What is "living" biology and what is "Inorganic"? In terms of the Charge Field?

Found this of interest. In the back of mind lately I've been looking at how define "living" tissues -"life" with regeneration of living cells, in other words, versus "dead" or non-living atomic structures. Why do RNA-DNA structures not "cross" to generate non-species just due to "molecules"? It is a tricky question with Miles' Charge Field.
------------

Origins of Organic Chemistry and Organic Synthesis
Prof. Dr. Curt Wentrup
First published: 23 March 2022 https://doi.org/10.1002/ejoc.202101492Citations: 1

The origins of organic chemistry and organic synthesis started in the middle ages, long before molecular compositions were known. Paradigm shifts caused by Lavoisier, Chevreuil, Wöhler, Liebig, Kolbe and Berthelot are highlighted. The graphic shows some early key organic molecules, but although synthesis and analysis had become well established sciences by the 1840s, the chemical structures remained essentially unknown.

Description unavailable
Abstract
The words organic and synthesis originate with Aristotle (meaning ‘instrumental’ and ‘put together’, respectively) but had different meanings over time. The iatrochemists prepared numerous pharmaceutical remedies in the 1600s but had no concept of organic chemistry. Buffon, Bergman and Gren defined organic bodies as living things in the 1700s, but discrete organic compounds remained unknown. In the late 1700s and early 1800s, organic natural products were isolated by Scheele, and Chevreuil separated carboxylic acids from saponification of fats. Organic chemistry had started. Lavoisier invented and Berzelius improved combustion analysis for organic characterization. Descartes’ dictum that synthesis is required to prove an analysis was enacted by Bergman and others. The concept of organic chemistry changed radically when Wöhler and Kolbe prepared organic compounds from the elements. Berthelot's syntheses of non-natural fats in 1853 started modern synthetic organic chemistry as the chemistry of carbon compounds, regardless of whether occurring in Nature or not.

1 Introduction
Considering the enormous breath of the subject,1 it is not common for chemistry educators to cover the history of organic chemistry in any depth due to time limitations, and textbooks do not devote much space to it. Therefore, students may not acquire a clear understanding of why the subject is actually called “Organic Chemistry”, and those who profess it organic chemists. In this Perspective, the origins of organic chemistry and the words organic and inorganic, which in fact have had somewhat different meanings over time, are traced chronologically. The term organic comes from Greek οργανον, organon, instrument, and has roots going back to Aristotle (384–322 BC). Aristotle distinguished non-living and living things (animals and plants), and the organised, living body was the instrument of the soul (soma organikon) in the same sense that the eye is the instrument of vision (“every organ is for the sake of something or the instrument of something”).2 As we shall see below, Berzelius followed this lead and referred to the organs as instruments. In addition, the changing meanings of the word synthesis and its use in (organic) chemistry are also reviewed. Originally, the concept of synthesis (from Greek σύν together +θϵσις to place or put) meant just that: putting things together, but not in the way we understand it as forming chemical compounds.

2 Before Organic Chemistry: Paracelsus, Boyle, Croll, Hartmann
For the famous alchemist, iatrochemist and medical practitioner Paracelsus,3, 4 working in the first half of the 1500s, chemistry was still very much inorganic. Organic chemistry was unknown. Having discarded the four traditional elements of Empedocles and Aristotle (fire, air, water, and earth), he stated around 1527–1530 that all living bodies (and indeed all things) were composed of the three fundamental substances or Grundsubstanzen (tria principia, tribus primis, or tria prima), mercury, sulfur, and salt (Mercurius, Schwefel und Salz).5, 6 These three principles were to be understood in a philosophical, alchemical, not a literal chemical sense. The words stood for properties or characters rather than the chemical elements. They gave rise to the physical properties of volatility (Verflüchtbarkeit), oiliness and flammability (Öligkeit, Brennbarkeit), and solidity or solidification (Festigkeit, Erstarrung). If any of these principles was present in too high or too low quantity, then illnesses would result. For example, an excess of mercury can cause paralysis and depression, and its salt may lead to diarrhea and dropsy; sulfur rising to the brain causes stupor and epilepsy, fever and the plague. Precipitation of mercury causes gout and arthritis, and distilling (subliming) it from one organ to another can lead to madness, mania, etc.1b, 7 Although Paracelsus did not undertake deliberate organic chemistry, he most likely did perform an organic synthesis of diethyl ether, “sweet oil of vitriol” or “sweet sulfur”, by heating ethanol (Weingeist) with sulfuric (vitriolic) acid,7 a process also attributed to Valerius Cordus and to 13th century Raymund Lull.8

The atomist Robert Boyle at Oxford rejected the tria principia and instead defined elements as follows: “I now mean by Element, as those Chymists that speak plainest do by their Principles, certain Primitive and Simple, or perfectly unmingled bodies; which not being made of any other bodies, or of one another, and the Ingredients of which all those call'd perfectly mixt Bodies [i. e. compounds] are immediately compounded, and into which they are ultimately resolved.”9 On the continent, however, chemistry continued to be highly influenced by Paracelsus.

The Danish royal physician Petrus Severinus (Peder Sørensen) was one of the principal promoters of Paracelsus’ teachings.10 In his Idea medininæ philosophicæ, Severinus brought together Hippocrates’ medicine, platonism and Paracelsus’ often contradictory chemical and metaphysical concepts in a philosophical whole.10a Oswald Croll, a medical doctor from the University of Marburg later working in Prague under the tutelage of emperor Rudolf II, and Johannes Hartmann, professor publicus chymiatriae in Marburg, a stronghold of Paracelsianism, restated Paracelsus’ doctrines in the mid-17th century.11, 12 Paracelsus, Severinus, Croll and especially Hartmann were fiercely opposed and derided (e. g. “fece Paracelsica”) by Andreas Libavius in Coburg.13, 14 On the practical side, Croll and Hartmann described numerous medicines and chemical preparations in a detailed manner, thereby demystifying many of Paracelsus’ vague recipes, including the preparation of spirit of vitriol and the sweet oleum vitrioli, yellow (HgO) and green precipitates of mercury (from Hg+Cu 4 : 1 in nitric acid; said to be effective against Gonorrhea and Lue Gallica (syphilis)), white and red flowers of antimony (the trioxide and oxysulfide), laudanum opiatum (analgesic made from opium), aurum potabile anglicum,15 oil of cinnamon, oil of camphor, balsam of fennel, balsam of St. John's wort, etc. etc., the organic preparations usually obtained by extraction and distillation. Formulations often included the addition of, or distillation with, spiritus vini (alcohol, which had been obtained by distillation of wine since the 12th century1f, 16). Already Dioscorides17 and Galen18 used opium and many herbal oils and extracts medicinally in the 1st and 2nd centuries, and Dioscorides also described several preparations based on minerals, such as kadamela (calamine), ios xustos (verdigris), molubdoeides (loadstone), stimmi (antimony sulphide), chrusokolla (malachite), kinnabari (cinnabar, HgS) and udraguros (mercury). The “father of medicine” Hippocrates, was reluctant to use drugs of any sort but did use some vegetal remedies.19

Paracelsus dismissed the medical doctrine of Galen and other medieval doctors and philosophers, instead touting inorganic, chemically prepared and in part dangerously toxic medicines, even though he still used herbal remedies. As for Hartmann, he not only taught chymiatria as the first chemistry professor in the world; he also set up the first university chemistry teaching laboratory two centuries before Liebig's celebrated laboratory in Giessen. Here, students, including several foreigners, learned the preparation of many inorganic and organic substances and medicaments. Among the many laboratory rules, the students had to give the director (Hartmann) an oath of submission, loyalty, and diligence, and agree not to reveal anything to unworthy outsiders. Instead, they should keep what they had learned to themselves and use it for the benefit of fellow men in need. Coats and swords were under no circumstances allowed in the laboratories, the students were not to drink, sleep, shout, or fight, and if they behaved otherwise, they would be punished with a fine or banned from the community.20

In summary, the alchemists, medical practitioners and iatrochemists used numerous herbal medicaments, some of which had been known since antiquity. They prepared many inorganic chemicals, and also some organics like ethanol (spirit of wine), acetic acid (aceto destillato), and diethyl ether, but organic chemistry as such did not yet exist. The concepts of organic compound and organic synthesis had not yet been formulated, and the chemical nature of living (organic) bodies was unknown.

3 Organic Molecules and Bodies: Gassendi, Charleton, Buffon, Bonnet, Bergman, Gren
To Pierre Gassendi in France in 1658 atoms (atomis) were “the smallest parts” (minimae partes) which combined to form corpuscles called moleculae (corpuscule=small body; molecule=small mass).21 Similarly, Walter Charleton in England spoke of atoms composing “certain Moleculae, small masses, of various figures” (shapes).22 In 1749 Georges-Louis Leclerc, Comte de Buffon used the term molécules organiques, which were hypothesized to be taken up from the matière organique in food to serve as nourishment and in the development and reproduction of the corps organisés, i. e. organised, living bodies. The concept of organised, living bodies goes back to Aristotle's De Anima.2b These bodies did not need those molecules which were not organic, the molécules brutes, and they were excreted. Buffon's molécules were less well defined than those of Gassendi and Charleton and were not to be understood with their current meaning as well-defined assemblies of atoms, but rather as tiny organic particles (for an extract in French, see the Supporting Information, Section S2).23, 24

In 1762 Charles de Bonnet in Geneva again used molécules organiques as well as corpuscules and particules organiques and très petits parties organiques in his hypotheses on the corps organisés, where he held that pre-existing ‘germs’ in living bodies were responsible for reproduction with the help of the male semen.14a, 25 In contrast to the organised bodies in the animal and plant kingdoms, those in the mineral kingdom were unorganised.

Torbern Bergman in Uppsala (Figure 1 and Figure 2) distinguished inorganic and organic bodies (oorganiska and organiska kroppar or corpora inorganica et organica) in 1777.26, 27, 28

Details are in the caption following the image
Figure 1
Open in figure viewer
PowerPoint
T. Bergman's corpora inorganica et organica.26b

Details are in the caption following the image
Figure 2
Open in figure viewer
PowerPoint
From left to right: Bergman, Scheele, and Berzelius.

Bergman classified organic and inorganic bodies (organische und unorganische Körper) as follows:26a, 29 “1) The highest form of natural bodies found on the surface of the Earth can be divided into organic and inorganic. 2) The organic bodies possess numerous inner vessels, through which the nourishment is extracted, prepared and distributed, and therefore enable the growth, maintenance and reproduction of the bodies. 3) Organic bodies are also called living bodies, and depending on whether they possess sense or not, they form the two classes animals and plants, which are usually considered as two kingdoms of Nature. 4) Inorganic bodies are those which lack organic structure and can only grow by external addition of parts” (for the original Swedish and German texts, see Supporting Information, Section S3).

