Chemistry / Experiment Review

Vol. 2, NO. 3 / September 2016

Two Experiments in Abiogenesis

James Tour

Letters to the Editors

In response to “Two Experiments in Abiogenesis

Sidney Becker, Ines Thoma, Amrei Deutsch, Tim Gehrke, Peter Mayer, Hendrik Zipse, and Thomas Carell, “A High-Yielding, Strictly Regioselective Prebiotic Purine Nucleoside Formation Pathway,” Science 352, No. 6,287 (2016): 833–36, doi:10.1126/science.aad2808.

Brian Cafferty, David Fialho, Jaheda Khanam, Ramanarayanan Krishnamurthy, and Nicholas Hud, “Spontaneous Formation and Base Pairing of Plausible Prebiotic Nucleotides in Water,” Nature Communications 7, no. 11,328 (2016), doi:10.1038/ncomms11328.

In my essay “Animadversions of a Synthetic Chemist,” I wrote that, “The coupling of a ribose with a nucleotide is the first step [in abiogenesis], and even those engrossed in prebiotic research have difficulty envisioning that process, especially for purines and pyrimidines.”1 Thomas Carell’s group has accomplished that coupling through the condensation of formamidopyrimidines with ribose providing the natural N-9 nucleosides with high regioselectivity. Starting with 2,4,5,6-tetraaminopyrimidine-sulfate and suspending it in formic acid and sodium formiate, the mixture was heated to 101°C for two hours. The solvent was evaporated under reduced pressure and water was added to dissolve the product. Concentrated ammonium hydroxide was then used to raise the mixture to pH 8. The solution was cooled overnight at 4°C, yielding substantial amounts of formylated tetraminopyrimide as a crystalline solid. This was isolated from the other products. Then, they allowed the formylated product to interact with 15 equivalents of homochiral ribose by grinding the two together thoroughly in the solid state and heating the mixture in an oven at 100°C for eight hours. The team purchased its ribose. I have already shown how hard it is for the world’s best synthetic chemists to make even a gross diastereomeric and racemic mixture of that 5-carbon carbohydrate.2 The solid was then placed in a sealed tube, away from exogenous air (which is tough to do in nature), and treated with concentrated ammonium hydroxide, or basic amino acids, or borax, at 100°C for between one and 14 days. The reaction consumes the ribose starting material; hence a 15-fold excess was used. This resulted in a mixture of products. No bulk separation was attempted. The mixture was subjected to liquid chromatography and mass spectrometry.

This advance by Carell and his team relied on the use of pre-formylated purines and pyrimidines; this made possible their coupling with commercially purchased homochiral ribose. The authors did mention the problems raised by the oxidative instability of aminopyrimidines. There is no reason to suppose that nature could have commanded these exquisite laboratory skills. Often seven major products, and many more minor products, were formed in these reactions, where the combined yield of the anomeric nucleosides could be as high as 60%. When starting with racemic glyceraldehydes and glycoaldehyde, rather than purified homochiral ribose, the yields of the racemic nucleosides dropped to less than 1%, and that 1% contained as many as 16 different isomers. No attempt was made to extract the trace, which was likely less than 0.1%, of targeted nucleosides from the other >99.9% of the gross reaction mixtures.

This work underscores the difficulties in obtaining even trace amounts of a single desired nucleoside. To make matters worse, it was obtained along with an unusable mixture of products. Impurities are not innocuous. They retard subsequent reactions, first by consuming precious starting materials, and then by consuming the reaction’s final product. The synthesis was complicated, no matter the advanced chemical methods, no matter the purified starting materials, no matter the oxygen-free containment systems, and no matter the most sophisticated laboratories.

