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Introduction: Over the last few years, hypnotic and anxiolytic medications have had their clinical efficacy questioned in the context of concerns regarding dependence, tolerance alongside other adverse effects. It remains unclear how these concerns have impacted clinical prescribing practice. Materials and Methods: This is a study reviewing community-dispensed prescribing data for patients on the East Practice Medical Center list in Arbroath, Scotland, in 2007, 2011 and 2015. Anxiolytic and hypnotic medications were defined in accordance with the British National Formulary chapter 4.1.1 and chapter 4.1.2. All patients receiving a drug within this class in any of the study years were collated and anonymized using primary care prescribing data. The patients′ age, gender, name of the prescribed drug(s), and total number of prescriptions in this class over the year were extracted. Results: The proportion of patients prescribed a benzodiazepine medication decreased between 2007 and 2015: 83.8% (n = 109) in 2007, 70.5% (n = 122) in 2011, and 51.7% (n = 138) in 2015 (P = 0.006). The proportion of these patients prescribed a nonbenzodiazepine drug increased between 2007 and 2015: 30% (n = 39) in 2007, 46.2% (n = 80) in 2011, and 52.4% (n = 140) in 2015 (P = 0.001). There was a significant increase in the number of patients prescribed melatonin (P = 0.020). Discussion: This study reports a reduction in benzodiazepine prescriptions in primary care alongside increases in nonbenzodiazepine and melatonin prescribing, with an increase in prescribing rates of this drug class overall. Conclusion: Changes in this prescribing practice may reflect the medicalization of insomnia, local changes in prescribing practice and alongside national recommendations.

In spite of widespread interest in the unique size-dependent properties and consequent applications of gold nanoparticles (AuNPs), synthetic protocols that reliably allow for independent tuning of surface chemistry and core size, the two critical determinants of AuNP properties, remain limited. Often, core size is inherently affected by the ligand structure in an unpredictable fashion. Functionalized ligands are commonly introduced using postsynthesis exchange procedures, which can be inefficient and operationally delicate. Here, we report a one-step protocol for preparing monolayer-stabilized AuNPs that is compatible with a wide range of ligand functional groups and also allows for the systematic control of core size. In a single-phase reaction using the mild reducing agent tert -butylamine borane, AuNPs that are compatible with solvents spanning a wide range of polarities from toluene to water can be produced without damaging reactive chemical functionalities within the small-molecule surface-stabilizing ligands. We demonstrate that the rate of reduction, which is easily controlled by adjusting the period over which the reducing agent is added, is a simple parameter that can be used irrespective of the ligand structure to adjust the core size of AuNPs without broadening the size distribution. Core sizes in the range of 2-10 nm can thus be generated. The upper size limit appears to be determined by the nature of each specific ligand/solvent pairing. This protocol produces high quality, functionally sophisticated nanoparticles in a single step. By combining the ability to vary size-related nanoparticle properties with the option to incorporate reactive functional groups at the nanoparticle-solvent interface, it is possible to generate chemically reactive colloidal building blocks from which more complex nanoparticle-based devices and materials may subsequently be constructed., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Transient states maintained by energy dissipation are an essential feature of dynamic systems where structures and functions are regulated by fluxes of energy and matter through chemical reaction networks. Perfected in biology, chemically fueled dissipative networks incorporating nanoscale components allow the unique properties of nanomaterials to be bestowed with spatiotemporal adaptability and chemical responsiveness. We report the transient dispersion of gold nanoparticles in water, powered by dissipation of a chemical fuel. A dispersed state that is generated under non-equilibrium conditions permits fully reversible solid-liquid or liquid-liquid phase transfer. The molecular basis of the out-of-equilibrium process is reversible covalent modification of nanoparticle-bound ligands by a simple inorganic activator. Activator consumption by a coupled dissipative reaction network leads to autonomous cycling between phases. The out-of-equilibrium lifetime is tunable by adjusting the pH value, and reversible phase cycling is reproducible over several cycles., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The future of materials chemistry will be defined by our ability to precisely arrange components that have considerably larger dimensions and more complex compositions than conventional molecular or macromolecular building blocks. However, exerting structural and constitutional control in the assembly of nanoscale entities presents a considerable challenge. Dynamic covalent nanoparticles are emerging as an attractive category of reaction-enabled solution-processable nanosized building block through which the rational principles of molecular synthetic chemistry can be extended into the nanoscale. From a mixture of two hydrazone-based dynamic covalent nanoparticles with complementary reactivity, specific molecular instructions trigger selective assembly of intimately mixed heteromaterial (Au-Pd) aggregates or materials highly enriched in either one of the two core materials. In much the same way as complementary reactivity is exploited in synthetic molecular chemistry, chemospecific nanoparticle-bound reactions dictate building block connectivity; meanwhile, kinetic regioselectivity on the nanoscale regulates the detailed composition of the materials produced. Selectivity, and hence aggregate composition, is sensitive to several system parameters. By characterizing the nanoparticle-bound reactions in isolation, kinetic models of the multiscale assembly network can be constructed. Despite ignoring heterogeneous physical processes such as aggregation and precipitation, these simple kinetic models successfully link the underlying molecular events with the nanoscale assembly outcome, guiding rational optimization to maximize selectivity for each of the three assembly pathways. With such predictive construction strategies, we can anticipate that reaction-enabled nanoparticles can become fully incorporated in the lexicon of synthetic chemistry, ultimately establishing a synthetic science that manipulates molecular and nanoscale components with equal proficiency.