Only few discrete organic substances were known to Bergman in 1777. Ethanol (spiritus vini) had been obtained by distillation of wine since the 12th century.1f, 16 Some vegetable acids and salts, such as tartaric acid and tartar (potassium hydrogen tartrate and calcium tartrate), sugar (an “essential salt”), “sugar acid” (oxalic acid, prepared by Bergman and Johan Afzelius by oxidation of sugar with nitric acid30), acetocella salt (potassium hydrogen oxalate) from sorrel, citric acid, and acetic acid were known. Apart from formic acid isolated from ants, there was little knowledge about the composition of oils and fats from the animal kingdom such as tallow, spermaceti oil, and whale oil.26a, 27 Bergman divided mineral bodies (substances) in four classes, salts, earths, metals, and phlogistic bodies, phlogiston being a combustible element supposed to be released in combustion and decomposition, so volatile and/or combustible materials such as petroleum, bitumen, and diamond were thought to be rich in phlogiston.31 The phlogiston theory was overthrown by Antoine Lavoisier (see Section 4), but many, including Bergman and Scheele (Figure 2), continued to believe in it.

In 1794 Friedrich A. C. Gren in Halle wrote about changes in the mixtures of organic bodies (organische Körper) happening “by themselves” (von selbst) (Figure 3).32 These changes would happen even in the absence of air and heat and could cause numerous changes of the properties and mixture of these bodies and eventually their complete decomposition. Since also inorganic bodies were known to undergo change “von selbst” (e. g. weathering of ores, some stones and salts, and corrosion of metals), he proposed the name fermentation as a suitable, general description for such changes. He then went on to describe fermentation of wine, distillation of the formed alcohol etc, the brewing of beer, and the putrefaction of fruit in considerable detail. Although there was still no understanding of the composition of organische Körper in terms of individual compounds, it is clear that he was thinking in terms of chemical reactions, e. g. of sugar (Zuckerstoff).

Details are in the caption following the image
Figure 3
Open in figure viewer
PowerPoint
Changes to mixtures of organic bodies happening by themselves. F.A.C. Gren, 1794.32

Thus, in the 1700s natural philosophers and chemists defined organised organic bodies not in a chemical sense but as living things as opposed to the unorganised, inorganic things. Organic chemistry remained unknown as a subject. However, Gren now started to see chemical transformations, which he called fermentations, taking place within vegetal organic bodies.

4 Chemical Analysis: Lavoisier, Berthollet, Vauquelin, Berzelius
In 1794, Lavoisier reported his epochal quantitative (if not exact) combustion analysis with a detailed description of the apparatus (Figure 4) and determined that organic bodies (spirit of wine (ethanol), olive oil and bees’ wax) burned to CO2 and H2O and were composed of carbon and hydrogen.33

Details are in the caption following the image
Figure 4
Open in figure viewer
PowerPoint
Lavoisier's apparatuses for combustion analysis, 1784.33

He had already determined the composition of water by synthesis and decomposition in 1783.34 In further work in 1786 he described organic compounds containing C, H, and O; for example he concluded that sugar contained some oxygen in the form of crystal water, but more importantly, it contained large amounts of oxygen and hydrogen attached to carbon. He also noted that N may be present, as had been discovered by Berthollet.35 The realization by Priestley, Scheele and Lavoisier that the combustion was due to the element oxygen (Priestley's “pure air” or “dephlogisticated air” and Scheele's “fire air”)34c resulted in the eventual overthrow of the phlogiston theory, although many, including Scheele and Bergman (Section 2), continued to believe in it.

Substantial experimental innovations in combustion analysis were made by Jöns Jakob Berzelius (Figure 2) in Stockholm. In 1806 he determined by chemical analysis that the major constituent of living bodies was carbon together with water, nitrogen, sulfur, phosphoric acid, potash (K2CO3), soda (NaHCO3), lime (CaCO3), talc (Mg silicate), silicate, iron, and hydrochloric acid.36 In his textbook on chemistry37 he refined this as C, H, O, N, S, P, K, Na, Ca, Mg, Si and Fe and added Cl and F, but there was still no understanding of the chemical processes or the composition of the organic bodies. Further: “Other elements have hitherto not been found. The animal body contains carbon and acid in major, and sulfur and iron in the least quantities…All are equally necessary; lack or excess of any causes a change in the phenomenon of life, which will not cease until the deficiency has been rectified.” Here he followed a reasoning similar to Paracelsus’ theories of the causes of illnesses (Section 2), although now in terms of the actual elements. He also opined that the composition of plants is less complicated than that of animals, since they mostly contain just carbon, water, and acid apart from earths and salts and sometimes nitrogen (for an extract in Swedish, see the Supporting Information, Section S3).

Berzelius also defined organic and inorganic bodies once again without mentioning ether Bergman or Gren (failure to cite important, prior work is not a new phenomenon). Bergman had died in 1784 and Gren in 1798. In his Lectures on Animal Chemistry36 Berzelius divided Nature in two parts, organic and inorganic (organisk and oorganisk). Organic bodies (organiska kroppar) are alive, and they are alive thanks to the Vital Force. They are the plants and the animals. The notion that bodily functions are due to a vitalistic principle existing in all living creatures has roots going back at least to ancient Egypt.38

Berzelius defined the vital force thus: “the nature of living bodies is not founded in their inorganic elements, but in something else, which causes the inorganic elements in all living bodies to bring forth a special and specific result for each type. This something, which we call the Vital Force (Lebenskraft) is external to the inorganic elements and is not part of their properties, such as weight, solidity, electrical polarity, etc., but we do not know what it is” (for the original German text, see Supporting Information, Section S4).37

Berzelius then defined organic chemistry:36 “The part of physiology which describes the composition of living bodies together with the chemical processes taking place in them is called organic chemistry (organisk Kemi), and that which describes their inner and outer structure with the mechanical processes derived therefrom is called anatomy.” Notably, organic chemistry was seen as a branch of physiology (the study of the function of living things), not of chemistry as such. He also preferred a new term “organology” instead of physiology, but never insisted on its use. The other branch of physiology, anatomy, dealt with the mechanical function of living things. Berzelius referred to the organs and the seats of the senses as instruments (of vision, of hearing, etc) in an Aristotelian sense.

Berzelius was by nature ultra-conservative and obdurate, not easily accepting new ideas of others. In later life he dismissed and derided the ideas of, for examples, Jean-Baptiste Dumas (substitution theory and the theory of types), Charles Gerhardt (new theory of types), and Auguste Laurent, who made his dualistic, electrochemical theory untenable. Dumas was called inter alia a vagabond, a thief, and a tightrope dancer.39 Although a growing number of compounds was being isolated and identified as discrete organic molecules, Berzelius was at first highly sceptical. In Paris, Fourcroy and Vauquelin had isolated a new acid called “yellow acid” (acide jaune) from the treatment of meat with nitric acid. Berzelius dismissed this40 and reasoned that yellow acid was nothing but malic acid in combination with the muscle fibre, which had been coloured yellow by the nitric acid. They also investigated the urine of several species of animal and the droppings of birds.41 Vauquelin found the droppings of pigeons to be acidic and thought that it was due to an acid different from all then known acids [uric acid is a common constituent of bird droppings]. The interest in examining the constituents of both human and animal excrements goes back to the ambition of the alchemists to isolate an elixir capable of turning mercury into silver and base metals into gold.42

Again Berzelius was dismissive and denied the existence of several new acids: “Since Vauqvelin has not published anything further on this, I have reason to believe that this acid, as well as “fat acid” (fettsyra), “animal acid” (djursyra) and milk acid (mjölksyra), are just acetic acid (ättiksyra) disguised by the animal material”.36, 43 It was not yet known that fats are composed of fatty acids and glycerol, proteins (albumin, egg whites) of amino acids, and carbohydrates (sugar, starch), of sugar molecules.

In summary, the major advance in organic chemistry that took place in the late 1700s and early 1800s was that, thanks in large part to Lavoisier and Berzelius, the elemental composition of organic materials could now be determined. Other than Bergman and Gren, Berzelius could therefore start talking about organic and inorganic chemistry. Organic nature was the world of living things, but the chemical constituents of the organic bodies were still largely unknown. Although at first disputed by Berzelius, more and more discrete organic compounds were being isolated from organic materials. Although there was no concept of structure, chemical compositions could at least be determined.

5 Organic Compound: Fatty Acids, Van Helmont, Scheele, Tachenius, and Chevreuil
It is likely that already Van Helmont had obtained glycerol as a “sweet oil from olive oil” (dulce enim tunc oleum olivarum ex oleo) by heating olive oil (oleum olivarum) with a base (salis circulati Paracelsici), although of course he did not know the chemical composition.44 Carl Wilhelm Scheele in Uppsala (Figure 2) isolated glycerol (fett-södme; Ölsüs or fat-sweetness; the name glycerine was given by Chevreuil, see below) from the decomposition of fresh olive oil by boiling with Bleiglätte (PbO) or of fresh almond oil with silfver-glitt (another name for PbO) in 1783 (Figure 5). The same sweet material was obtained from rose oil, linseed oil, milk oil, butter, and fat from the gut of a pig.45 He noted that the properties were completely different from those of ordinary sugar (i. e. sucrose, which had been known since antiquity), but he thought he obtained the known sugar acid of Bergman and Afzelius30 (oxalic acid, usually contaminated with mesoxalic acid46) by forced distillation with nitric acid. Scheele believed in phlogiston and reasoned that the fett-södme must contain more phlogiston than ordinary sugar, because much more nitric acid was required for its destruction. Scheele isolated and purified several organic acids in the 1760s–1780s including tartaric, citric, malic, oxalic, mucic, lactic, and uric (see Scheme 1 for some relevant formulas),47 and HCN was obtained by distillation of acidified Prussian blue.48

Details are in the caption following the image
Figure 5
Open in figure viewer
PowerPoint
Publication of Scheele's isolation of glycerol (fett-södme; Ölsüs; fat-sweetness) 1783.45

Details are in the caption following the image
Scheme 1
Open in figure viewer
PowerPoint
Some organic compounds known by the late 1700s (but structures unknown at the time).

In his treatise on acids and alkalis the maverick Westphalian pharmacist, medical doctor and alchemist Otto Tachenius in Venice asserted in 1666 that all oils or fats contained a hidden acid, which is released in the production of soap by treatment with alkali (“alkali cum oleo fit sapo”): “All oils and fats have a hidden acid (occulto acido), on which the alkalis act, and consume it, otherwise soap could never be made: for the distilled olive oil does corrode and dissolve silver imperceptibly, when cast on it for but a short time, which would not be, unless acidity were in it; the thick residuum better preserves iron from rust [glycerol is a known corrosion inhibitor], inasmuch as the aforesaid acid has been taken away by distillation, and is turned, by a strong fire, into an alkalized coal (carbonem, alcalizatum), which is plain to the eye, by the removal (affusione) of any acid spirit. This is the reason the chief Armourers of this noble city [Venice], before they oil their armour, cause the oil to evaporate at a gentle fire, almost to the half.”49 The saponification process had been known and used industrially since ancient times, but the chemistry was not understood.

Tachenius can be said to have been ahead of his time by 150 years. He had deep insight into the nature of acids and bases, but the practical and theoretical framework of chemistry that would be needed to take this further had not yet been developed. Moreover, his books, purportedly seeking legitimacy through the authority of Hippocrates, were largely conceived as polemic attacks on Johann Zwelfer and other members of the medical establishment.50

It was not until the 1800s that Michel Eugène Chevreuil (Figure 6), an assistant of Vauquelin, saponified fats to glycerol and separated the fatty acids (butyric acid in 1817,51 caproic acid from butter fat, and valeric (“delphinic” or “phocenic”) acid from dolphin and porpoise oil as well as caproic, capric, palmitic and stearic acids.52 He determined their elemental composition in meticulous analytical experiments and coined the name glycerine for the principe doux from Greek glykys, sweet.53, 54 With this, Chevreuil showed for the first time that the “organic bodies” were composed of discrete organic compounds. This was an epochal advance, because for Bergman, Gren, Berzelius and their contemporaries, the chemical nature of the organic bodies had remained elusive.

