On the Emergence of Autonomous Chemical Systems through Dissipation Kinetics.

This work addresses the kinetic requirements for compensating the entropic cost of self-organization and natural selection, thereby revealing a fundamental principle in biology. Metabolic and evolutionary features of life cannot therefore be separated from an origin of life perspective. Growth, self-organization, evolution and dissipation processes need to be metabolically coupled and fueled by low-entropy energy harvested from the environment. The evolutionary process requires a reproduction cycle involving out-of-equilibrium intermediates and kinetic barriers that prevent the reproductive cycle from proceeding in reverse. Model analysis leads to the unexpectedly simple relationship that the system should be fed energy with a potential exceeding a value related to the ratio of the generation time to the transition state lifetime, thereby enabling a process mimicking natural selection to take place. Reproducing life's main features, in particular its Darwinian behavior, therefore requires satisfying constraints that relate to time and energy. Irreversible reaction cycles made only of unstable entities reproduce some of these essential features, thereby offering a physical/chemical basis for the possible emergence of autonomy. Such Emerging Autonomous Systems (EASs) are found to be capable of maintaining and reproducing their kind through the transmission of a stable kinetic state, thereby offering a physical/chemical basis for what could be deemed an epigenetic process.

How great is the stabilization of crowded polyphenylbiphenyls by London dispersion?

Decaphenylbiphenyl (1) and 2,2',4,4',6,6'-hexaphenylbiphenyl (2) are bulky molecules expected to be greatly destabilized by steric crowding. Herein, through a combined experimental and computational approach, we evaluate the molecular energetics of crowded biphenyls. This is complemented by the study of phase equilibria for 1 and 2. Compound 1 shows a rich phase behavior, displaying an unusual interconversion between two polymorphs. Surprisingly, the polymorph with distorted molecules of C1 symmetry is found to have the highest melting point and to be the one that is preferentially formed. The thermodynamic results also indicate that the polymorph displaying the more regular D2 molecular geometry has larger heat capacity and is probably the more stable at lower temperatures. The melting and sublimation data clearly reveal the weakening of cohesive forces in crowded biphenyls due to the lower molecular surface area. The experimental quantification of the intramolecular interactions in 1 and 2 indicated, using homodesmotic reactions, a molecular stabilization of about 30 kJ mol-1. We attribute the origin of this stabilization in both compounds to the existence of two parallel-displaced π⋯π interactions between the ortho-phenyl substituents on each side of the central biphenyl. Computational calculations with dispersion-corrected DFT methods underestimate the stabilization in 1, unless the steric crowding is well balanced in a homodesmotic scheme. This work demonstrates that London dispersion forces are important in crowded aromatic systems, making these molecules considerably more stable than previously thought.

On the Chemical Origin of Biological Cognition.

One of life's most striking characteristics is its mental dimension, one whose very existence within a material system has long been a deep scientific mystery. Given the current scientific view that life emerged from non-life, how was it possible for 'dead' matter to have taken on mental capabilities? In this Perspective we describe the existence of a recently discovered non-equilibrium state of matter, an energized dynamic kinetic state, and demonstrate how particular chemical systems once activated into that kinetic state could manifest rudimentary cognitive behavior. Thus, contrary to a common view that biology is not reducible to physics and chemistry, recent findings in both chemistry and biology suggest that life's mental state is an outcome of its physical state, and therefore may be explicable in physical/chemical terms. Such understanding offers added insight into the physico-chemical process by which life was able to emerge from non-life and the perennial 'what is life?' question. Most remarkably, it appears that Darwin, through his deep understanding of the evolutionary process, already sensed the existence of a connection between life's physical and mental states.

Heterotrimetallic Assemblies with 1,2,4,5-Tetrakis(diphenylphosphino)benzene Bridges: Constructs for Controlling the Separation and Spatial Orientation of Redox-Active Metallodithiolene Groups.