Emerging nanotechnologies demand the manipulation of nanoscale components with the same predictability and programmability as is taken for granted in molecular synthetic methodologies. Yet installing appropriately reactive chemical functionality on nanomaterial surfaces has previously entailed compromises in terms of reactivity scope, functionalization density, or both. Here, we introduce an idealized dynamic covalent nanoparticle building block for divergent and adaptive post-synthesis modification of colloidal nanomaterials. Acetal-protected monolayer-stabilized gold nanoparticles are prepared via operationally simple protocols and are stable to long-term storage. Tunable surface densities of reactive aldehyde functionalities are revealed on-demand, leading to a wide range of adaptive surface engineering options from one nanoscale synthon. Analytically tractable with molecular precision, interfacial reaction kinetics and dynamic surface constitutions can be probed in situ at the ensemble level. High functionalization densities combined with rapid equilibration kinetics enable environmentally adaptive surface constitutions and rapid nanoparticle property switching in response to simple chemical effectors., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The structures and physicochemical properties of surface-stabilizing molecules play a critical role in defining the properties, interactions, and functionality of hybrid nanomaterials such as monolayer-stabilized nanoparticles. Concurrently, the distinct surface-bound interfacial environment imposes very specific conditions on molecular reactivity and behavior in this setting. Our ability to probe hybrid nanoscale systems experimentally remains limited, yet understanding the consequences of surface confinement on molecular reactivity is crucial for enabling predictive nanoparticle synthon approaches for postsynthesis engineering of nanoparticle surface chemistry and construction of devices and materials from nanoparticle components. Here, we have undertaken an integrated experimental and computational study of the reaction kinetics for nanoparticle-bound hydrazones, which provide a prototypical platform for understanding chemical reactivity in a nanoconfined setting. Systematic variation of just one molecular-scale structural parameter-the distance between reactive site and nanoparticle surface-showed that the surface-bound reactivity is influenced by multiscale effects. Nanoparticle-bound reactions were tracked in situ using 19 F NMR spectroscopy, allowing direct comparison to the reactions of analogous substrates in bulk solution. The surface-confined reactions proceed more slowly than their solution-phase counterparts, and kinetic inhibition becomes more significant for reactive sites positioned closer to the nanoparticle surface. Molecular dynamics simulations allowed us to identify distinct supramolecular architectures and unexpected dynamic features of the surface-bound molecules that underpin the experimentally observed trends in reactivity. This study allows us to draw general conclusions regarding interlinked structural and dynamical features across several length scales that influence interfacial reactivity in monolayer-confined environments.