Details are in the caption following the image
Figure 6
Open in figure viewer
PowerPoint
From left to right: Lavoisier, Chevreuil, and Berthelot.

Chervreuil himself was surprised that nobody had done this before: “When we started the study of physical sciences, we were astounded by the void existing at the time in organic chemistry….I will use the term immediate principle (principe immédiat) of the organised bodies (corps organisés) or immediate organic principles (principes immédiats organiques) for those compounds where the elements are joined through the vital force (sous l'influence de la vie).” Thus, to Chervreuil, life was still necessary to form organic compounds. He also specified what an organic compound is: “In plant or animal chemistry an organic compound (composé organique) is considered as an immediate principle species, because one can evidently not separate several sorts of material from it without altering its nature” (for the original French text, see the Supporting Information, Section S6).53

In summary, organic compounds started to become better known, especially through the work of Scheele. Organic chemistry as defined by Berzelius was now an active area of research, which consisted essentially in the isolation and analysis of organic compounds from plant materials. Chevreuil defined the concept chemical compound and showed for the first time that organic materials (fats) in living things in the animal kingdom are in fact composed of discrete organic molecules amenable to chemical manipulation. However, organic synthesis was still to be invented.

6 Artificial Urea, Isomerism, Vital Force: Isomerism, Wöhler and Liebig
As Berzelius and Chrevreuil had stated, a vital force was required for anything to be alive, and that was also the case for anything derived from such things, including organic chemicals. Hence it was thought impossible to create organic compounds from inorganic (“dead”) things. Therefore, Wöhler's sensational synthesis of urea from ammonium cyanate in 1828 and Kolbe's synthesis of acetic acid from the elements in 1845 (see below) caused a paradigm shift. Wöhler's synthesis was carried out by treating silver oxycyanate with an aqueous solution of ammonium chloride, or lead oxycyanate with “liquid ammonia” (i. e. aq. ammonia). Instead of the expected ammonium cyanate, the organic compound urea was formed (Scheme 2):55

Details are in the caption following the image
Scheme 2
Open in figure viewer
PowerPoint
Wöhler's urea synthesis 1828.

In his personal announcement to Berzelius on 22 February 1828,56 he wrote “I must write to you again already now, because I can barely hold my chemical water, so to speak. I can make urea [Harnstoff] without the need for a kidney or an animal at all, whether man or dog. Ammonium cyanate is urea.” He further established that his artificial urea was identical with natural urea from urine, “pisse-Harnstoff [sic!], which in every respect I had made myself. This would be an incontestable example that two different bodies [compounds] can contain the same proportion of the same elements, and that only the different kind of combination gives rise to the different properties.” Further, “Can this artificial preparation of urea be regarded as an example of the formation of an organic substance from inorganic bodies?” (see the German text in the Supporting Information, Section S7).

In his reply on 7 March 1828,57 and again in his Lärbok i Kemien (Lehrbuch der Chemie) Berzelius wrote that it was highly remarkable that the saltiness completely disappeared when the acid HNCO combined with ammonia, and that urea, in spite of having the same composition as a salt, was not a salt.58 Even Dumas, who was not exactly a friend of Wöhler, who had called him a swindler,59 wrote: “All chemists applaud the brilliant discovery of Mr. Wöhler of the artificial formation of urea. I have myself, more than anybody, the sincere desire to see the same principle applied to analogous cases, to which it seems to be key”60 (see the Supporting Information, Section S7, for the French text).

Two years later, Liebig and Wöhler showed that crystalline ammonium cyanate is in fact formed first, when anhydrous HNCO vapor is mixed with ammonia vapor, and that it rearranges very easily to urea (Scheme 3), for example, on melting or on evaporation of an aqueous solution.61 Furthermore, they found that ammonium cyanate was also formed first in Wöhler's original preparations.

Details are in the caption following the image
Scheme 3
Open in figure viewer
PowerPoint
Liebig and Wöhler's refined urea synthesis 1830.

Liebig acknowledged that “Woehler has found a way to obtain it [urea] artificially; it is the first material produced in the act of animal life, whose reproduction by chemical means has been achieved62 (see the Supporting Information, Section S7, for the French text). Hermann Kolbe noted in 1854 that Wöhler's achievement constituted a synthesis almost immediately from the elements, the natural division which until then had separated organic from inorganic compounds had fallen, and a classification of chemical compounds into organic and inorganic in the earlier sense had no natural basis.63 The “earlier sense” was of course that organic compounds were totally different from inorganic ones, being obtainable only from organic, i. e. living things (or things that had at least been alive). In actual fact, HNCO and NH3 could both be prepared without the intervention of an organic compound, so Wöhler's synthesis was truly absolute. Much later, high-temperature pyrolysis of a gaseous mixture of CO2 and NH3 was used by Mixter to synthesize urea.64 Probably isocyanic acid, HNCO, is formed first, and this combines with ammonia. Conversely, Wöhler reported that destructive distillation of urea gave rise to ammonia and isocyanic acid.65, 66

The possibility that different entities could result from a different arrangement of atoms (primordia), just as the rearrangement of the letters in a word generates a different word, was suggested already by Lucretius (ca. 99–55 BC).67 That different compounds with the same atoms in the same proportions could be formed simply by variation of the positions of the atoms (particulis primis partes) was likewise suggested by the anti-Aristotelian Sebastian Basso in 1649 (situs partium variationem, aliæ in aliarum naturam facilè transeant).68 The proof that this was indeed possible was given by Liebig and Wöhler. In 1822–1824 Liebig, in part with Gay-Lussac, had analysed the elemental composition of silver fulminate, AgCNO.69, 70 Wöhler analysed silver cyanate, AgOCN, in 1824 and formulated it as a salt of “cyanic acid”, HOCN (which in fact exists as isocyanic acid, HNCO).71 Since the two analyses were identical, Liebig, with characteristic self-confidence, concluded that Wöhler's analysis must be wrong, and Liebig's own analysis of (impure) silver cyanate actually suggested that it contained less oxygen than the silver fulminate (71 % AgO).72 However, after conferring with Wöhler, Liebig analysed a sample of pure silver cyanate himself and confirmed Wöhler's composition (75.5 % AgO).73, 74 The two became life-long friends and collaborators. Wöhler acknowledged Gay-Lussac75 for the realization that in silver fulminate and silver cyanate the same particles were arranged in different ways.76 This work contributed to Berzelius′ formulation of the concept of isomerism, first put forward in 1830, when he was considering the terms homo-synthetic (homo-synthetiska) and isomeric (isomeriska) bodies (kroppar) from the Greek omos+synthesis and isomeros, respectively, for compounds put together of same parts.77 He settled on isomeric, which he restated in 1831.78 Notably, bodies now had the meaning discrete chemical compounds, not (living) bodies. Apart from cyanic and fulminic acids, ammonium cyanate and urea, Berzelius mentioned tartaric and racemic tartaric acids.79 However, it is important to realize that the constitutions of all these compounds remained unknown. Although cyanic and fulminic acids were known to contain the elements H, C, N, and O, the way they were arranged and connected was unknown.

Liebig still believed in the vital force (Lebenskraft):80 “When we distinguish the effects of the chemical force and the vital force, we will be on the way to gain further insight into the latter. Chemistry will never be able to produce an eye, a hair, or a leaf.”81 Nevertheless, he also believed that it would become possible one day to synthesize natural organic compounds such as quinine, morphine, albumin, and fibrin: “There is enough experience to give us hope that it will become possible to make compounds like quinine, morphine, and the substances of eggwhite or muscle fibres with all their properties”.

Gerhardt82 maintained that urea and all other artificial natural products that had been synthesized were only products of combustion, or waste, and therefore less complicated than the organic bodies from which they were formed in living things and pointed out that nobody had (yet) achieved the preparation of uric acid from urea, sugar from alcohol, salicin from salix oil or wood from methanol (“spirit of wood”, Holzgeist, obtained by dry distillation of wood) (see further in the Supporting Information, Section S8).

In conclusion, by the 1820s–1840s a better understanding of the chemical composition of organic compounds had been achieved. Wöhler had made the first organic compound, urea, from inorganic materials, thereby delivering a serious blow to the Vital Force theory. It was understood that atoms could have fixed positions within molecules, which could give rise to isomerism, but since there was still no structural theory, the constitutions of the growing number of organic compounds were not known.

7 Organic Compound from the Elements: Acetic Acid, Kolbe
The next synthesis of an organic compound directly from the elements, without any organic material involved at any stage, was achieved by Hermann Kolbe in Marburg.83 He performed an important series of experiments demonstrating that acetic acid, which had previously only been isolated from organic materials, could be prepared from the elements, i. e. by purely non-biological means. This involved the synthesis of CS2 from carbon and sulfur at red heat, and its reaction with chlorine to yield CCl4. Pyrolysis of CCl4 through a red-hot porcelain tube filled with pieces of porcelain afforded tetrachloroethene and chlorine, probably via intermediate formation of dichlorocarbene. The tetrachloroethene under water was converted by sunlight to trichloroacetic acid, and reduction of the latter with mercury-potassium alloy or by hydrogen generated by electrolysis of water yielded acetic acid (Scheme 4).

Details are in the caption following the image
Scheme 4
Open in figure viewer
PowerPoint
Kolbe's synthesis of acetic acid from the elements 1845.

Kolbe emphasized that these reactions showed a “transition from simple inorganic compounds to compounds usually considered to belong exclusively in the domain of organic chemistry; so here, as in few other cases, it became impossible to draw a line between Organic and Inorganic” (for an excerpt of the German text, see the Supporting Information, Section S9).

Liebig and Wöhler84 stated in 1837 that “The philosophy of chemistry will draw the conclusion from this work that the production of all organic materials in our laboratories must be considered not only likely but certain, inasmuch as they no longer belong to the organism. Sugar, salicin, and morphine will be produced artificially. Of course, we do not yet know the ways to reach this goal, because we do not know the precursors from which these compounds are generated, but we shall get to know them” (for the German text, see the Supporting Information, Section S10).

The work of Wöhler and Kolbe demonstrated that organic compounds can be synthesized from inorganic, “dead” things. A special vital force is not necessary. Organic synthesis had been started, and the synthesis of complicated organic molecules seemed within reach.

8 Non-natural Organic Compounds: Organic Synthesis, Berthelot
In 1853–54 Pierre Eugène Marcellin Berthelot (Figure 6) achieved the combination of numerous natural carboxylic acids with glycerol:85 “The object of the present work is [was] to combine glycerol with fatty acids so produced by chemical means…it regards the artificial preparation of the neutral principles of natural fats, i. e. the synthesis of these bodies themselves. The synthesis of these various substances, neutral natural fats, fatty acids, glycerol, [and] the knowledge of their role and their ratios has taken place in several phases, which are recounted here.” Moreover, he also combined glycerol with other carboxylic acids and thus for the first time made organic compounds not known to occur in nature:86 “I achieved the combination of glycerol with other acids, namely acetic, valeric, benzoic, sebacic, etc. The method used is the one that is used to etherify [esterify] fatty acids…” (For the French texts, see the Supporting Information, Section S11).

