Par-delà la synthèse : l’auto-organisation

The evolution of the universe from the particle to the thinking organism has taken place through self-organization. Chemistry has a major role to play in understanding these processes leading to the generation of complex matter. Chemistry has developed a highly powerful molecular synthetic chemistry, mastering the combination and recombination of atoms into increasingly complex molecules through selective chemical reactions. Supramolecular chemistry is harnessing intermolecular forces for the generation of informed supramolecular systems and processes through supramolecular synthetic chemistry implementing molecular information carried by electromagnetic interactions. Supramolecular chemistry has been actively exploring systems undergoing self-organization, i.e., systems capable of spontaneously generating well-defined functional supramolecular architectures by self-assembly from their components, under the control of interactional molecular recognition events, thus behaving as programmed chemical systems. Molecular chemistry may similarly take advantage of the selectivity of covalent reactions to assemble complex molecular architectures through self-organization processes implementing functional molecular recognition. Supramolecular/non-covalent and molecular/covalent SELF-ORGANIZATION may thus be considered as the ULTIMATE SYNTHETIC CHEMISTRY, whereby chemical objects at both levels are generated on the basis of recognition processes involving either interactional or reactional features. Illustrations from the supramolecular domain will serve as illustrations. Supramolecular entities as well as molecules containing reversible bonds are able to undergo a continuous change in constitution by reorganization and exchange of building blocks. This capability defines a Constitutional Dynamic Chemistry (CDC) on both the molecular and supramolecular levels. CDC introduces a paradigm shift with respect to constitutionally static chemistry. It takes advantage of dynamic constitutional diversity to allow variation and selection and thus leads towards the emergence of adaptive and evolutive chemistry.     

An N‐Heterocyclic Carbene with a Saturated Backbone and Spatially‐Defined Steric Impact

The synthesis and coordination chemistry of a saturated analogue of a “bulky‐yet‐flexible” N‐heterocyclic carbene (NHC) ligand are described. “SIPaul” is a 4,5‐dihydroimidazol‐2‐ylidene ligand with unsymmetrical aryl N‐substituents, and is one of the growing class of “bulky‐yet‐flexible” NHCs that are sufficiently bulky to stabilize catalytic intermediates, but sufficiently flexible that they do not inhibit productive chemistry at the central metal atom. Here, the synthesis of SIPaul.HCl and its complexes with copper, silver, iridium, palladium, and nickel, and its selenourea, are reported. The steric impact of the ligand is quantified using percent buried volume (% V_bur), whereas the electronic properties are probed and quantified using the Tolman Electronic Parameter (TEP) and δ_Se of the corresponding selenourea. This work shows that despite the often very different performance of saturated versus unsaturated carbenes in catalysis, the effect of backbone saturation on measurable properties is very small.     

Applications of Pillar[n]arene‐Based Supramolecular Assemblies

Macrocycles are an important player in supramolecular chemistry. In 2008, a new class of macrocycles, “pillar[n]arenes”, were first discovered. Research efforts in the area of pillar[n]arenes have elucidated key properties, such as their shape, reaction mechanism, host–guest properties, and their versatile functionality, which has contributed to the development of pillar[n]arene chemistry and their applications to various fields. This Minireview describes how pillar[n]arene‐based supramolecular assemblies can be applied to supramolecular gel formation, reactions, light‐harvesting systems, drug‐delivery systems, biochemical applications, separation and storage materials, and surface chemistry.     

Dynamic Covalent Organocatalysts Discovered from Catalytic Systems through Rapid Deconvolution Screening

The first example of a bifunctional organocatalyst assembled through dynamic covalent chemistry (DCC) is described. The catalyst is based on reversible imine chemistry and can catalyze the Morita–Baylis–Hillman (MBH) reaction of enones with aldehydes or N‐tosyl imines. Furthermore, these dynamic catalysts were shown to be optimizable through a systemic screening approach, in which large mixtures of catalyst structures were generated, and the optimal catalyst could be directly identified by using dynamic deconvolution. This strategy allowed one‐pot synthesis and in situ evaluation of several potential catalysts without the need to separate, characterize, and purify each individual structure. The systems were furthermore shown to catalyze and re‐equilibrate their own formation through a previously unknown thiourea‐catalyzed transimination process.     