Nanoparticle-based devices, materials and technologies will demand a new era of synthetic chemistry where predictive principles familiar in the molecular regime are extended to nanoscale building blocks. Typical covalent strategies for modifying nanoparticle-bound species rely on kinetically controlled reactions optimised for efficiency but with limited capacity for selective and divergent access to a range of product constitutions. In this work, monolayer-stabilized nanoparticles displaying complementary dynamic covalent hydrazone exchange reactivity undergo distinct chemospecific transformations by selecting appropriate combinations of 'nucleophilic' or 'electrophilic' nanoparticle-bound monolayers with nucleophilic or electrophilic molecular modifiers. Thermodynamically governed reactions allow modulation of product compositions, spanning mixed-ligand monolayers to exhaustive exchange. High-density nanoparticle-stabilizing monolayers facilitate in situ reaction monitoring by quantitative 19 F NMR spectroscopy. Kinetic analysis reveals that hydrazone exchange rates are moderately diminished by surface confinement, and that the magnitude of this effect is dependent on mechanistic details: surface-bound electrophiles react intrinsically faster, but are more significantly affected by surface immobilization than nucleophiles. Complementary nanoparticles react with each other to form robust covalently connected binary aggregates. Endowed with the adaptive characteristics of the dynamic covalent linking process, the nanoscale assemblies can be tuned from extended aggregates to colloidally stable clusters of equilibrium sizes that depend on the concentration of a monofunctional capping agent. Just two 'dynamic covalent nanoparticles' with complementary thermodynamically governed reactivities therefore institute a programmable toolkit offering flexible control over nanoparticle surface functionalization, and construction of adaptive assemblies that selectively combine several nanoscale building blocks., (This journal is © The Royal Society of Chemistry 2020.)

Despite extensive advances in the field of molecular recognition, the real-time monitoring of small molecule binding to nanoparticles (NP) remains a challenge. To this end, we report on a versatile approach, based on quartz crystal microbalance with dissipation monitoring, for the stepwise in situ quantification of gold nanoparticle (AuNPs) immobilisation and subsequent uptake and release of binding partners. AuNPs stabilised by thiol-bound ligand shells of prescribed chemical composition were densely immobilised onto gold surfaces via dithiol linkers. The boronate ester formation between salicylic acid derivatives in solution and boronic acids in the AuNP ligand shell was then studied in real time, revealing a drastic effect of both ligand architecture and Lewis base concentration on the interaction strength. The binding kinetics were analysed with frequency response modelling for a thorough comparison of binding parameters including relaxation time as well as association rate constant. The results directly mirror those from previously reported in-depth studies using nuclear magnetic resonance spectroscopy. By achieving quantitative characterisation of selective binding of analytes with molecular weight below 300 Da, this new method enables rapid, low cost, rational screening of AuNP candidates for molecular recognition.

Surface chemical composition is fundamental to determining properties on the nanoscale, making precise control over surface chemistry critical to being able to optimise nanomaterials for virtually any application. Surface-engineering independent of the preparation of the underlying nanomaterial is particularly attractive for efficient, divergent synthetic strategies, and for the potential to create reactive, responsive and smart nanodevices. For monolayer-stabilised nanoparticles, established methods include ligand exchange to replace the ligand shell in its entirety, encapsulation with amphiphilic (macro)molecules, noncovalent interactions with surface-bound biomolecules, or a relatively limited number of covalent bond forming reactions. Yet, each of these approaches has considerable drawbacks. Here we show that dynamic covalent exchange at the periphery of the nanoparticle-stabilizing monolayer allows surface-bound ligand molecular structure to be substantially modified in mild and reversible processes that are independent of the nanoparticle-molecule interface. Simple stoichiometric variation allows the extent of exchange to be controlled, generating a range of kinetically stable mixed-monolayer compositions across an otherwise identical, self-consistent series of nanoparticles. This approach can be used to modulate nanoparticle properties that are defined by the monolayer composition. We demonstrate switching of nanoparticle solvent compatibility between widely differing solvents - spanning hexane to water - and the ability to tune solubility across the entire continuum between these extremes, all from a single nanoparticle starting point. We also demonstrate that fine control over mixed-monolayer composition influences the assembly of discrete, colloidally stable nanoparticle clusters. By carefully assessing monolayer composition in each state, using both in situ and ex situ methods, we are able to correlate the molecular-level details of the nanoparticle-bound monolayer with system-level properties and behaviour. These empirically determined relationships contribute fundamental insights on nanoscale structure-function relationships, which are currently beyond the capabilities of ab initio prediction.