The important achievement of Berthelot was the synthesis of new organic compounds, which were not known to exist in Nature. This can be said to represent the beginning of organic synthesis in the modern sense, that is, the synthesis of any carbon compound, whether natural or not.

9 Synthesis and Analysis, Synkrisis and Diakrisis: Aristotle, Geber, Libavius, Sennert, Billich, Juncker
The term synthesis (syn+thesis, put together) has roots going back to Aristotle (4th century BC), but for Aristotle the term did not have the meaning we understand today; instead, synthesis was the loose “putting together” (mixing) of different particles, like grains of barley and wheat in a jar. A mixis in contrast was strong and permanent.87, 88 To the Iranian alchemist Geber (ca. 850–950 A.D.) this was a fortissima compositio, obtained from the minimae partes, which were composed of the four Aristotelian elements (compositio is the Latin equivalent of the Greek synthesis).89 Aristotle also used two other (Greek) terms, synkrisis (aggregation or combination) and diakrisis (differentiation or separation) which for many 17th century chemists became virtually synonymous with synthesis and analysis (Greek ana+lysis, breaking up).90 Daniel Sennert in Wittenberg was a follower of the Greek atomist Democritus (ca. 460–370 BC) (“everything is made of indivisible atoms”). For Sennert, therefore, the Aristotelian generatione and corruptione were nothing but synkrisis and diakrisis. In 1611, he explained laboratory processes in terms of synkrisis and diakrisis.91 The terms had been used previously by Andreas Libavius13a and by Anton Günther Billich in Oldenburg.92 Johann Juncker in Halle93 later made extensive use of diakrisis and synkrisis as equivalent to analysis and synthesis, and redintegration for reversible reactions (e. g. sulfuric acid+iron iron vitriol), where both diakrisis and synkrisis are involved.

10 Analysis and Synthesis, “Completing the Proof”: Descartes, Newton, Boyle, Kant, Bergman, Dalton
In the 1640s René Descartes (Figure 7) advocated the use of analysis and synthesis as methods of demonstration that something is true and emphasized that it was necessary to confirm the outcome of an analysis by synthesis.94 While this was formulated as a general principle and deemed very useful in geometry, it could equally well have applied to (in)organic chemistry–organic synthesis did not yet exist. Using wording similar to Descartes to describe his famous synthesis of white light, Isaac Newton compounded (in the Latin edition: componere=put together) white light by mixing the rays of colored light, “therein to experience the Truth of the foregoing Propositions” (namely that he had separated the colored rays).95 The notion of the necessity of synthesis to confirm the result of analysis, “to complete the proof”, was taken up by several 17th and 18th century chemists and philosophers, including the phlogiston champion Georg Ernst Stahl,96 Bergman, and Lavoisier (see the decomposition of water into hydrogen and oxygen (an analysis), and the proof by its re-synthesis from the elements (Section 4)). The same principle has been widely applied in the determination of structure of organic natural products until very recently.

Details are in the caption following the image
Figure 7
Open in figure viewer
PowerPoint
René Descartes, Principia Philosophiae.94

In 1661 Boyle (who was influenced by Democritus, Gassendi, Descartes, and Sennert) used analysis with the meaning taking apart or decompose, and Redintegration for recombination: “Redintegration of an analyz'd body if it can be accurately and really performed, may give much light to many particulars in philosophy, and would certainly be very welcome both to the embracers of the Atomical Hypothesis, and generally to those other Modern Naturalists…”. As an example, illustrating “dissipation and reunion of component particles to constitute other bodies of a very different nature”, Sal Ammoniak (NH4Cl), is formed from spirit of urine (NH3) and spirit of salt (HCl), but “as strictly as they are united in the compound, may be readily divorc'd” (by distillation).97

The Naturphilosoph Immanuel Kant98 theorised about organic and organised bodies and debated analytical and synthetic judgments epistemologically.99 In 1777 Bergmann reiterated the need for both analysis and synthesis in chemistry:26a, 100 “Synthesis or assemblage of bodies is the proper control to show whether analysis is correct.” As organic synthesis was unknown, the principle could only be applied in inorganic chemistry at the time. Bergman further opined that it would not be possible to synthesize the organic bodies (Swedish kroppar, German Körper): “as I said before, one can make many inorganic bodies through art [i. e. chemistry], but there is no reason to believe that this will ever be possible for the organic bodies. Even if their elements are known, this is not enough, because the most distinguished feature of the organic bodies is the unique way they are built, which cannot be copied by the art, and which Nature itself can only perform in one way” (for the Swedish and German texts, see the Supporting Information, Section S12).

Dalton explicitly used the terms synthesis and analysis in relation to the combinations of atoms to form molecules in 1808: “Chemical analysis and synthesis go no farther than to the separation of particles one from another, and to their reunion.”101 It followed from his text that the particles could be either atoms or combinations of atoms. The combinations could be binary, ternary, etc., so CO2, “carbonic acid”, for example, was a ternary compound of one carbon and two oxygen atoms.

Thus, progress in chemical synthesis during the 1700s and early 1800s made it possible to use synthesis as a tool to prove the composition of organic compounds as derived by analysis. By the middle of the 19th century synthesis and analysis had become established branches of chemical science,83, 85, 102, 103 but the structures of organic molecules were still very poorly understood, albeit hotly debated.39, 59, 104 Although Berzelius, Wöhler, Liebig and Kolbe had been instrumental in the development of organic chemistry during the first half of the 1800s, they were either simply dismissive or fiercely opposed to the new structural ideas now being advanced by younger chemists, who would radically change the understanding of chemistry.39, 105 Liebig and Wöhler looked mostly sceptically at the “playing with formulas” (“Formelspielerei”) of Gerhardt, Laurent, Edward Frankland, Alexander Williamson and August Kekulé.105, 106 Berzelius called Gerhardt a scientific fool,107 and after Berzelius’ death in 1848 Kolbe took up the fight105 against the revolutionary structural theories being put forward by Kekulé and, a little later, Jacobus van't Hoff and Joseph Le Bel.

11 Conclusion
The term organic chemistry developed out of organic or organised, that is, living, bodies (corps organisés) in contrast to the non-organic bodies, which were unorganised. This was long before discrete organic compounds were known, and the molécules organiques of Gassendi, Charleton and the Comte de Buffon were not molecules in the modern sense but tiny fragments of organic material. Bergman defined organic and unorganic bodies, but the former as well as Gren's organische Körper were still living things rather than individual compounds, although Gren started to see chemical reactions occurring within them. Lavoisier, Berthollet and Berzelius determined by combustion analysis that organic compounds consist primarily of C, H, O, and N, with smaller amounts of S, P, and other elements and thereby made an empirical, chemical understanding of organic materials possible. Chrevreuil caused a paradigm shift when he isolated individual fatty acids and glycerol from the saponification of fats, thus demonstrating for the first time that organic materials are in fact composed of discrete organic molecules. Berthelot built on this to create organic synthesis, that is, the synthesis of natural as well as non-natural organic compounds. Wöhler caused another paradigm shift, when he made the first organic compound, urea, fully from inorganic materials (NH3 and HNCO), and Kolbe subsequently synthesized acetic acid from the elements. Until that time, organic chemistry had been essentially the isolation and analysis of natural products.

The combined achievements of Chevreuil, Lavoisier, Wöhler, Liebig, Kolbe and Berthelot (Figures 6 and can be seen as the end of the Vital Force theory, even though many would still cling to it, and the beginning of organic chemistry as we know it, namely the chemistry of carbon compounds regardless of whether they exist in nature or not.

Details are in the caption following the image
Figure 8
Open in figure viewer
PowerPoint
From left to right: Wöhler, Liebig, and Kolbe.

The philosophical concepts of synthesis and analysis and the related synkrisis and diakrisis had been used in classical Greece and up through the Middle Ages. Descartes emphasized the need for synthesis to follow analysis as a proof for anything to be correct, and Bergman defined these terms in a chemical sense in the late 1700s, before organic chemical compounds were properly known. Dalton used synthesis and analysis in relation to the combinations of atoms in 1808. Gerhardt thought only Nature did real synthesis, but Kolbe and Berthelot used the term with the meaning we understand as synthetic chemistry today.

https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/ejoc.202101492 (more at link)

This guy tries to take the question in depth. Of course most science on the creation of "life" fall back on big numbers for accepting the Organic derived from InOrganic structures-molecules...but of course that should be lab-ready if so...hence the "fall-back" explanation (number of earth like planets, galaxies, atomic structures, billions of years, etc.). The time-range and creation of diverse living entities on Earth is interesting. Actually for me personally this is the key question -- what makes something living and non-living in terms of structures -- like why doesn't Iron "live" or is a Frankenstein molecule really possible given billions of years? There are volumes of PAHs in space -- "organic" matter-structures floating there -- why don't these come alive -- is it just fats-DNA-RNA-proteins?
--------------
Volume 5 Supplement 3

Origin and Early Evolution of Life
ORIGIN OF LIFE

Published: 27 September 2012
Prebiotic Chemistry: What We Know, What We Don't
H. James Cleaves II

Evolution: Education and Outreach volume 5, pages342–360 (2012)Cite this article


The Miller–Urey apparatus. The 500-liter flask contained heated water, evaporating upward and coming into contact with the gases contained in the five-liter flask. The molecules created by contact with the electric discharge were returned to the 500-cubic centimeter flask by the condenser. Reproduced from Lazcano and Bada (2003)

Full size image
Chemical analysis of the resulting products revealed a surprisingly efficient synthesis of a number of amino acids found in biochemistry, including glycine, and racemic alanine and aspartic acid (Miller 1953). While there had been earlier laboratory demonstrations of organic synthesis using electric discharges (see, for example, Löb 1913), this experiment is generally considered the first conducted in the context of trying to understand the origin of life. It is thus widely deemed to have opened the modern experimental period of research into the mechanism of the origin of life and to have been the first intentional example of “prebiotic chemistry.”

Coincidentally, Watson and Crick published their structure for the DNA double helix within a week of the publication of Miller's results (Watson and Crick 1953). Until that time, it had been widely debated whether proteins or nucleic acids were the carriers of genetic inheritance (though the evidence was strongly in favor of the latter): the structure of DNA left little doubt. This close historical juxtaposition of discoveries reveals a common motif in prebiotic chemistry and in origins-of-life models in general: discoveries in other fields frequently drive advances in origin of life models.

All modern organisms are composed of cells, a fact recognized since the 1800s. However, the understanding of the molecular-scale functioning of cells has undergone remarkable development, allowing more precise questions to be posed regarding the origin of the first living cell.

Modern cells share a variety of common biochemical characteristics which are believed to be evidence of a common ancestry: all are bounded by lipid membranes, all contain DNA, all contain ribosomes, and all use a very similar genetic code to produce the protein enzymes that carry out cellular metabolism.

The general flow of information in cells is known as the “central dogma” of biology (Fig. 2), which holds that DNA encodes various RNA molecules, which in turn are used to make coded proteins. These RNA molecules include ribosomal RNA (rRNA), which folds into ribosomes (that also contain numerous structurally important peptides) - the protein-manufacturing machines of the cell, transfer RNA (small folded RNA adapter molecules that ensure the precise amino acid coded by a DNA strand gets incorporated into the proper location in a protein) and messenger RNA (into which coded genetically encoded messages of DNA are transcribed before being translated into proteins). DNA is itself copied using various protein enzymes and small RNA primers.