Metallodithiolene complexes of the type [(R2C2S2)M(η2-tpbz)] [R = CN, Ph, or p-anisyl; M = Ni2+, Pd2+, or Pt2+; tpbz = 1,2,4,5-tetrakis(diphenylphosphino)benzene] chelate transition metals ions to form trimetallic arrays [[(R2C2S2)M(tpbz)]2M']n+, where M' is square planar Pt2+, tetrahedral Cu+, Ag+, or Au+, or octahedral {ReBr(CO)}/{Re(CO)2}+. Forcing conditions (190 °C reflux in decalin, 72 h) are demanded for the Re+ compounds. With third-row metals at the nexus, the compounds are stable to air. Twelve members of the set have been characterized by X-ray diffraction and reveal dithiolene centroid-centroid distances ranging from 22.4 to 24.0 Å. Folding around each tpbz intrachelate P···P axis such that the MP2/M'P2 planes meet the tpbz P2C6P2 mean plane at non-zero values gives rise to core topologies that appear "S-like" or herringbone-like for M' = Pt2+ or {ReBr(CO)}/{Re(CO)2}+. Calculations reveal that departure from idealized D2h/D2d/C2v symmetries is induced by steric crowding between Ph groups and that dynamic, fluxional behavior is pertinent to the solution phase because multiple, lower-symmetry minima of comparable energy exist. Spectroscopically, the formation of the trimetallic arrays is marked by a shift of the open end 31P nuclear magnetic resonance signal from approximately -14.5 ppm to approximately +41, approximately +20.5, and approximately +28.5 ppm for M' = Pt2+, Au+, and {ReBr(CO)}/{Re(CO)2}+, respectively. Electrochemically, dithiolene-based oxidations are observed for the R = Ph and M' = Pt2+ or Au+ compounds but at potentials that are anodically shifted relative to charge-neutral [[(R2C2S2)M]2(µ-tpbz)]. The compounds reported clarify the possibilities for the synthesis of assemblies in which weakly coupled spins may be created in their modular (R2C2S2)M and M' parts.

The Pursuit of Perphenylterphenyls.

Tetradecaphenyl-p-terphenyl (2) was synthesized from 2,3,5,6-tetraphenyl-1,4-diiodobenzene (11) by two methods. Ullmann coupling of 11 with pentaphenyliodobenzene (9) gave compound 2 in 1.7 % yield, and Sonogashira coupling of 11 with phenylacetylene, followed by a double Diels-Alder reaction of the product diyne 12 with tetracyclone (6), gave 2 in 1.5 % overall yield. The latter reaction also gave the monoaddition product 4-(phenylethynyl)-2,2',3,3',4',5,5',6,6'-nonaphenylbiphenyl (13) in 4 % overall yield. The X-ray structures of compounds 2 and 13 show them to possess core aromatic rings distorted into shallow boat conformations. Density functional calculations indicate that these unusual structures are not the lowest energy conformations in the gas phase and may be the result of packing forces in the crystal. In addition, while uncorrected DFT calculations indicate that the strain energy in compound 2 is approximately 50 kcal/mol, dispersion-corrected DFT calculations suggest that it is essentially unstrained, due to compensating, favorable, intramolecular interactions of its many phenyl rings. An attempted synthesis of tetradecaphenyl-o-terphenyl (4) by reaction of diphenylhexatriyne (14) with three equivalents of tetracyclone at 350 °C gave only the diadduct 2-(phenylethynyl)-2',3,3',4,4',5,5',6,6'-nonaphenylbiphenyl (15) in 17 % yield. Even higher temperatures failed to produce 4 and lowered the yield of 15, perhaps due to rapid decomposition of the starting materials. Ullmann coupling of 3,4,5,6-tetraphenyl-1,2-diiodobenzene (16) and compound 9 also failed to give compound 4.

Unidirectional coherent energy transport via conjugated oligo(p-phenylene) chains.

We discovered a way to funnel high-frequency vibrational quanta rapidly and unidirectionally over large distances using oligo(p-phenylene) chains. After mid-IR photon photoexcitation of a -COOH end group, the excess energy is injected efficiently into the chain, forming vibrational wavepackets that propagate freely along the chain. The transport delivers high-energy vibrational quanta with a range of transport speeds reaching 8.6 km/s, which exceeds the speed of sound in common metals (∼5 km/s) and polymers (∼2 km/s). Efficiencies of energy injection into the chain and transport along the chain are found to be very high and dependent on the extent of conjugation across the structure. By tuning the degree of conjugation via electronic doping of the chain, the transport speed and efficiency can be controlled. The study opens avenues for developing materials with controllable energy transport properties for heat management, schemes with efficient energy delivery to hard-to-reach regions, including transport against thermal gradients, and ways for initiating chemical reactions remotely.

Synthesis and Structures of Polyphenylphenanthrenes.

1,2,3,4,5,6,7,8-Octaphenylphenanthrene (4) and decaphenylphenanthrene (5) were prepared by very short syntheses (two or three steps) from tetraphenylfuran and polybrominated benzene derivatives. The X-ray structures of compounds 4 and 5 show them to be quite crowded, with the phenanthrene cores twisted by about 40° due to the clash of the C4 and C5 phenyl groups. Compound 4 was resolved by chromatography on a chiral support, and its free energy of activation for racemization was determined to be 24.6 kcal mol-1 at 40 °C. Computational studies indicate that compound 5 has a racemization barrier approximately 6 kcal mol-1 lower than 4, and thus 5 would not be configurationally stable at room temperature.

On the conditions for mimicking natural selection in chemical systems.