Rational and generalisable methods for engineering surface functionality will be crucial to realising the technological potential of nanomaterials. Nanoparticle-bound dynamic covalent exchange combines the error-correcting and environment-responsive features of equilibrium processes with the stability, structural precision, and vast diversity of covalent chemistry, defining a new and powerful approach for manipulating structure, function and properties at nanomaterial surfaces. Dynamic covalent nanoparticle (DCNP) building blocks thus present a whole host of possibilities for constructing adaptive systems, devices and materials that incorporate both nanoscale and molecular functional components. At the same time, DCNPs have the potential to reveal fundamental insights regarding dynamic and complex chemical systems confined to nanoscale interfaces., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

The quantitative assembly and disassembly of a new type of dynamic covalent nanoparticle (NP) building block is reported. In situ spectroscopic characterization reveals constitutionally adaptive NP-bound monolayers of boronate esters. Ditopic linker molecules are used to produce covalently connected AuNP assemblies, displaying open dendritic morphologies, and which, despite being linked by covalent bonds, can be fully disassembled on application of an appropriate chemical stimulus.

A [2]rotaxane, a [3]rotaxane and the corresponding thread containing two succinamide (succ) binding stations and a central redox-active pyromellitimide (pmi) station were studied. Infrared spectroelectrochemical experiments revealed the translocation of the macrocycle between the succinamide station and the electrochemically reduced pmi station (radical anion and dianion). Remarkably, in the [3]rotaxane, the rings can be selectively translocated. One-electron reduction leads to the translocation of one of the two macrocycles from the succinamide to the pyromellitimide station, whereas activation of the shuttle through two-electron reduction results in the translocation of both macrocycles: the dianion, due to its higher electron density and hence greater hydrogen-bond accepting affinity, is hydrogen bonded to both macrocycles. Systems with such an on-command contraction are known as molecular muscles. The relative strengths of the binding between the macrocycle and the imide anions could be estimated from the hydrogen-bond-induced shifts in the C=O stretching frequencies of hydrogen-bond accepting amide groups of the macrocycle., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We demonstrate a straightforward nonbiomolecular approach for self-assembly of binary NP planet-satellite superstructures, which display remarkable colloidal and structural stability under variations in temperature, pH, ionic strength and solvent. The readily scalable process produces highly homogeneous samples and is tolerant to variations in building block size and shape, giving rapid access to a structurally diverse range of robust binary NP assemblies.

Existing methods for the covalent functionalization of nanoparticles rely on kinetically controlled reactions, and largely lack the sophistication of the preeminent oligonucleotide-based noncovalent strategies. Here we report the application of dynamic covalent chemistry for the reversible modification of nanoparticle (NP) surface functionality, combining the benefits of non-biomolecular covalent chemistry with the favorable features of equilibrium processes. A homogeneous monolayer of nanoparticle-bound hydrazones can undergo quantitative dynamic covalent exchange. The pseudomolecular nature of the NP system allows for the in situ characterization of surface-bound species, and real-time tracking of the exchange reactions. Furthermore, dynamic covalent exchange offers a simple approach for reversibly switching-and subtly tuning-NP properties such as solvophilicity.

The mechanical behaviour of molecular machines differs greatly from that of their macroscopic counterparts. This applies particularly when considering concepts such as friction and lubrication, which are key to optimizing the operation of macroscopic machinery. Here, using time-resolved vibrational spectroscopy and NMR-lineshape analysis, we show that for molecular machinery consisting of hydrogen-bonded components the relative motion of the components is accelerated strongly by adding small amounts of water. The translation of a macrocycle along a thread and the rotation of a molecular wheel around an axle both accelerate significantly on the addition of water, whereas other protic liquids have much weaker or opposite effects. We tentatively assign the superior accelerating effect of water to its ability to form a three-dimensional hydrogen-bond network between the moving parts of the molecular machine. These results may indicate a more general phenomenon that helps explain the function of water as the 'lubricant of life'.