Fig. 2
figure 2
The central dogma of information flow in biology. The circular arrow leading back to DNA represents the fact that DNA is a template for its own replication, a process which is mediated by protein and RNA

Full size image
The fact that proteins are needed to make DNA and DNA is needed to make proteins leads to a “chicken or egg paradox”: which logically would have had to arise first? The central role of RNA in this process led some to speculate that it could be the solution to the paradox (Crick 1968; Orgel 1968; Woese 1968), and this led to the notion of an “RNA World” (Gesteland and Atkins 1993), a putative period in which RNA functioned as both catalyst and genetic molecule. Some scientists interpret the RNA World to mean that life began with a self-replicating RNA molecule, while others interpret it to mean that life passed through a period in which RNA was merely extremely important in biochemistry. The perceived simplicity of the first interpretation has driven considerable research into the prebiotic synthesis of RNA.

As recently as the 1990s, the living world was divided into five kingdoms, the animals, plants, fungi, protists, and bacteria (Whittaker 1969). Comparison of rRNA sequences (which presumably are resistant to evolutionary drift) has revised this classification scheme into three domains, phylogenetically organizable into an evolutionary tree of life (Fig. 3): the Eukarya (comprising the eukaryotes), the Bacteria, and the Archaebacteria (Woese et al. 1990). This last group has a number of unique characteristics, including specialized forms of metabolism and membrane lipids.

Fig. 3
figure 3
The reconstructed Tree of Life based on ribosomal RNA sequences. Figure reproduced from Pace (1997)

Full size image
Some analyses of this tree suggest hyperthermophilic archaebacteria are the oldest organisms on Earth (Wang et al. 2007), which has been used to argue that the types of environments these organisms inhabit presently were the earliest environments for life and thus likely sites of the origin of life. This idea remains controversial (Arrhenius et al. 1999; Gupta 2000). The reconstructed tree suggests that the Last Universal Common Ancestor (LUCA) of all modern biology was a single-celled prokaryote, albeit one with an already sophisticated and very modern biochemistry, suggesting a prior protracted period of biochemical evolution.

To address the question of the origin of LUCA, it is necessary to examine models for how the Earth formed, what geochemical environments may have been available on the early Earth, and what types of organics could have been produced in each.

History of the Earth and Solar System
The Earth is believed to be ∼4.5 billion years old, only 10–15 million years younger than the solar system itself (Dalrymple 1994). The accepted model for the origin of the solar system is the nebular hypothesis (Montmerle et al. 2006), which holds that the solar system condensed into a disk from a presolar nebula, a cloud of gas and dust composed of remnants of a previous supernova. Due to inelastic collisions during gravitational accretion of small particles, larger bodies formed, gradually coming to occupy orbits at varying distances from the nascent central star, our Sun.

These bodies were dramatically altered in composition when the Sun accreted enough mass to trigger the ignition of thermonuclear fusion in its interior, releasing vast amounts of energetic electromagnetic radiation. Lower boiling point compounds in the surrounding disk were driven outward from the Sun, as in a distillation, each condensing beyond its relative condensation point. Thus, volatile components such as methane, water, and N2 coalesced into outer solar system bodies such as the gas and ice giant planets (Saturn, Jupiter, Neptune, and Uranus) and the Oort cloud and Kuiper belt comets, while higher boiling-point compounds such as metal oxides and silicates, which make up the bulk of the inner rocky planets, condensed nearer in.

The smaller resultant bodies, comets, meteors, and interstellar dust particles (IDPs) continue to impact the planets presently, and it is likely that this flux was higher around the time that life formed on Earth. The presence of extraterrestrial organic molecules in meteorites, comets, and IDPs is firmly established and has led to proposals that these were sources of organic compounds possibly necessary for the origin of life (Oró 1961; Anders 1989; Chyba et al. 1990; Chyba and Sagan 1992).

The flux of extraterrestrial organics to the early Earth has been estimated based on the lunar cratering record (Chyba and Sagan 1992). These may have contributed significantly to the primitive Earth's prebiotic organic inventory, even if the early Earth's atmosphere were oxidizing or neutral (Chyba and Sagan 1992; Thomas et al. 1996). Their components resemble the products of atmospheric synthesis under reducing conditions (Wolman et al. 1972); thus, their compositions are worth examining.

Comets
Comets are mixtures of dust and ice accreted early in the history of the solar system (Festou et al. 2004). In addition to water ice and various inorganic components, the volatile organic components of several comets have been measured spectroscopically (Ehrenfreund and Charnley 2000). Highly reactive organic compounds such as hydrogen cyanide (HCN) and formaldehyde (HCHO), among others, though variable from comet to comet, are often observed in high abundance (Table 1).

Table 1 The abundance of small molecules relative to water in comet Hale–Bopp as measured spectroscopically
Full size table
Measurement of the hydrogen isotope ratios of cometary water suggests that some of the Earth's oceans may be derived from comets (Chyba 1990; Meier et al. 1998). If this is true, comets could also have delivered organics, though the survival of these would depend on the nature of the delivery process (Oró 1961; Oró et al. 1980). Assuming that cometary nuclei have a one-gram per cubic centimeter density, a one-kilometer-diameter comet would contain 2 × 1011 moles of HCN, or 40 nanomoles per square centimeter of the Earth's surface. This is comparable to the yearly production of HCN in a reducing atmosphere from electric discharges and would be important if the Earth did not have a reducing atmosphere, assuming complete survival of the HCN on impact.

While comets are extremely cold, it appears that some aqueous-phase organic reactions have occurred in them, as evidenced by the detection of the simplest amino acid, glycine, in particles returned from comets (Elsila et al. 2009); thus comets could have delivered some more complex compounds as well.

Meteorites
Meteorites represent generally less volatile remnants of the early solar system, i.e., objects which formed closer to the Sun and underwent more significant thermal processing (Lauretta and McSween 2006). Their compositions range from metallic to stony. The latter category includes a class with which prebiotic chemists are particularly fascinated, the carbonaceous chondrites (CCs), which contain a significant organic component, usually one to two % by mass (Alexander et al. 2007). Besides a few recovered cometary grains, CCs remain the best-studied bona fide examples of “prebiotic chemistry,” represented by several hundred examplars in various curated collections around the world. CC organic material is variable in composition, but typically 70–99% is a complex high molecular weight kerogen-like material, with the remainder being small soluble organic compounds (Pizzarello et al. 2006).

A variety of organic compounds have been identified in CCs, including many found in modern biochemistry (Pizzarello et al. 2006). That these compounds are indigenous to the meteorites, and not terrestrial contamination, is suggested by the facts that they have unusual isotopic ratios and include types of compounds not typically found in biochemistry; and that compounds with stereocenters are found in nearly equal quantities with respect to their optical isomers, with some notable exceptions (Pizzarello and Cronin 2000; Glavin and Dworkin 2009). A brief summary of the types and relative abundances of compounds identified to date is shown in Table 2.

Table 2 Organic compounds detected in the Murchison carbonaceous chondrite
Full size table
IDPs
The input from IDPs may have been more important than that of comets or meteorites. Their present infall rate is large, and on the primitive Earth, it may have been greater by a factor of 100 to 1,000 (Love and Brownlee 1993). The organic composition of IDPs is poorly understood (Maurette 1998); the only molecules that have been identified to date are polycyclic aromatic hydrocarbons and α-aminoisobutyric acid (Gibson 1992; Clemett et al. 1993). Heterogeneous organic polymers loosely termed tholins (also produced by electric discharges, ionizing radiation, and ultraviolet light) could be major components of IDPs. Amino acids are released from tholins on acid hydrolysis (Khare et al. 1986); tholins could thus also be a source of organics. On entry to the Earth's atmosphere, IDPs could be heated and their tholins pyrolyzed, creating HCN and other molecules, which could then participate in terrestrial reactions (Mukhin et al. 1989; Chyba et al. 1990).

Formation of the Earth and the Origins of the Atmosphere and Oceans
As it is widely believed that life requires an aqueous environment, and it is a cornerstone of many ideas regarding the origins of Earth's early organics that the early atmosphere was reducing, it is worth discussing the origin of the Earth's oceans, atmosphere, and crust, as these have a complex interplay which affects their ability to produce organic compounds.

During solar system formation, as asteroids accreted, the heat generated from the radioactive decay of elements (such as 26Al and 40K) was trapped in the interiors of these bodies, which began to warm up. As asteroidal component melted and liquefied, they migrated inward or outward within these bodies depending on their densities. As asteroids accreted into planetesimal-sized objects, the internally trapped heat became great enough to melt rock and metal, and denser materials migrated inward to form metallic cores, as in the rocky planets.

Since much of this material was reduced iron, the migration of this metal to the Earth's core took with it a great deal of the planet's reducing equivalents. Much of the lighter material, including elements such as C, N, and H, migrated toward the surface, with the oxidation state of these elements determined by the equilibration conditions they were exposed to during migration.

Whether the early atmosphere was ever reducing remains contentious (Tian et al. 2005), but it seems unlikely that it was for very long. An N2/CO2-dominated atmosphere may be the most stable state in the absence of biology. O2 in the present atmosphere is almost entirely generated from biological photosynthesis. In the absence of biology, the lifetime of O2 would be extremely short due to its reaction with elements such as iron in the crust (for example, 1.5 O2 + 2 Fe2+ → Fe2O3). A consequence of the lack of O2 in the early atmosphere is that there would have also been little UV-absorbing ozone (O3), which would have allowed highly energetic bond-breaking UV radiation to reach the Earth's surface (Cleaves and Miller 1998). It is generally believed, in addition, that the early Sun produced a far larger amount of radiation in the UV region (Kasting and Siefert 2002) than at present.

The oxidation state of the early mantle likely governed the distribution of outgassed species. Holland (1962) proposed, based on the Earth accreting homogenously and cold that the Earth's atmosphere went through two stages: an early reduced stage before differentiation of the mantle and a later neutral/oxidized stage after differentiation. During the first stage, the redox state of the mantle was governed by the Fe°/Fe2+ redox pair. The atmosphere in this stage would be composed of H2O, H2, CO, and N2, with approximately 0.27–2.7 × 10−5 atmospheres of H2. Once Fe° had segregated into the core, the redox state of magmas would have been controlled by the Fe2+/Fe3+ pair or fayalite–magnetite–quartz buffer.

If the core differentiated rapidly (via rapid sinking of Fe° into the core), the early atmosphere may have resembled the composition of modern volcanic gases (Rubey 1951). Rubey estimated that a CH4-dominated atmosphere could not have persisted for more than 105–108 years due to photolysis. The Urey/Oparin atmosphere (CH4, NH3, H2O) model is thus based on astrophysical and cosmochemical constraints, while Rubey's model is based on extrapolation of the geological record. Although early theoretical work had an influence on research, modern thinking on the origin and evolution of the solar system, the Earth, and its atmosphere and oceans has not been shaped largely with the origin of life in mind. Rather, current origin-of-life theories are usually modified to fit frequently-changing geochemical models.