The work by Carell and his colleagues illustrates another frustrating problem in prebiotic chemistry. One group publishes their results reporting products in low yields and unusable gross mixtures. Another group then uses those products, in their pure and abundant form, as their starting materials. Carell’s group used homochiral ribose, claiming that, “Ribose is generated from glycoaldehyde and formaldehyde, formed from an early atmosphere containing humid CO2.”3 This reaction provides only ribose traces in unusable mixtures. Carell and his coworkers assumed ribose as a given. They also used purified aminopyrimidines, relying on research that generated them from small molecules, such as guanidine and hydrogen cyanide. The published protocols on which they reply report equally troubling mixtures of products. No overall bookkeeping standards are maintained from one published work to another. The shortcomings of past generations are subsumed in current work without ever being acknowledged.

“It is assumed,” Carell and his colleagues remark, “that life originated from a simple set of small molecules.”4 His work dispels any such illusions. Reckless general claims are a characteristic of the field. In describing the RNA-world hypothesis, Carrell and his colleagues argue that it would be easy to go from molecules to nucleosides, then to informational polymers, and finally to self-replicating systems. This is to assume, without evidence, that in prebiotic chemistry great oaks follow naturally from small acorns. Views such as this are acceptable in today’s scientific journals.

The article by Nicholas Hud and his team reports a solid and laudable achievement. Researchers used barbituric acid (BA) and melamine to show that those two conjoiners can react with pre-formed ribose-5- phosphate (R5P) to form C- and exocyclic-N-glycosides, respectively (BMP and MMP). Previous work had shown similar effective glycoside formations on R5P with other structural combinations, but Hud and his team extended these results to BA and melamine. BA and melamine can also form glycosides with the unphosphorylated ribose. The alpha (α) and beta (β) anomeric ratios were studied extensively using nuclear magnetic resonance spectroscopy.

Canonical base mononucleotides spontaneously self-assemble when BMP is mixed with MMP. Self-assembled adducts prefer the β-anomeric over the α-configuration by a ratio of 2:1. The fact that BA and melamine derivatives conjoin into a self-assembled adduct is not particularly noteworthy. There is a vast literature about the self-assembly of these and related planar molecular proton–donor–acceptor combinations. This self-assembly process forms structures with large circular dichroistic values; this is expected based on what is known in the field of helically-ordering homochiral structures. In the work of Hud and his colleagues, it is the purchased R5P that exhibits homochirality; their isolated structures are always built on a hexad assembly where there are three MMPs and three BMPs per cyclic unit. This stands in contrast to the Watson–Crick base pairing order found in RNA.

Hud and his group used a rich characterization suite and their chemical data analyses are superbly done. Had they confined themselves to supramolecular assembly of chiral conjoiners, their article would be a worthwhile contribution to the literature. But, it is a stretch to suggest that these proto-RNA structures—the MMP and BMP hexads—could have been the ancestral forms of canonical structures. Their article leaves the reader wondering. Are they suggesting that the recurring strings of hydrogen-bonded BMP-MMP in some way served as a template for RNA? Can there be anything meaningfully encoded in an alphabet-restricted regularly patterned hexad? Simple regular patterns cannot encode complex function.

Or are Hud and his colleagues suggesting that something transformed self-assembled BA and melamine into the canonical four bases? There is no conceivable prebiotic synthetic transformation that makes this plausible.

This cannot be what the authors are suggesting.


  1. James Tour, “Animadversions of a Synthetic Chemist,” Inference: International Review of Science 2, No. 2 (2016). 
  2. James Tour, “Animadversions of a Synthetic Chemist,” Inference: International Review of Science 2, No. 2 (2016). 
  3. Sidney Becker et al., “A High-Yielding, Strictly Regioselective Prebiotic Purine Nucleoside Formation Pathway,” Science 352, No. 6,287 (2016): 834, doi:10.1126/science.aad2808. 
  4. Sidney Becker et al., “A High-Yielding, Strictly Regioselective Prebiotic Purine Nucleoside Formation Pathway,” Science 352, No. 6,287 (2016): 833, doi:10.1126/science.aad2808. 

James Tour is a synthetic organic chemist at Rice University.

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