The emergence of natural selection, requiring that reproducing entities present variations that may be inherited and passed on, was arguably the most important breakthrough in the self-organization of life. In this Perspective, the assumptions governing biological reproduction are confronted with physico-chemical principles that control the evolution of material systems. In biology, the reproduction of living organisms is never considered to be reversible, whereas microscopic reversibility is an essential principle in the physical description of matter. Here, we show that this discrepancy places constraints on the possibility of finding kinetic processes in the chemical world that are equivalent to natural selection in the biological one. Chemical replicators can behave in a similar fashion to living entities, provided that the reproduction cycle proceeds in a unidirectional way. For this to be the case, kinetic barriers must hinder the reverse process. The system must, thus, be held far from equilibrium and fed with a non-degraded (low-entropy) form of energy. The ensuing constraints must be factored in when proposing scenarios that account for the origin of life at the molecular level.

How Prebiotic Chemistry and Early Life Chose Phosphate.

The very specific thermodynamic instability and kinetic stability of phosphate esters and anhydrides impart them invaluable properties in living organisms in which highly efficient enzyme catalysts compensate for their low intrinsic reactivity. Considering their role in protein biosynthesis, these properties raise a paradox about early stages: How could these species be selected in the absence of enzymes? This review is aimed at demonstrating that considering mixed anhydrides or other species more reactive than esters and anhydrides can help in solving the paradox. The consequences of this approach for chemical evolution and early stages of life are analysed.

Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA.

Molecular evolution can be conceptualized as a walk over a "fitness landscape", or the function of fitness (e.g., catalytic activity) over the space of all possible sequences. Understanding evolution requires knowing the structure of the fitness landscape and identifying the viable evolutionary pathways through the landscape. However, the fitness landscape for any catalytic biomolecule is largely unknown. The evolution of catalytic RNA is of special interest because RNA is believed to have been foundational to early life. In particular, an essential activity leading to the genetic code would be the reaction of ribozymes with activated amino acids, such as 5(4 H)-oxazolones, to form aminoacyl-RNA. Here we combine in vitro selection with a massively parallel kinetic assay to map a fitness landscape for self-aminoacylating RNA, with nearly complete coverage of sequence space in a central 21-nucleotide region. The method (SCAPE: sequencing to measure catalytic activity paired with in vitro evolution) shows that the landscape contains three major ribozyme families (landscape peaks). An analysis of evolutionary pathways shows that, while local optimization within a ribozyme family would be possible, optimization of activity over the entire landscape would be frustrated by large valleys of low activity. The sequence motifs associated with each peak represent different solutions to the problem of catalysis, so the inability to traverse the landscape globally corresponds to an inability to restructure the ribozyme without losing activity. The frustrated nature of the evolutionary network suggests that chance emergence of a ribozyme motif would be more important than optimization by natural selection.

The Chemical Likelihood of Ribonucleotide-α-Amino acid Copolymers as Players for Early Stages of Evolution.

How ribosomal translation could have evolved remains an open question in most available scenarios for the early developments of life. Rather than considering RNA and peptides as two independent systems, this work is aimed at assessing the possibility of formation and stability of co-polymers or co-oligomers of α-amino acids and nucleotides from which translation might have evolved. Here we show that the linkages required to build such mixed structures have lifetimes of several weeks to months at neutral pH and 20 °C owing to the mutual protecting effect of both neighboring phosphoramidate and ester functional groups increasing their stability by factors of about 1 and 3 orders of magnitude, respectively. This protecting effect is reversible upon hydrolysis allowing the possibility of subsequent reactions. These copolymer models, for which an abiotic synthesis pathway is supported by experiments, form a basis from which both polymerization and translation could have logically evolved. Low temperatures were identified as a critical parameter for the kinetic stability of the aminoacylated nucleotide facilitating the synthesis of the model. This observation independently supports the views that any process involving RNA aminoacyl esters, outstandingly including the emergence of translation, was more probable at 0 °C or below and might be considered a kinetic marker constraining the environment in which translation has evolved.

Dodecaphenyltetracene.

Dodecaphenyltetracene (4), the largest perphenylacene yet prepared, was synthesized from known tetraphenylfuran, hexaphenylisobenzofuran, and 1,2,4,5-tetrabromo-3,6-diphenylbenzene in three steps. The X-ray structure of the deep red, highly luminescent 4 shows it to be a D2 -symmetric molecule with an end-to-end twist of 97°. The central acene is encapsulated by the peripheral phenyl substituents, and as a result, the molecule is relatively unreactive and even displays reversible electrochemical oxidation and reduction.

in,in-Cyclophanes with Bridgehead Methyl Groups.

Two in,in-cyclophanes that contain methyl groups in their central cavities have been synthesized, and their X-ray structures have been determined. One of these molecules contains a very short nonbonded contact between a hydrogen atom and a methyl group, and the other is the first example of a macrobicyclic compound that contains two inwardly directed methyl groups.