Light atmospheric gases such as H2 would have been prone to rapid escape to space due to their low escape velocities, while others such as NH3 would be rapidly decomposed in the atmosphere by UV photolysis (Ferris and Nicodem 1972; Kuhn and Atreya 1979). Nevertheless, low levels of these compounds could have been maintained at steady state, and significant amounts of NH3 could have dissolved in the oceans if the pH of the early oceans was lower than the pKa of NH3 (∼9.2 at 25 degrees Celsius) (Bada and Miller 1968).

Water outgassed as steam and slowly condensed as the crust cooled, forming the Earth's surface waters. There is some evidence from zircons (weathering-resistant minerals found in crustal rocks) that liquid water was present as early as 4.4  billion years ago (Valley et al. 2002). The temperature and pH of the early oceans remain poorly constrained, with possible ranges between zero and 100 degrees Celsius and a pH range of 5 to 11 (Kempe and Degens 1985; Morse and Mackenzie 1998).

If a reducing atmosphere was required for terrestrial prebiotic organic synthesis, the crucial question is the source of H2. Miller and Orgel (1974) estimated the pH2 as 10−4 to 10−2 atmospheres, depending on the various sources and sinks. H2 could have been supplied to the primitive atmosphere by several sources (Tian et al. 2005), and it is unclear what would have governed this balance.

The oxidation state of the atmosphere is important for the production of HCN, an important reactant in the prebiotic synthesis of purines and amino acids (see below). In CH4/N2 atmospheres, HCN is produced abundantly (Chameides and Walker 1981; Stribling and Miller 1987), but in CO2/N2 atmospheres, most of the N atoms produced by splitting N2 recombine with O atoms to form NO x species (Chameides and Walker 1981). Reduced gas mixtures are generally more conducive to organic synthesis than oxidizing or neutral gas mixtures. Even mildly reducing gas mixtures produce copious amounts of organic compounds, and it seems likely that energy was the not the limiting factor (Stribling and Miller 1987).

Evidence for Life on Earth
Evidence for life on Earth was once restricted to animals leaving visible fossils, which extended back as far as the beginning of the Cambrian period (∼550 million years ago). Micropaleontologists began to find evidence for Precambrian life in the 1960s in the form of fossilized bacteria in cherts. Presently, the oldest commonly agreed upon fossil microorganisms (it cannot be ascertained whether these organisms were archaebacteria, bacteria, or perhaps members of another no-longer-existent line of organism) are dated back to approximately 3.45 billion years ago (Schopf 1993). There is evidence in some of the oldest known rock strata for isotopically light carbon, possibly formed via biological activity, as far back as 3.85 billion years ago (Mojzsis et al. 1996). This notion remains controversial, and there is evidence that nonbiological processes could also produce this signal (Brasier et al. 2002).

Rocks returned from the moon suggest that there was a “late heavy bombardment period” in which there was an anomalously high flux of large meteors hitting the Earth ∼3.9 billion years ago (Abramov and Mojzsis 2009), which could have been planet-sterilizing. Thus, using the most conservative evidence for life on Earth and the most generous evidence for liquid water, there is about a one-giga year period of time for life to originate. Using the most controversial evidence for biologically fixed carbon and accepting the late heavy bombardment period as having been planet-sterilizing, there is a mere 50 million years available for the origin of life. Unfortunately, we cannot presently say whether the origin of life requires a week, a month, or a year, much less 50 million or a billion years, highlighting our ignorance of some of the key step in this process (Lazcano and Miller 1994).

Top–Down and Bottom–Up Approaches
Prebiotic chemistry attempts to not only produce organic compounds which could have been used to assemble the first living organisms, but also to explain the self-assembly of the first living organisms. For many researchers, the goal of prebiotic chemistry is the synthesis of a simple living system with some of the common attributes of modern cells, i.e., a lipid membrane, RNA and/or DNA, and small protein-like peptides. For the ∼60 years since Miller's pioneering experiment, the synthesis of the components of modern cells has been the somewhat less ambitious goal. While the list of compounds which can be synthesized in the lab is impressive, not all modern cell constituents have been proven to be synthesizable under plausible prebiotic conditions, nor have all of them been found in meteorites. One possible explanation for this discrepancy is that some modern components are products of evolved biochemistry and were not added to the biochemical inventory until well after organisms had developed a considerable degree of complexity (Cleaves 2010).

We do not know which compounds were required for the origin of life. Prebiotic chemists tend to focus on compounds which are present in modern biochemistry, ignoring the large fraction of compounds found in meteorites or produced in simulations that are not found in biology. A recent study of the Murchison CC using sophisticated analytical instruments revealed the presence of many as around 14 million distinct low molecular weight organic compounds (Schmitt-Kopplin et al. 2010). This can be contrasted with the approximately 1,500 common metabolites found in contemporary cells (Morowitz 1979) and the some 600 small molecules positively identified in the Murchison meteorite to date (Table 2).

Our ignorance regarding the nature of the compounds required for the origin of life, though, does not stop us from attempting to understand how organic compounds form in prebiotic environments.

Prebiotic Syntheses of Biochemicals
Amino Acids
A variety of prebiotic processes can form amino acids, for example, Miller–Urey-type electric discharge experiments (Miller 1953) and reactions of HCN in water (Ferris et al. 1974), among others, and amino acids are found in a variety of CCs (Martins et al. 2007). One of the likely principal mechanisms of formation of amino acids in these samples is the Strecker synthesis (Fig. 4a), named for Adolf Strecker, a nineteenth-century chemist who was the first to artificially synthesize an amino acid in the laboratory. Evidence for this mechanism in the Miller-Urey (MU) experiment comes from measurements of the concentrations of HCN, aldehydes, and ketones in the water flask produced during the course of the reaction (Fig. 4B), which are derived from the CH4, NH3, and H2 originally introduced into the apparatus. This suggests that amino acids are not formed directly in the electric discharge but are the result of synthesis involving aqueous-phase reactions (Miller 1955).

Fig. 4
figure 4
Evidence for the Strecker amino acid synthesis and in the Miller–Urey experiment. a The cyanohydrin (top) and Strecker (bottom) mechanisms for the formation of hydroxy and amino acids from ammonia (NH3), hydrogen cyanide, and aldehydes or ketones. b Variations in the concentrations of ammonia, aldehydes, and hydrogen cyanide over the course of a Miller–Urey experiment. Fig. 4b reproduced from Miller (1957)

Full size image
Both amino and hydroxy acids can be synthesized at high dilutions of HCN and aldehydes in a simulated primitive ocean (Miller 1957). Reaction rates depend on temperature, pH, and HCN, NH3, and aldehyde concentrations but are rapid on geologic time scales. The half-lives for the hydrolysis of the amino- and hydroxy-nitrile intermediates (the rate-limiting steps in these reactions) are less than 1,000 years at zero degrees Celsius (Miller 1998). Corroborating this notion of rapid synthesis, the amino acids found in the Murchison meteorite were apparently formed in less than 105 years (Peltzer et al. 1984).

The Strecker amino acid synthesis requires the presence of NH3. As mentioned above, gaseous NH3 is rapidly decomposed by ultraviolet light, and during Archean times, the absence of a significant ozone layer would have limited NH3's atmospheric concentration. However, NH3 is extremely water soluble (depending on pH) and similar in size to K+; thus, it easily enters exchange sites on clays. Thus, a considerable amount of NH3 may have been dissolved or adsorbed on submerged mineral surfaces.

Spark discharge experiments using CH4, CO, or CO2 as a carbon source with various amounts of H2 show that methane is the best source of amino acids, but CO and CO2 are almost as good if a high H2/C ratio is used. Without added H2, amino acid yields are quite low, especially when CO2 is the sole carbon source (Stribling and Miller 1987). Recent results, however, suggest that amino acid yields from neutral atmospheres may be higher than previously thought. Buffering reaction pH near neutral (as dissolution of gaseous CO2 tends to lower the pH) and adding oxidation inhibitors (which may counteract the oxidative effects of NO x species generated in the reaction) increased the amino acid yields from CO2/N2/H2O electric discharge reactions several fold (Cleaves et al. 2008).

Lipids and Membrane-Forming Compounds
All modern life is cellular. Eukaryotic and bacterial cell membranes are composed of largely straight-chain fatty acid acyl glycerols while those of the archaea are composed of isoprenoid glycerol ethers (Ourisson and Nakatani 1994) (Fig. 5a, b). Either type could logically have been the primordial lipid component of cells, given uncertainties in rooting the tree of life. Long-chain fatty acids and their derivatives spontaneously form vesicles and micelles under appropriate conditions, and these can transiently trap various organic species and maintain proton gradients (Deamer et al. 2002).

Fig. 5
figure 5
Ether (a) and ester (b) lipids of biological membranes (R can be various small molecule constituents including phosphate). c Micrograph of cell-like boundary structures formed spontaneously from organic extracts of the Murchison meteorite. Fig. 5c image courtesy of NASA

Full size image
Most prebiotic simulations don't generate large amounts of fatty acids (Allen and Ponnamperuma 1967), with the exception of some hydrothermal vent simulations, which may use concentrations of reactants which are unreasonably high for these environments (McCollom et al. 1999). Heating glycerol with fatty acids and urea produces acylglycerols (Hargreaves et al. 1977). A prebiotic synthesis of long-chain isoprenoids lipids has been suggested based on the Prins reaction of formaldehyde with isobutene (Ourisson and Nakatani 1994); thus, there are plausible prebiotic routes to these types of compounds.

The Murchison CC contains small amounts of straight-chain fatty acids, though some of these may be contamination (Yuen and Kvenvolden 1973). Amphiphilic components have been observed in the Murchison meteorite and in various laboratory simulations of prebiotic chemistry (Dworkin et al. 2001) (Fig. 5c), though the composition of these remains undetermined.

Nucleic Acids
Modern organisms store their genetic information in DNA and transcribe it into RNA. The difference between these molecules is the use of deoxyribose and thymine in DNA and ribose and uracil in RNA. Although some now doubt that RNA itself is prebiotic, numerous laboratory experiments show the ease of formation of purines, pyrimidines, and sugars, albeit in low yield.

Purines
The first evidence that purines could be synthesized abiotically was provided in 1961 when Oró reported the formation of adenine (formally a pentamer of HCN, C5H5N5) from concentrated solutions of NH4CN refluxed for a few days. Adenine was produced up to 0.5% yield along with 4-aminoimidazole-5 carboxamide (AICA) and an intractable polymer (Oró and Kimball 1961). It is surprising that a synthesis requiring at least five steps should produce such high yields of adenine. The initial step is the dimerization of HCN followed by further reaction to give HCN trimer and HCN tetramer, diaminomaleonitrile (DAMN) (Fig. 6).

Fig. 6
figure 6
Proposed mechanisms for formation of DAMN, AICN from DAMN, and purines from the reaction of AICN with small molecules produced in HCN oligomerization and MU-type experiments

Full size image
Ferris and Orgel (1966) demonstrated that a photochemical rearrangement of DAMN proceeds in high yield in sunlight to give amino imidazole carbonitrile (AICN) (Fig. 6). Other purines, including guanine, can be produced by variations of this synthesis from AICN and its amide (AICA) and other small molecules generated from HCN (Sanchez et al. 1967, 1968) (Fig. 6). These mechanisms are likely an oversimplification. In dilute solution, adenine synthesis may also involve the formation and rearrangement of precursors such as 2- and 8-cyano adenine (Voet and Schwartz 1983).