Rotaxane molecular shuttles were studied in which a tetralactam macrocyclic ring moves between a succinamide station and a second station in which the structure is varied. Station 2 in all cases is an aromatic imide, which is a poor hydrogen-bond acceptor in the neutral form, but a strong one when reduced with one or two electrons. When the charge density on the hydrogen-bond-accepting carbonyl groups in station 2 is reduced by changing a naphthalimide into a naphthalene diimide radical anion, the shuttling rate changes only slightly. When station 2 is a pyromellitimide radical anion, however, the shuttling rate is significantly reduced. This implies that the shuttling rate is not only determined by the initial unbinding of the ring from the first station, as previously supposed. An alternative reaction mechanism is proposed in which the ring binds to both stations in the transition state., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Time-resolved vibrational spectroscopy is used to investigate the inter-component motion of an ultraviolet-triggered two-station molecular shuttle. The operation cycle of this molecular shuttle involves several intermediate species, which are observable in the amide I and amide II regions of the mid-IR spectrum. Using ab initio calculations on specific parts of the rotaxane, and by comparing the transient spectra of the normal rotaxane with that of the N-deuterated version, we can assign the observed vibrational modes of each species occurring during the shuttling cycle in an unambiguous way. The complete time- and frequency-dependent data set is analyzed using singular value decomposition (SVD). Using a kinetic model to describe the time-dependent concentrations of the transient species, we derive the absorption spectra associated with each stage in the operation cycle of the molecular shuttle, including the recombination of the charged species.

High-resolution IR spectroscopy has been employed to study isolated, switchable [2]rotaxanes. IR absorption spectra of two-station rotaxanes, their separate thread, and macrocycle components, as well as those of the individual stations incorporated into the thread, have been measured in the 1800-1000 cm(-1) region. These spectra have been fully analyzed, aided by quantum chemical predictions of the IR spectra. From these analyses, a comprehensive picture emerges of the conformational structure and binding interactions between the mechanically interlocked components of the rotaxane., (© 2011 American Chemical Society)

The first experiments on trapped rotaxanes are presented, combining collision induced fragmentation and in-trap laser spectroscopy. The intrinsic optical properties of three rotaxanes and their non-interlocked building blocks (thread and macrocycle) isolated in a quadrupolar ion trap are investigated. The excitation and relaxation processes under thermal activation as well as under photo-activation are addressed. The light and collision induced fragmentation pathways show that the degradation mechanisms occurring in the rotaxane are highly dependent on the nature of the thread. In the prospective of operating photoswitchable molecules, photo-activation is achieved in a controlled way by depositing photo-energy in the desired sub-unit of a mechanically interlocked structure.

Rotaxanes comprise macrocycles that can shuttle between docking stations along an axle. We explored the nanosecond shuttling mechanism by reversing the relative binding affinities of two stations through ultraviolet-induced transient reduction. We monitored the ensuing changes in the CO-stretching bands of the two stations and the shuttling macrocycle by means of an infrared probing pulse. Because hydrogen-bond scission and formation at the initial and final stations led to well-resolved changes in the respective CO-stretch frequencies, the departure and arrival of the macrocycle could be observed separately. We found that the shuttling involves two steps: thermally driven escape from the initial station, followed by rapid motion along the track ending either at the initial or final station. By varying the track's length, we found that the rapid motion approximates a biased one-dimensional random walk. However, surprisingly, the direction of the overall motion is opposite that of the bias.

