at the 2-, 3- and 5-positions of the ring system are described. The dominant inter­molecular inter­action in each case is an N—H⋯O hydrogen bond, which generates either chains or inversion dimers. Weak C—H⋯O, C—H⋯π and π–π inter­actions occur in these structures but there is no consistent pattern amongst them. Two of these compounds act as modest enhancers of CB1 cannabanoid signalling and two are inactive., The crystal structures of four indole derivatives with various substituents at the 2-, 3- and 5-positions of the ring system are described, namely, ethyl 3-(5-chloro-2-phenyl-1H-indol-3-yl)-3-phenyl­propano­ate, C25H22ClNO2, (I), 2-bromo-3-(2-nitro-1-phenyl­eth­yl)-1H-indole, C16H13BrN2O2, (II), 5-meth­oxy-3-(2-nitro-1-phenyl­eth­yl)-2-phenyl-1H-indole, C23H20N2O3, (III), and 5-chloro-3-(2-nitro-1-phenyl­eth­yl)-2-phenyl-1H-indole, C22H17ClN2O2, (IV). The dominant inter­molecular inter­action in each case is an N—H⋯O hydrogen bond, which generates either chains or inversion dimers. Weak C—H⋯O, C—H⋯π and π–π inter­actions occur in these structures but there is no consistent pattern amongst them. Two of these compounds act as modest enhancers of CB1 cannabanoid signalling and two are inactive.

The syntheses and structures of two N-substituted thio-imidazoles are reported. The geometrical parameters for both compounds, including essentially planar imidazole rings, are consistent with previous structural studies of related materials. The only possible non-van der Waals’ interactions influencing the molecular packing are weak C–H⋯π bonds. Crystal data: C12H14N2S (N-methyl-N′-2-phenylethyl-imidazol-2-thione), M r = 218.31, monoclinic, P21/n, (No. 14), a = 6.8441(2) A, b = 12.9960(4) A, c = 13.4703(4) A, β = 97.7729(16)°, V = 1187.12(6) A3, Z = 4, R(F) = 0.039, wR(F 2) = 0.104. C19H20N2S (N,N′-bis((s)-1-phenylethyl)imidazol-2-thione), M r = 308.43, orthorhombic, P212121 (No. 19), a = 10.4060(3) A, b = 10.6712(3) A, c = 14.8932(3) A, V = 1653.81(7) A3, Z = 4, R(F) = 0.038, wR(F 2) = 0.085.

Methylthioninium (MT) is a tau aggregation inhibitor with therapeutic potential in Alzheimer's disease (AD). MT exists in equilibrium between reduced [leucomethylthioninium (LMT)] and oxidized (MT(+)) forms; as a chloride salt [methylthioninium chloride (MTC), "methylene blue"], it is stabilized in its MT(+) form. Although the results of a phase 2 study of MTC in 321 mild/moderate AD subjects identified a 138-mg MT/day dose as the minimum effective dose on cognitive and imaging end points, further clinical development of MT was delayed pending resolution of the unexpected lack of efficacy of the 228-mg MT/day dose. We hypothesized that the failure of dose response may depend on differences known at the time in dissolution in simulated gastric and intestinal fluids of the 100-mg MTC capsules used to deliver the 228-mg dose and reflect previously unsuspected differences in redox processing of MT at different levels in the gut. The synthesis of a novel chemical entity, LMTX (providing LMT in a stable anhydrous crystalline form), has enabled a systematic comparison of the pharmacokinetic properties of MTC and LMTX in preclinical and clinical studies. The quantity of MT released in water or gastric fluid within 60 minutes proved in retrospect to be an important determinant of clinical efficacy. A further factor was a dose-dependent limitation in the ability to absorb MT in the presence of food when delivered in the MT(+) form as MTC. A model is presented to account for the complexity of MT absorption, which may have relevance for other similar redox molecules.

The liquid crystalline phase behavior of 4-[6-(4'-cyanobiphenyl-4-yl)hexyloxy]benzoic acid (CB6OBA) and 4-[5-(4'-cyanobiphenyl-4-yloxy)pentyloxy]benzoic acid (CBO5OBA) is described. Both acids show an enantiotropic nematic phase attributed to the formation of supramolecular complexes by hydrogen bonding between the benzoic acid units. In addition, CB6OBA provides the first example of hydrogen bonding driving the formation of the twist-bend nematic phase. The observation of the twist-bend nematic phase for CB6OBA, but not CBO5OBA, is attributed to the more bent molecular shape of the complexes formed by the former, reinforcing the view that shape is a key factor in stabilizing this new phase. Temperature-dependent FTIR spectroscopy reveals differences in hydrogen bonding between the two nematic phases shown by CB6OBA which suggest that the open hydrogen-bonded complexes may play an important role in stabilizing the helical arrangement found in the twist-bend nematic phase.

The mol­ecule of the title compound, C21H16N2O, has crystallographic twofold rotation symmetry, with the C=O group lying on the rotation axis. Inter­molecular N—H⋯O hydrogen bonds result in a chain structure containing R21(6) loops. This ortho­rhom­bic structure probably represents a correction of a previous study where space group P21 was found [Kurth & Lewis (2003), J. Am. Chem. Soc. 125, 13760–13767].

The title compound, C13H15BrINO, contains two mol­ecules in the asymmetric unit which are linked into dimeric associations by way of very short C—I⋯O inter­actions [I⋯O = 2.998 (4) and 3.044 (4) A]. The cyclo­pentane rings of both mol­ecules are disordered; the site occupancy ratios are ca 0.54:0.46 and 0.59:0.41.

The crystal packing of the title compound, C7H5BrO4·H2O, is influenced by O—H...O hydrogen bonds.