The steady-state concentration of HCN in primitive terrestrial waters would have depended on the pH and temperature of the oceans and the input rate of HCN from atmospheric synthesis. Assuming favorable HCN production rates, steady-state concentrations of HCN of 2 × 10−6  molar at pH eight and zero degree Celsius in the primitive oceans have been estimated (Miyakawa et al. 2002b). At 100 degrees Celsius and pH eight, this was estimated at 7 × 10−13 molar. Oligomerization and hydrolysis compete at approximately 10−2 molar concentrations of HCN at pH nine (Sanchez et al. 1966a, b), although it has been shown that adenine is still produced from solutions as dilute as 10−3 molar (Miyakawa et al. 2002a, b). If the concentration of HCN were as low as estimated, it is possible that DAMN formation may have only occurred on the primitive Earth in eutectic solutions of HCN–H2O, which would require that some regions of the Earth were frozen. High yields of DAMN are obtained by cooling dilute HCN solutions to negative ten to −30 degrees Celsius for a few months (Sanchez et al. 1966a, b). Production of adenine by HCN polymerization is accelerated by the presence of HCHO and other aldehydes, which could have also been available in the prebiotic environment (Schwartz and Goverde 1982).

The polymerization of concentrated NH4CN solutions also produces guanine between −80 and −20 degrees Celsius (Levy et al. 1999). Adenine, guanine, and amino acids have also been detected in dilute solutions of NH4CN kept frozen for 25 years at −20 and −78 degrees Celsius, as well as in the aqueous products of MU experiments frozen for five years at −20 degrees Celsius (Levy et al. 2000).

In addition to producing the biological purines, HCN oligomerization also produces nonbiological purines such as 2,6-diamino- and dioxopurines and the parent compound purine. This same suite of purines has been identified in CCs (Callahan et al. 2011), making a compelling case that similar mechanisms are responsible for their syntheses in CCs.

Formamide (HCONH2), the hydrolysis product of HCN, has also been shown to produce purines, albeit under more extreme conditions (Bredereck et al. 1961; Saladino et al. 2007).

Pyrimidines
The first “prebiotic” synthesis of pyrimidines investigated was that of uracil (U) from malic acid and urea (Fox and Harada 1961). The prebiotic synthesis of cytosine (C) from cyanoacetylene (HCCCN) and cyanate (NCO−) was later described (Sanchez et al. 1966a, b; Ferris et al. 1968) (Fig. 7). HCCCN is produced by the action of spark discharges on CH4/N2 mixtures, and NCO− is produced from cyanogen or the decomposition of urea. The high concentrations of NCO− required for this reaction may be unrealistic, as it rapidly hydrolyzes to CO2 and NH3. Urea is more stable, depending on the concentrations of NCO− and NH3. It was later found that the reaction of dilute cyanoacetaldehyde (CAA) (produced from the hydrolysis of HCCCN) with urea concentrated by evaporation in laboratory simulations of drying beaches gives large (>50%) yields of C (Robertson 1995) (Fig. 7). Evaporating CAA with guanidine produces 2, 4-diaminopyrimidine in high yield (Robertson et al. 1996), which hydrolyses to U and C, providing a mechanism for the accumulation of pyrimidines in the prebiotic environment. A eutectic reaction producing the biological pyrimidines has also been demonstrated (Cleaves et al. 2006). U (albeit in low yields) and its biosynthetic precursor orotic acid were also identified in the hydrolysis products of HCN polymer (Ferris et al. 1978; Voet and Schwartz 1982), and U has been identified in CCs (Stoks and Schwartz 1979)

Fig. 7
figure 7
Possible mechanisms for the prebiotic synthesis of pyrimidines from the reaction of HCCCN or CAA with urea concentrated in drying lagoon models

Full size image
.

The reaction of U with formaldehyde and formate gives thymine (T) in good yield (Choughuley et al. 1977). T is also synthesized from the UV-catalyzed dehydrogenation of dihydrothymine, produced from the reaction of β-aminoisobutryic acid with urea (Schwartz and Chittenden 1977).

Sugars
Many biological sugars have the empirical formula (CH2O) n , a point underscored by Butlerov's 1861 discovery of the formose reaction, which showed that a diverse assortment of sugars can be formed by the reaction of HCHO under basic conditions (Butlerow 1861). The Butlerov synthesis is complex and incompletely understood. It depends on the presence of catalysts, with Ca(OH)2 or CaCO3 being the most completely investigated. In the absence of base catalysts, little or no sugar is obtained. Clays such as kaolin catalyze the formation of sugars, including ribose, in small yields from dilute (0.01 molar) HCHO solutions (Gabel and Ponnamperuma 1967; Reid and Orgel 1967; Schwartz and Degraaf 1993).

The Butlerov synthesis is autocatalytic and proceeds through glycoaldehyde, glyceraldehyde, and dihydroxyacetone. The reaction is also catalyzed by glycolaldehyde, acetaldehyde, and various other organic catalysts (Matsumoto et al. 1984).

The reaction may proceed as shown in Fig. 8. The reaction tends to stop when the formaldehyde has been consumed and ends with the production of C4–C7 sugars that can form cyclic acetals and ketals.

Fig. 8
figure 8
A simplified scheme of the formose reaction

Full size image
The reaction produces all of the epimers and isomers of the small C2–C6 sugars, some of the C7 ones, and various dendroaldoses and dendroketoses, as well as polyols such as glycerol and pentaerythritol, and is generally not particularly selective, although methods of overcoming this have been investigated. Of special interest is the observation that borate can skew the product mixture in favor of certain sugars, including ribose (Prieur 2001; Ricardo et al. 2004). Inclusion of acetaldehyde in the reaction produces deoxyribose (Oró 1965).

Problems with the formose reaction as a source of sugars on the primitive Earth have been noted. One is the complexity of the product mixture. More than 40 different sugars were identified in one reaction mixture (Decker et al. 1982). Another problem is that the conditions of synthesis are also conducive to the degradation of sugars (Reid and Orgel 1967). Sugars undergo various reactions on short geological time scales that are seemingly prohibitive to their accumulation in the environment. At pH seven, the half-life for ribose decomposition is 73 minutes at 100 degrees Celsius and 44 years at zero degree Celsius (Larralde et al. 1995). Most other sugars are similarly labile.

Additionally, when aqueous solutions of HCN and HCHO are mixed, the major product is glycolonitrile (Schlesinger and Miller 1973), which could preclude the formation of sugars and purines in the same location (Arrhenius et al. 1994). Nevertheless, both sugar derivatives and nucleic acid bases have been found in the Murchison meteorite (Cooper et al. 2001; Callahan et al. 2011), and it seems likely that the chemistry which produced the compounds found in Murchison meteorite was from aqueous reactions of simple species such as HCN and HCHO. This suggests that the synthesis of sugars, amino acids, and purines from HCHO and HCN may take place under certain conditions.

Nucleosides, Nucleotides
The earliest attempts to produce nucleosides prebiotically involved simply heating purines or pyrimidines in the dry state with ribose (Fuller et al. 1972). Using hypoxanthine and a mixture of salts reminiscent of those found in seawater, up to eight % of β-D-inosine was formed, along with the α-isomer. Adenine and guanine gave lower yields, and in both cases, a mixture of α- and β-isomers was obtained (Fuller et al. 1972). Direct heating of ribose and U or C has thus far failed to produce uridine or cytidine. Pyrimidine nucleoside syntheses have been demonstrated which start from ribose, cyanamide, and cyanoacetylene; however, α-D-cytidine is the major product (Sanchez and Orgel 1970). This can be photo-anomerized to β-D-cytidine in low yield. Sutherland and coworkers (Ingar et al. 2003) demonstrated that cytidine-3′-phosphate can be prepared from arabinose-3-phosphate, cyanamide, and HCCCN in a one-pot reaction. The prebiotic source of arabinose-3-phosphate is unclear; nevertheless, it remains possible that more creative methods of prebiotic pyrimidine nucleoside synthesis can be found.

More recently, reactions using more complex reagents added in precise orders, with the products isolated and carried through to the next step, have been shown to produce significant yields of ribotides (Powner et al. 2007). These reactions give good yields of the pyrimidine ribotides (Powner and Sutherland 2008), and a related series of reactions could produce the purine ribotides (Powner et al. 2010). It is not clear that these syntheses solve previously raised objections to the plausibility of prebiotic nucleoside and nucleotide synthesis (Shapiro 1984).

Prebiotic phosphorylation of nucleosides has also been demonstrated, but again with caveats. Small amounts of condensed phosphates are emitted in volcanic fumaroles (Yamagata et al. 1991), and heating orthophosphate at relatively low temperatures in the presence of ammonia results in a high yield of condensed phosphates (Osterberg and Orgel 1972). Trimetaphosphate (TMP) has been shown to be an active phosphorylating agent for various molecules including amino acids and nucleosides (Schwartz 1969; Rabinowitz and Hampai 1978; Yamagata et al. 1991). However, it has also been suggested that condensed phosphates are not likely to be prebiotically abundant materials (Keefe and Miller 1995).

Early attempts to produce nucleotides using organic condensing reagents such as H2CN, NCO−, or dicyanamide (Lohrmann and Orgel 1968) were generally inefficient due to the competition of the alcohol groups of the nucleosides with water in an aqueous environment. Nucleosides can be phosphorylated with acidic phosphates such as NaH2PO4 when dry heated (Beck et al. 1967). These reactions are catalyzed by urea and other amides, particularly if NH3 is included in the reaction. Nucleosides can also be phosphorylated in high yield by heating ammonium phosphate with urea at moderate temperatures, as might occur in a drying lagoon (Lohrmann and Orgel 1971). Heating uridine with urea and ammonium phosphate gave yields of nucleotides as high as 70%. In the case of purine nucleotides, however, there is also considerable glycosidic cleavage due to the acidic microenvironment created. Thus, another problem with the “prebiotic” RNA world is that the synthesis of purine nucleosides is somewhat robust, but nucleotide formation may be difficult, while nucleotide formation from pyrimidine nucleosides is robust, but nucleoside formation may be difficult.

Common calcium phosphate minerals such as apatite are themselves reasonable phosphorylating reagents. Yields as high as 20% of nucleotides were achieved by heating nucleosides with apatite, urea, and ammonium phosphate (Lohrmann and Orgel 1971). Heating ammonium phosphates with urea leads to a mixture of high molecular weight polyphosphates (Osterberg and Orgel 1972). Although these are not especially good phosphorylating reagents under prebiotic conditions, they may degrade, especially in the presence of divalent cations at high temperatures, to cyclic phosphates such as TMP.

The difficulties with prebiotic ribose synthesis and nucleoside formation have led some to speculate that perhaps a simpler genetic molecule with a more robust prebiotic synthesis preceded RNA (Joyce et al. 1987). Substituting sugars besides ribose has been proposed (Eschenmoser 2004). Oligomers of some of these also form stable base-paired structures with both RNA/DNA and themselves, opening the possibility of genetic takeover from a precursor polymer to RNA/DNA. Such molecules may suffer from the same drawbacks as RNA with respect to prebiotic chemistry, such as the difficulty of selective sugar synthesis, sugar instability, and the difficulty of nucleoside formation. It has been demonstrated based on the suggestion of Joyce et al. (1987) and proposed chemistry (Nelsestuen 1980; Tohidi and Orgel 1989) that backbones based on acyclic nucleoside analogs may be more easily obtained under reasonable prebiotic conditions, for example by the reaction of nucleobases with acrolein obtained from mixed formose reactions (Cleaves 2002).