Five Decades Ago: From the “Transuranics” to Nuclear Fission

The discovery of nuclear fission is one of the most outstanding episodes in the history of chemistry: It starts in the spring of 1934 when Enrico Fermi and his group irradiate uranium with neutrons and seem to succeed in going beyond uranium, the then heaviest known element, reaching the first transuranic element; it continues with Otto Hahn, Lise Meitner and Fritz Strassmann who believe to have found additional transuranic elements; with Irène Curie and Paul Savitch who observe an activity which somehow does not fit into that scheme; again with Otto Hahn and Fritz Strassmann who first identify this activity as radium but then on the 17th of December 1938 after rigorous chemical tests realize that the activity is instead barium, thus discovering the fission of the uranium atom into two lighter nuclei; and with Lise Meitner and Otto Robert Frisch who explain nuclear fission on the basis of an already known nuclear model; Otto Robert Frisch finally performs a physical experiment on the 13th of January 1939 which corroborates the fission of uranium. This discovery of nuclear fission is not only an event of historic dimensions, it is also an excellent example of how science evolves, not by successive logical steps but rather through strange detours.     

Exploring the Potential Energy Surface of E2P4 Clusters (E=Group 13 Element): The Quest for Inverse Carbon‐Free Sandwiches

Inverse carbon‐free sandwich structures with formula E₂P₄ (E=Al, Ga, In, Tl) have been proposed as a promising new target in main‐group chemistry. Our computational exploration of their corresponding potential‐energy surfaces at the S12h/TZ2P level shows that indeed stable carbon‐free inverse‐sandwiches can be obtained if one chooses an appropriate Group 13 element for E. The boron analogue B₂P₄ does not form the D_4h‐symmetric inverse‐sandwich structure, but instead prefers a D_2d structure of two perpendicular BP₂ units with the formation of a double B?B bond. For the other elements of Group 13, Al–Tl, the most favorable isomer is the D_4h inverse‐sandwich structure. The preference for the D_2d isomer for B₂P₄ and D_4h for their heavier analogues has been rationalized in terms of an isomerization‐energy decomposition analysis, and further corroborated by determination of aromaticity of these species.     

Complexation equilibria involving salts in non-aqueous solvents: ion pairing and activity considerations

Complexation of anions, cations and even ion pairs is now an active area of investigation in supramolecular chemistry; unfortunately it is an area fraught with complications when these processes are examined in low polarity organic media. Using a pseudorotaxane complex as an example, apparent K_a2 values (=[complex]/{[salt]_o?[complex]}{[host]_o?[complex]}) for pseudorotaxane formation from dibenzylammonium salts ( 2 ‐X) and dibenzo‐[24]crown‐8 ( 1 , DB24C8) in CDCl₃/CD₃CN 3:2 vary with concentration. This is attributable to the fact that the salt is ion paired, but the complex is not. We report an equilibrium model that explicitly includes ion pair dissociation and is based upon activities rather than molar concentrations for study of such processes in non‐aqueous media. Proper analysis requires both a dissociation constant, K_ipd, for the salt and a binding constant for interaction of the free cation 2 ⁺ with the host, K_a5; K_a5 for pseudorotaxane complexation is independent of the counterion (500 M ^?1), a result of the complex existing in solution as a free cation, but K_ipd values for the salts vary by nearly two orders of magnitude from trifluoroacetate to tosylate to tetrafluoroborate to hexafluorophosphate anions. The activity coefficients depend on the nature of the predominant ions present, whether the pseudorotaxane or the ions from the salt, and also strongly on the molar concentrations; activity coefficients as low as 0.2 are observed, emphasizing the magnitude of their effect. Based on this type of analysis, a method for precise determination of relative binding constants, K_a5, for multiple hosts with a given guest is described. However, while the incorporation of activity coefficients is clearly necessary, it removes the ability to predict from the equilibrium constants the effects of concentration on the extent of binding, which can only be determined experimentally. This has serious implications for study of all such complexation processes in low polarity media.     