It has recently become possible to synthesize mechanical devices the size of a single molecule. Although it is tempting to regard such molecular machines as nanoscale versions of their macroscopic analogs, many notions from macroscopic mechanics no longer apply at a molecular level. For instance, the concept of viscous friction is meaningless for a molecular machine because the size of the solvent molecules that cause the friction is comparable to that of the machine itself. Furthermore, in many cases, the interactions between a molecular machine and its surroundings are comparable to the force driving the machine. As a result, a certain amount of intrinsic randomness exists in the motion of molecular machines, and the details of their mechanics are largely unknown. For a detailed understanding of the mechanical behavior of molecular machines, experiments that probe their motion on an ultrafast time scale, such as two-dimensional (2D) vibrational spectroscopy, are essential. This method uses coupling between vibrational modes in a molecule to investigate the molecular conformation. The coupling shows up as off-diagonal peaks in a 2D graph of the vibrational response of the molecule, analogous to the spin coupling observed in multidimensional NMR spectroscopy. Both spin coupling and vibrational coupling are sensitive probes of the molecular conformation, but 2D vibrational spectroscopy shows orders of magnitude better time resolution than NMR. In this Account, we use 2D vibrational spectroscopy to study molecular machines based on rotaxanes. These devices consist of a linear thread and a macrocycle that is noncovalently locked onto the thread. In the rotaxanes we study, the macrocycle and the thread both contain CO and NH groups. By determining the coupling between the stretching modes of these goups from the cross peaks in the 2D spectrum, we directly and quantitatively probe the relative position and orientation of the macrocycle and the thread for both a small model rotaxane and a rotaxane-based molecular shuttle. Our results demonstrate the feasibility of using time-resolved 2D-IR experiments to measure externally triggered structural changes of molecular devices with subpicosecond time resolution. We can observe each of the elementary events that underlie the mechanical motion separately. With this ability to investigate the nature of the mechanical motions at the molecular level and with unprecedented time resolution, we expect that 2D-IR spectroscopy on molecular machines will lead to new insights into their function.

Although the desirability of developing synthetic molecular machine systems that can function on surfaces is widely recognized, to date the only well-characterized examples of electrochemically switchable rotaxane-based molecular shuttles which can do so are based on the tetracationic viologen macrocycle pioneered by Stoddart. Here, we report on a [2]rotaxane which features succinamide and naphthalene diimide hydrogen-bonding stations for a benzylic amide macrocycle that can shuttle and switch its net position both in solution and in a monolayer. Three oxidation states of the naphthalene diimide unit can be accessed electrochemically in solution, each one with a different binding affinity for the macrocycle and, hence, corresponding to a different distribution of the rings between the two stations in the molecular shuttle. Cyclic voltammetry experiments show the switching to be both reversible and cyclable and allow quantification of the translational isomer ratios (thermodynamics) and shuttling dynamics (kinetics) for their interconversion in each state. Overall, the binding affinity of the naphthalene diimide station can be changed by 6 orders of magnitude over the three states. Unlike previous electrochemically active amide-based molecular shuttles, the reduction potential of the naphthalene diimide unit is sufficiently positive (-0.68 V) for the process to be compatible with operation in self-assembled monolayers on gold. Incorporating pyridine units into the macrocycle allowed attachment of the shuttles to an acid-terminated self-assembled monolayer of alkane thiols on gold. The molecular shuttle monolayers were characterized by X-ray photoelectron spectroscopy and their electrochemical behavior probed by electrochemical impedance spectroscopy and double-potential step chronoamperometry, which demonstrated that the redox-switched shuttling was maintained in this environment, occurring on the millisecond time scale.

Motor proteins and other biological machines are highly efficient at converting energy into directed motion and driving chemical systems away from thermodynamic equilibrium. But even though these biological structures have inspired the design of many molecules that mimic aspects of their behaviour, artificial nanomachine systems operate almost exclusively by moving towards thermodynamic equilibrium, not away from it. Here we show that information about the location of a macrocycle in a rotaxane-a molecular ring threaded onto a molecular axle-can be used, on the input of light energy, to alter the kinetics of the shuttling of the macrocycle between two compartments on the axle. For an ensemble of such molecular machines, the macrocycle distribution is directionally driven away from its equilibrium value without ever changing the relative binding affinities of the ring for the different parts of the axle. The selective transport of particles between two compartments by brownian motion in this way bears similarities to the hypothetical task performed without an energy input by a 'demon' in Maxwell's famous thought experiment. Our observations demonstrate that synthetic molecular machines can operate by an information ratchet mechanism, in which knowledge of a particle's position is used to control its transport away from equilibrium.