More exotic alternatives to nucleosides have been proposed, for example peptide nucleic acid (PNA) analogs (Nielsen et al. 1994). Miller and coworkers were able to demonstrate the prebiotic synthesis of the components of PNA under the same chemical conditions required for the synthesis of the purines or pyrimidines (Nelson et al. 2000). The vast majority of possible alternative structures have not been investigated with respect to prebiotic plausibility.

Environmental Considerations
Whether in meteorites or on Earth, prebiotic chemistry may have occurred largely in an aqueous environment, as water is a ubiquitous component of the solar system and the Earth's surface. Among the variables of the local environment which could affect the way this chemistry occurs are pH, temperature, inorganic compounds such as metals, mineral surfaces, the impact of sunlight, etc. The potential role of mineral surfaces on prebiotic chemistry is an especially complex and under-explored aspect of this chemistry. Although we do not presently know which compounds were essential for the origin of life, it seems possible to preclude certain environments if even fairly simple organic compounds were involved (Cleaves and Chalmers 2004).

Stability of Biomolecules at High Temperatures
High temperatures cause reactions to occur more quickly, they are also destructive to most bioorganic compounds. Although some progress has been made in synthesizing small molecules under conditions simulating hydrothermal vents, most biological molecules have hydrolytic half-lives on the order of minutes to seconds at the temperatures associated with on-axis hydrothermal vents and are still rather unstable at the lower temperatures of off-axis vent environments. Ribose and other sugars are extremely thermolabile (Larralde et al. 1995), but pyrimidines and purines, and many amino acids, are nearly as labile. At 100 degrees Celsius, the half-life (t1/2) for deamination of cytosine is 21 days, and 204 days for adenine (Levy and Miller 1998). Some amino acids are more stable: alanine has a t1/2 for decarboxylation of ∼1.9 × 104 years at 100 degrees Celsius, but serine decarboxylates to ethanolamine with a t1/2 of 320 days (Vallentyne 1964). White (1984) measured the decomposition of various compounds at 250 degrees Celsius and pH seven and found t1/2 values for amino acids from 7.5 seconds to 278 minutes, peptide bonds from less than one minute to 11.8 minutes, glycoside cleavage in nucleosides from less than one second to 1.3 minutes, decomposition of nucleobases from 15 to 57 minutes, and phosphate esters from 2.3 to 420 minutes. The half-lives for polymers would be even shorter as there are so many more potential breakage points.

Minerals
There are approximately 4,400 known naturally occurring minerals on Earth today (Hazen et al. 2008). This number was likely smaller on the early Earth, as many minerals are produced by oxidation with environmental O2, biological deposition, or the vast amounts of time which have passed since the Earth formed.

Minerals may have complex effects on prebiotic organic synthesis (Lahav and Chang 1976) by concentrating reactants and by lowering activation barriers to bring compounds into more rapid equilibrium (Marshall-Bowman et al. 2010).

Shallow Pools
Since Darwin's time, it has been supposed that life may have originated in shallow tidal pools. Possible advantages of such environments include evaporative concentration, constrained diffusion mineral catalysis, and the penetration of sunlight into such pools. Additionally, if the Earth's surface was colder at this time, or at least as clement as at present, then it is possible that periodic freezing events could have significantly concentrated compounds.

Hydrothermal Vents
The discovery of hydrothermal vents at mid-ocean ridges and the appreciation of their significance in the element balance of the hydrosphere were a major discovery in oceanography (Corliss et al. 1979). Since the process of hydrothermal circulation probably began early in Earth's history, it is likely that vents were also present. Large amounts of ocean water now pass through the vents, with the whole ocean going through them approximately every ten million years (Edmond et al. 1982). This flow was probably greater during the early history of the Earth, since the heat flow from the planet's interior was greater. The topic has received a great deal of attention, partly because of uncertainty regarding the oxidation state of the early atmosphere.

There are various types of hydrothermal environments on the modern Earth, including subaerial hot springs and submarine hydrothermal vents. In the latter, temperatures range from ∼four to 350 degrees Celsius, with pH ranging from zero to 11 (Martin et al. 2008). Various minerals precipitate as the heated vent water enters the surrounding ocean water, leading to the formation of baroque rock formations. It has been speculated that the pores in such minerals may have served to concentrate organic species via thermophoresis (Baaske et al. 2007).

Following the vents' discovery, a hypothesis suggesting a hydrothermal emergence of life was published (Corliss et al. 1981), which suggested that amino acids and other organic compounds could be produced during passage of the effluent through the temperature gradient from ∼350 degrees Celsius to ∼zero degree Celsius, roughly the temperature of modern ambient ocean waters. Polymerization of the organic compounds thus formed, followed by their self-organization, was also proposed in this environment.

At first glance, submarine hydrothermal springs appear to be ideally suited for organic synthesis, given the geological plausibility of a hot early Earth. Vents exist along the active tectonic areas of the Earth, and in at least some of them, potentially catalytic minerals interact with an aqueous reducing environment rich in H2, H2S, CO, CO2, CH4, and NH3. Unfortunately, it is difficult to corroborate these speculations with the composition of the effluents of modern vents, as much of the organic material released from modern sources is simply environmentally processed biological material.

Modern hydrothermal vent fluids do contain some organic compounds, though it remains unclear what percentage are derived from organisms living in the vents or biologically derived matter entrained into the vent fluids and reworked, and what percentage is derived from truly abiotic processes. For example, for amino acids, the bulk of the evidence available supports a biological origin (Bassez et al. 2009). Presently, the amount and type of organic matter found in hydrothermal vent environments unequivocally thought to be of abiotic origin are limited to a few parts per million of small hydrocarbons such as CH4 and ethane (McCollom et al. 2010).

One of the most articulate autotrophic vent origin-of-life hypotheses stems from the work of Wächtershäuser (1988, 1992), who argued that life began with the appearance of an autocatalytic, two-dimensional chemolithotrophic metabolic system based on the formation of the insoluble mineral pyrite (FeS2). The FeS/H2S combination is a strong reducing agent and has been shown to reduce some organic compounds under mild conditions. Wächtershäuser's scenario fits well with the environmental conditions found at deep-sea hydrothermal vents, where H2S, CO2, and CO are abundant; however, the FeS/H2S system does not reduce CO2 to amino acids, purines, or pyrimidines, although there is more than enough free energy to do so (Keefe et al. 1995). Pyrite formation can produce molecular hydrogen and reduce nitrate to NH3, and HCCH to H2CCH2 (Maden 1995). More recent experiments have shown that the activation of amino acids with carbon monoxide and (Ni, Fe)S can lead to peptide bond formation (Huber and Wachtershauser 1998), though the degree to which these experiments mimic geochemical environments is a subject of debate.

In general, organic compounds are decomposed rather than created at hydrothermal vent temperatures, although temperature gradients exist. Sowerby and coworkers have shown (Sowerby et al. 2001) that concentration on mineral surfaces would tend to concentrate organics created at hydrothermal vents in cooler zones. The presence of reduced metals at high temperatures could facilitate Fischer–Trospch-type (FTT) syntheses. FTT catalysts are poisoned by water and sulfide, though some of the likely catalysts such as magnetite may be immune to such poisoning (Holm and Andersson 1998).

Submarine hydrothermal vents do not seem to presently synthesize organic compounds more complex than simple hydrocarbons such as CH4 and ethane (McCollom et al. 2010). More likely, they decompose them over short time spans ranging from seconds to a few hours. The origin of life in hydrothermal vents thus may be problematic.

This does not imply that hydrothermal vents were a negligible factor on the primitive Earth. If mineral assemblages were sufficiently reducing, vents may have been a source of atmospheric NH3, CO, CH4, and H2. The concentrations of biomolecules in primitive Earth environments would have been governed by the rates of production and the rates of destruction. Submarine hydrothermal vents would have likely been more important for the destruction of organic compounds, fixing the upper limit for their concentrations in the primitive oceans.

Prebiotic Chemistry Beyond Earth
Of the eight accepted planets in our solar system and their moons, several appear compatible with the synthesis of organic compounds, and several are known to contain them. Fewer appear to be compatible with the existence of liquid water or the more complicated evolution of these compounds. For example, the extreme temperatures of Venus' or Mercury's sunlit side are likely too hostile for the synthesis of complex organics. The immediate sub-surface of Mars appears to harbor both liquid and solid water (Rennó et al. 2009), and it is widely believed that liquid water once flowed on Mars' surface. Meteorites likely impacted Mars' surface at this time, and it is reasonable to expect that some of these were CCs. The nature of Mars' early atmosphere remains unknown, but Mars and Earth may have been similar early in their history.

Proceeding outward from the Sun, complex organic chemistry likely occurs in the atmospheres of Saturn and Jupiter. The conditions on the solid surfaces of these planets are thought to be too hostile for more complex organic chemistry. Nevertheless, the presence of various organic species has been confirmed in their atmospheres (Lodders 2010).

Outer-Planet Moons
A number of outer-planet moons have intriguing environments which appear to foster prebiotic chemistry and could conceivably be capable of sustaining biology. For example, Saturn's moon Titan is now known to harbor a rich organic chemistry (Waite et al. 2007). Jupiter's moon Europa is covered with a thick ice layer which may harbor a watery ocean several kilometers thick (Manga and Wang 2007). If this ocean does exist, its organic content remains unknown.

Extrasolar Planets
For centuries, the existence of planets beyond our solar system has been the subject of intense philosophical and scientific speculation (Urey et al. 1963; Dick 1999). The first extrasolar planet was confirmed in 2003 (Hatzes et al. 2003). Recent astronomical observations have since yielded hundreds of planets orbiting other suns (http://www.exoplanet.eu/; http://nsted.ipac.caltech.edu/). Methods to date have favored the detection of large planets with orbits very close to their parent suns, but soon, advances will allow detection of smaller planets with orbits compatible with the existence of liquid surface water. Our solar system contains three rocky Earth-like planets, two of which are almost in the habitable zone.

There is no solid reason to expect that our solar system is anomalous. Given the billions of Sun-like stars in any galaxy, there may be many rocky Earth-like planets in stellar habitable zones in the universe (Laughlin 2010), some of which may have undergone similar periods of evolution compatible with the origin and evolution of life. The detection of such planets and possible signatures of alien biochemistry may not be far off, assuming that the origin of life is facile. The detection of even one such planet would strongly reinforce the idea that it is.

Unknowns and the Future
A basic tenet of the heterotrophic theory of the origin of life is that the origin of the first living systems depended on environmentally supplied organic molecules. As summarized here, there has been no shortage of discussion as to how the formation of these molecules occurred. Organic compounds may have accumulated on the primitive Earth via numerous mechanisms including contributions from endogenous atmospheric synthesis, deep-sea hydrothermal vent synthesis, and exogenous delivery. Though this raises the issue of the relative significance of the various sources, it also recognizes the wide variety of potential sources of organic compounds.

https://evolution-outreach.biomedcentral.com/articles/10.1007/s12052-012-0443-9 (more at link)