Chemical Ecology—A Chapter of Modern Natural Products Chemistry

The chemical reaction of arthropods to their environment, i.e. their chemical ecology, can be studied particularly well with water beetles. Stenus comma, an aquatic beetle weighing only 2.5 mg, saves itself from drowning with the aid of an alkaloid, and the water beetle Ilybius fenestratus defends itself against small mammalian predators with a compound belonging to the same class. The water beetle Platambus maculatus employs a diterpene for precisely the same purpose and the whirligig beetle a norsesquiterpene, which also offers protection against troublesome microorganisms. As chemical artists, the ants can hardly be surpassed. In particular, the myrmecine ants guarantee their food supplies with plant growth substances. Since these compounds, depending upon concentration, can also act as inhibitors, we are confronted with an excellent example of an ecological equilibrium being established with the aid of organic chemicals. Even the little parasitic bombardier beetle Paussus favieri is tolerated, on account of its defensive chemistry, in the nest of the myrmecine ant Pheidole. In contrast, inorganic compounds are largely responsible for the stability of spiders' webs.     

A Hundred Years of Stereochemistry—The Principal Development Phases in Retrospect

The theory of the arrangement of atoms in space was initiated in 1874 by van't Hoff and Le Bel. The starting points were mainly in the fields of structural chemistry and optical activity. After early difficulties, stereochemistry gained acceptance in the last quarter of the 19th century and led to many interesting investigations and discoveries: the investigation of geometrical isomerism, the Baeyer strain theory, the stereochemistry of nitrogen, the determination of the configurations of carbohydrates, Walden inversion, and the beginning of inorganic stereochemistry all fall in this period. Theoretical verification of the principal stereochemical hypotheses and the exact determination of the steric arrangement of atoms by physical methods were achieved only in the 20th century.     

Catalytic activity of water molecules in gas-phase glycine dimerization

The dimerization of glycine is the simplest oligomerization of amino acids and plays an important role in biology. Although this reaction is thermodynamically unfavorable in the aqueous phase, it has been shown to be spontaneous in the gas phase and proceeds via two different concerted reaction mechanisms known as cis and trans. This may have profound implications in prebiotic chemistry as common atmospheric prenucleation clusters are thought to have participated in gas-phase reactions in the early Earth's atmosphere. We hypothesize that particular arrangements of water molecules in these clusters could lead to lowering of the reaction barrier of amino acid dimerization and could lead to abiotic catalysis toward polypeptides. We test our hypothesis on a system of the cis transition state of glycine dimerization solvated by one to five water molecules using a combination of a genetic algorithm-based configurational sampling, density functional theory geometries, and domain-based local pair natural orbital coupled-cluster electronic structure. First, we discuss the validity of the model chemistries used to obtain our results. Then, we show that the Gibbs free energy barrier for the concerted cis mechanism can indeed be lowered by the addition of up to five water molecules, depending on the temperature.     

Thioamides: Versatile Bonds To Induce Directional and Cooperative Hydrogen Bonding in Supramolecular Polymers

The amide bond is a versatile functional group and its directional hydrogen‐bonding capabilities are widely applied in, for example, supramolecular chemistry. The potential of the thioamide bond, in contrast, is virtually unexplored as a structuring moiety in hydrogen‐bonding‐based self‐assembling systems. We report herein the synthesis and characterisation of a new self‐assembling motif comprising thioamides to induce directional hydrogen bonding. N,N′,N′′‐Trialkylbenzene‐1,3,5‐tris(carbothioamide)s (thioBTAs) with either achiral or chiral side‐chains have been readily obtained by treating their amide‐based precursors with P₂S₅. The thioBTAs showed thermotropic liquid crystalline behaviour and a columnar mesophase was assigned. IR spectroscopy revealed that strong, three‐fold, intermolecular hydrogen‐bonding interactions stabilise the columnar structures. In apolar alkane solutions, thioBTAs self‐assemble into one‐dimensional, helical supramolecular polymers stabilised by three‐fold hydrogen bonding. Concentration‐ and temperature‐dependent self‐assembly studies performed by using a combination of UV and CD spectroscopy demonstrated a cooperative supramolecular polymerisation mechanism and a strong amplification of supramolecular chirality. The high dipole moment of the thioamide bond in combination with the anisotropic shape of the resulting cylindrical aggregate gives rise to sufficiently strong depolarised light scattering to enable depolarised dynamic light scattering (DDLS) experiments in dilute alkane solution. The rotational and translational diffusion coefficients, D_trans and D_rot, were obtained from the DDLS measurements, and the average length, L, and diameter, d, of the thioBTA aggregates were derived (L=490 nm and d=3.6 nm). These measured values are in good agreement with the value L_w=755 nm obtained from fitting the temperature‐dependent CD data by using a recently developed equilibrium model. This experimental verification validates our common practice for determining the length of BTA‐based supramolecular polymers from model fits to experimental CD data. The ability of thioamides to induce cooperative supramolecular polymerisation makes them effective and broadly applicable in supramolecular chemistry.     