The widespread use of controlled molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular systems, which by and large rely upon electronic and chemical effects to carry out their functions, and the machines of the macroscopic world, which utilize the synchronized movements of smaller parts to perform specific tasks. This is a scientific area of great contemporary interest and extraordinary recent growth, yet the notion of molecular-level machines dates back to a time when the ideas surrounding the statistical nature of matter and the laws of thermodynamics were first being formulated. Here we outline the exciting successes in taming molecular-level movement thus far, the underlying principles that all experimental designs must follow, and the early progress made towards utilizing synthetic molecular structures to perform tasks using mechanical motion. We also highlight some of the issues and challenges that still need to be overcome.

Here we correlate chemical (covalent), physical (thermodynamic), and statistical (population distribution) descriptions of behavior with the way that two new types of simple molecular machines (the threads of rotaxanes) perform the task of transporting a Brownian substrate (the rotaxane macrocycle) between two distinguishable binding sites. The first machine-substrate ensemble is a [2]rotaxane that operates through a mechanism that intrinsically causes it to change the average position of the macrocycle irreversibly. This contrasts with the behavior of classic stimuli-responsive molecular shuttles that act as reversible molecular switches. The second system is a compartmentalized molecular machine that is able to pump its substrate energetically uphill using the energy provided by a photon by means of an olefin photoisomerization. Resetting this compartmentalized molecular machine does not undo the work it has carried out or the task performed, a significant difference to a simple molecular switch and a characteristic we recognize as "ratcheting" (see Scheme 8). The ratcheting mechanism allows the [2]rotaxane to carry out the transport function envisaged for the historical thought-machines, Smoluchowski's Trapdoor and Maxwell's Pressure Demon, albeit via an unrelated mechanism and using an input of energy. We define and exemplify the terms "ratcheting" and "escapement" in mechanical terms for the molecular level and outline the fundamental phenomenological differences that exist between what constitutes a two-state Brownian switch, a two-state Brownian memory or "flip-flop", and a (two-stroke) Brownian motor. We also suggest that considering the relationship between the parts of a molecular machine and a substrate in terms of "statistical balance" and "linkage" could be useful in the design of more complex systems and in helping to understand the role of individual amino acids and peptide fragments during the directional transport of substrates by biological pumps and motors.

Thin films of fumaramide [2]rotaxane, a mechanically interlocked molecule composed of a macrocycle and a thread in a "bead and thread" configuration, were prepared by vapor deposition on both Ag(111) and Au(111) substrates. X-ray photoelectron spectroscopy (XPS) and high-resolution electron-energy-loss spectroscopy were used to characterize monolayer and bulklike multilayer films. XPS determination of the relative amounts of carbon, nitrogen, and oxygen indicates that the molecule adsorbs intact. On both metal surfaces, molecules in the first adsorbed layer show an additional component in the C 1s XPS line attributed to chemisorption via amide groups. Molecular-dynamics simulation indicates that the molecule orients two of its eight phenyl rings, one from the macrocycle and one from the thread, in a parallel bonding geometry with respect to the metal surfaces, leaving three amide groups very close to the substrate. In the case of fumaramide [2]rotaxane adsorption on Au(111), the presence of certain out-of-plane phenyl ring and Au-O vibrational modes points to such bonding and a preferential molecular orientation. The theoretical and experimental results imply that the three-dimensional intermolecular configuration permits chemisorption at low coverage to be driven by interactions between the three amide functions of fumaramide [2]rotaxane and the Ag(111) or Au(111) surface.

The circumrotation of a submolecular fragment in either direction in a synthetic molecular structure is described. The movement of a small ring around a larger one occurs through positional displacements arising from biased Brownian motion that are kinetically captured and then directionally released. The sense of rotation is governed solely by the order in which a series of orthogonal chemical transformations is performed. The minimalist nature of the [2]catenane flashing ratchet design permits certain mechanistic comparisons with the Smoluchowski-Feynman ratchet and pawl. Even when no work has to be done against an opposing force and no net energy is used to power the motion, a finite conversion of energy is intrinsically required for the molecular motor to undergo directional rotation. Nondirectional rotation has no such requirement.