An Exceptionally Close, Non-Bonded Hydrogen-Hydrogen Contact with Strong Through-Space Spin-Spin Coupling.

Condensation of 1,8,13-tris(mercaptomethyl)triptycene and tris(bromomethyl)methane yields an in,in-cyclophane with two inwardly directed methine groups. Based on X-ray analysis and DFT and MP2 calculations, the hydrogen-hydrogen non-bonded contact distance is estimated to be 1.50-1.53 Å. Furthermore, the two in-hydrogen atoms show obvious spin-spin coupling with J=2.0 Hz.

How and why kinetics, thermodynamics, and chemistry induce the logic of biological evolution.

Thermodynamic stability, as expressed by the Second Law, generally constitutes the driving force for chemical assembly processes. Yet, somehow, within the living world most self-organisation processes appear to challenge this fundamental rule. Even though the Second Law remains an inescapable constraint, under energy-fuelled, far-from-equilibrium conditions, populations of chemical systems capable of exponential growth can manifest another kind of stability, dynamic kinetic stability (DKS). It is this stability kind based on time/persistence, rather than on free energy, that offers a basis for understanding the evolutionary process. Furthermore, a threshold distance from equilibrium, leading to irreversibility in the reproduction cycle, is needed to switch the directive for evolution from thermodynamic to DKS. The present report develops these lines of thought and argues against the validity of a thermodynamic approach in which the maximisation of the rate of energy dissipation/entropy production is considered to direct the evolutionary process. More generally, our analysis reaffirms the predominant role of kinetics in the self-organisation of life, which, in turn, allows an assessment of semi-quantitative constraints on systems and environments from which life could evolve.

The Prebiotic C-Terminal Elongation of Peptides Can Be Initiated by N-Carbamoyl Amino Acids.

The formation of peptides upon 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-promoted activation of N-carbamoylamino acids (CAA), was considered in the scope of our recent works on carbodiimide promoted C-terminus elongation of peptides in a prebiotic context. Thus EDC promoted activation of CAA derivatives of Tyr(Me) or Ala in dilute aqueous medium pH 5.5-6.5 in the presence of excess of AA, resulted in peptide formation by C-terminus activation/elongation. Kinetic results similar to those of EDC-mediated activation of N-acyl-AA lead us to postulate the formation of a 2-amino-5(4H)-oxazolone intermediate by cyclization of the activated CAA, in spite of the absence of epimerization occurred at CAA residues. Thus, in a prebiotic context, CAA may have played a similar role as N-acyl-AA in the initiation of C-terminus peptide elongation.

Mixed Anhydride Intermediates in the Reaction of 5(4H)-Oxazolones with Phosphate Esters and Nucleotides.

5(4H)-Oxazolones can be formed through the activation of acylated α-amino acids or of peptide C termini. They constitute potentially activated intermediates in the abiotic chemistry of peptides that preceded the origin of life or early stages of biology and are capable of yielding mixed carboxylic-phosphoric anhydrides upon reaction with phosphate esters and nucleotides. Here, we present the results of a study aimed at investigating the chemistry that can be built through this interaction. As a matter of fact, the formation of mixed anhydrides with mononucleotides and nucleic acid models is shown to take place at positions involving a mono-substituted phosphate group at the 3'- or 5'-terminus but not at the internal phosphodiester linkages. In addition to the formation of mixed anhydrides, the subsequent intramolecular acyl or phosphoryl transfers taking place at the 3'-terminus are considered to be particularly relevant to the common prebiotic chemistry of α-amino acids and nucleotides.

Hairpin Furans and Giant Biaryls.

The thermal reaction of two cyclopentadienones with 5,5'-binaphthoquinone or 6,6'-dimethoxy-5,5'-binaphthoquinone in refluxing nitrobenzene (210 °C) gives, in a single synthetic step that includes two Diels-Alder additions, two decarbonylations, and two dehydrogenations, giant biaryl bisquinones (compounds 13, 14, 15, 18, and 21). However, when two cyclopentadienones react with 6,6'-dimethoxy-5,5'-binaphthoquinone in nitrobenzene at higher temperatures (250-260 °C), the resulting products are molecular ribbons composed of two twisted aromatic systems fused to a heteropentahelicene (19, 20, and 22). These molecules are representatives of a new class of chiral polycyclic aromatic compounds, the "hairpin furans". Interestingly, reheating a dimethoxy-substituted giant biaryl (e.g., 21) in nitrobenzene at 260 °C does not yield the corresponding hairpin furan (22), and mechanistic studies indicate that some intermediate or byproduct of the synthesis of the giant biaryls is a reagent or catalyst necessary for the conversion of the dimethoxybiaryl to the furan.