The First Synthesis of the Sterically Encumbered Adamantoid Phosphazane P4(NtBu)6: Enabled by Mechanochemistry

All reported attempts to synthesize the tert‐butyl‐substituted adamantoid phosph(III)azane P₄(N^tBu)₆ have failed, leading to the classification of this molecule as inaccessible and a literature example of steric control in chemistry of phosphorus‐nitrogen compounds. We now demonstrate that this structure is readily accessible by a solvent‐free mechanochemical milling approach, highlighting the importance of mechanochemical reaction environments in evaluating chemical reactivity.     

Molecular Logic Circuits

Miniaturization has been an essential ingredient in the outstanding progress of information technology over the past fifty years. The next, perhaps ultimate, limit of miniaturization is that of molecules, which are the smallest entities with definite size, shape, and properties. Recently, great effort has been devoted to design and investigate molecular‐level systems that are capable of transferring, processing, and storing information in binary form. Some of these nanoscale devices can, in fact, perform logic operations of remarkable complexity. This research—although far from being transferred into technology—is attracting interest, as the nanometer realm seems to be out of reach for the “top‐down” techniques currently available to microelectronics industry. Moreover, such studies introduce new concepts in the “old” field of chemistry and stimulate the ingenuity of researchers engaged in the “bottom‐up” approach to nanotechnology.     

Synthesis and Characterization of Some Novel Glycodendrimers and N-alkyldendrimers with Amide Core and Triazole Functionality through Click Chemistry

The syntheses of various types of 1,2,3-triazole-based dendrimers 1–4 with sugar pyranosylazides and N-ethyl and N-heptylazides as a surface unit and benzene-1,3,5-tricorboxlyic amide as core unit through click chemistry approach are described.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Current Methods for Determination of L-Carnitine and Acylcarnitines

L-Carnitine as endogenous compound plays an important role within several metabolic pathways and a deficiency of L-carnitine can cause adverse effects in physiological and/or mental state of health and disease. The prevention of diseases related to carnitine deficiency requires, first of all, the exact determination of L-carnitine and its esters in biological material at pmol/cm³ level. A series of analytical procedures based on biochemical assays as well as on physical methods are available today. Determination of free and total carnitine is sometimes sufficient for a clinical diagnosis, but in most cases, such as in newborn screening for genetic disorders, detailed qualitative and quantitative L-carnitine/acylcarnitine profiling is needed. Technological progress has also revolutionized the determination of carnitines. Today, comprehensive and diagnostically relevant information can be obtained by mass spectrometry. An overview is given of the technical and methodological developments in carnitine analysis and some applications, such as in neonatal screening, diabetes mellitus, and cardiomyopathy.     

Organometallic Homogeneous Catalysis—Quo vadis?

Homogeneous catalysis is the success story of organometallic chemistry. Otto Roelen's initial discovery of hydroformylation in 1938 not only entailed large-capacity production plants but was later followed by systematic research into the catalytic chemistry of the ever-growing class of organometallic compounds. Further developments in industrial chemistry towards clean, low-temperature, low-pressure, and economic processes—in feedstock or in the fine chemicals and polymer area—clearly depend on improved catalysts. Molecularly defined, tailor-made structures are the safest prerequisites for chemical selectivity; hence, organometallic compounds with their overwhelming variety of compositions and structures offer the most promising approach. Wilkinson's catalysts [HRh(CO){P(C₆H₅)₃] and [ClRh{P(C₆H₅)}₃}₃] are outstanding examples. On the other hand, process technology has to be considered also (for example catalyst-product separation and hear-exchange problems). The following review attempts to critically assess the future trends and present demands in the applied area of orgnometallic catalysis–a “gentle art” that is far from being a mature field.     