A series of [2]rotaxanes containing succinamide and naphthalimide hydrogen-bonding stations for a benzylic amide macrocycle is described. Electrochemical reduction and oxidation of the naphthalimide group alters its ability to form hydrogen bonds to the macrocycle to such a degree that redox processes can be used to switch the relative macrocycle-binding affinities of the two stations in a rotaxane by over 8 orders of magnitude. The structure of the neutral [2]rotaxane in solution is established by (1)H NMR spectroscopy and shows that the macrocycle exhibits remarkable positional integrity for the succinamide station in a variety of solvents. Cyclic voltammetry experiments allow the simultaneous stimulation and observation of a redox-induced dynamic process in the rotaxane which is both reversible and cyclable. Model compounds in which various conformational and co-conformational changes are prohibited demonstrate unequivocally that the redox response is the result of shuttling of the macrocycle between the two stations. At room temperature in tetrahydrofuran the electrochemically induced movement of the macrocycle between the two stations takes approximately 50 micros.

Ehrlich ascites cells were grown in mice and were isolated by centrifugation of the ascites fluid. The cells were lysed with distilled water, and the floating fat particles were collected by centrifugation. The particles contained about 90% neutral and 10% polar lipid. The neutral lipid was made up of about 50% triacylglycerol, 30% alkyldiacylglycerol, 3% cholesteryl esters, 3% free cholesterol and 4% free diacylglycerols. The phospholipid fraction was comprised of about 50% phosphatidylcholine, 35% phosphatidylethanolamine, 10% sphingomyelin and small amounts (less than 5% total) of serine and/or inositol phosphatides. The triacylglycerol and alkyldiacylglycerol fractions possessed total carbon number and fatty acid compositions closely similar to those reported in the literature for whole ascites cells and for a cell membrane preparation. Likewise, the fatty acid composition of phospholipids from the granules in general was similar to that reported for Ehrlich ascites cells. On the basis of the polar and neutral lipid ratio, the lipid granules of the ascites cells were calculated to possess lipid core diameters of 30-50 nm, which were 40-70 times smaller than those (up to 2 mu) measured for the lipid granules of the intact cells by electron microscopy. The characterization of the lipid composition of the Ehrlich ascites lipid granules was completed by determining the molecular species composition of the diacyl, alkylacyl and alkenylacyl phosphatidylethanolamines and of the diacyl and alkylacyl phosphatidylcholines of the ascites cells. It is concluded that the alkyldiacylglycerols of the Ehrlich ascites cells occur largely in the cytoplasmic lipid granules, which appear to consist of many particles of the size and structure of very low density lipoproteins enclosed in membranous sacs.

1. The significance of the term nucleolus has been discussed. 2. A detailed method for the isolation of nucleoli from already isolated rat or cat liver nuclei has been presented. 3. The presence of DNA in isolated liver cell nucleoli has been indicated by histochemical methods. 4. The percentages of DNA and RNA in the isolated nucleoli have been determined by chemical analysis. 5. The specific activities of aldolase, arginase, and catalase have been determined for two subnuclear fractions and for the isolated nucleoli of rat and cat liver, and the relative amounts of these enzymes in the same subnuclear fractions and nucleoli of rat liver have been measured. 6. The significance of the above findings has been discussed and consideration has been given to what types of isolated nuclei might best serve as starting material for the isolation of nucleoli. 7. A new hypothesis has been presented that nucleoli of the liver cell type may function primarily in furnishing (directly or indirectly) templates for the synthesis of the particular enzymes that must govern the chemistry of mitosis.

1. The nuclei of cells from the thymus of the calf were isolated by three different techniques; the citric acid, the sucrose-calcium chloride, and the non-aqueous. 2. The mean dry weights of the nuclei were determined by chemical methods and by microscopic interferometry. There was a close correlation between the results from the interferometric and chemical methods. 3. The range of values about that mean was determined in each sample: the nuclei isolated in aqueous media contained approximately 45 per cent less material than those isolated in non-aqueous media. 4. The variations in dry weight with varying nuclear type are discussed. 5. The possible relationship between DNA content and dry weight is discussed.