Supramolecular Inorganic Chemistry: Small Guests in Small and Large Hosts

A key reaction in the biological and material world is the controlled linking of simple (molecular) building blocks, a reaction with which one can create mesoscopic structures, which, for example, contain cavities and display specifically desired properties, but also compounds that exhibit typical solid-state structures. The best example in this context is the chemistry of host–guest interactions, which spans the entire range from three- and two-dimensional to one- and “zero-dimensional”, discrete host structures. Members of the class of multidimensional compounds have been classified as such for a long time, for example, clathrates and intercalation compounds. Thus far, however, there are no classifications for discrete inorganic host–guest compounds. The first systematic approach can be applied to novel polyoxometalates, a class of compounds which has only recently become known. Molecular recognition; tailor-made, molecular engineering; control of fragment linkage of spin organization and crystallization; cryptands and coronands as “cages” for cations, anions or anion–cation aggregates as sections of ionic lattices; anions within anions, receptors; host–guest interactions; complementarity, as well as the dialectic terms reduction and emergence are important terms and concepts of supramolecular inorganic chemistry. Of particular importance for future research is the comprehension of the mesoscopic area (molècular assemblies)—that between individual molecules and solids (“substances”)—which acts in the biological world as carrier of function and information and for which interesting material properties are expected. This area is accessible through certain variations of “controlled” self-organization processes, which can be demonstrated by using examples from the chemistry of polyoxometalates. The comprehension of the laws that rule the linking of simple polyhedra to give complex systems enables one to deal with numerous interdisciplinary areas of research: crystal physics and chemistry, heterogeneous catalysis, bioinorganic chemistry (biomineralization), and materials science. In addition, conservative self-organization processes, for example template-directed syntheses, are of importance for natural philosophy in the context of the question about the inherent properties of material systems.     

Targeted Ultrasound‐Assisted Cancer‐Selective Chemical Labeling and Subsequent Cancer Imaging using Click Chemistry

Metabolic sugar labeling followed by the use of reagent‐free click chemistry is an established technique for in vitro cell targeting. However, selective metabolic labeling of the target tissues in vivo remains a challenge to overcome, which has prohibited the use of this technique for targeted in vivo applications. Herein, we report the use of targeted ultrasound pulses to induce the release of tetraacetyl N‐azidoacetylmannosamine (Ac₄ManAz) from microbubbles (MBs) and its metabolic expression in the cancer area. Ac₄ManAz‐loaded MBs showed great stability under physiological conditions, but rapidly collapsed in the presence of tumor‐localized ultrasound pulses. The released Ac₄ManAz from MBs was able to label 4T1 tumor cells with azido groups and significantly improved the tumor accumulation of dibenzocyclooctyne (DBCO)‐Cy5 by subsequent click chemistry. We demonstrated for the first time that Ac₄ManAz‐loaded MBs coupled with the use of targeted ultrasound could be a simple but powerful tool for in vivo cancer‐selective labeling and targeted cancer therapies.     

Current Methods for Determination of <Emphasis Type="Italic">L</Emphasis>-Carnitine and Acylcarnitines

Summary. L-Carnitine as endogenous compound plays an important role within several metabolic pathways and a deficiency of L-carnitine can cause adverse effects in physiological and/or mental state of health and disease. The prevention of diseases related to carnitine deficiency requires, first of all, the exact determination of L-carnitine and its esters in biological material at pmol/cm³ level. A series of analytical procedures based on biochemical assays as well as on physical methods are available today. Determination of free and total carnitine is sometimes sufficient for a clinical diagnosis, but in most cases, such as in newborn screening for genetic disorders, detailed qualitative and quantitative L-carnitine/acylcarnitine profiling is needed. Technological progress has also revolutionized the determination of carnitines. Today, comprehensive and diagnostically relevant information can be obtained by mass spectrometry. An overview is given of the technical and methodological developments in carnitine analysis and some applications, such as in neonatal screening, diabetes mellitus, and cardiomyopathy.