organic species makes the mixtures more complex and less likely to support life. Shapiro has provided a thoughtful and detailed discussion of the difficulties.17-22 Briefly summarized, it suggests that existing prebiotic chemistry experiments do not offer plausible hypotheses for routes to complex biomolecules. In the complex chemical mixtures generated under prebiotic conditions, one may be able to find trace amounts of amino acids and perhaps nucleobases. Some might indeed catalyze reactions that have some utility. But other compounds may well inhibit catalysis or catalyze undesired reactions. For example, Joyce and Orgel pointed out that the clay-catalyzed condensation of nucleotides to yield small chains performed best, under the conditions that they considered, if only one enantiomer of the starting material was present. If both were present, the desired reaction with the desired enantiomer might be inhibited by the other enantiomer.23 Furthermore, the combination of any bifunctional molecule into an information-bearing polymer would be expected to be terminated at an early stage by the presence of an excess of molecules that bear only one functionality.24

Even crystallization, a well-documented method of obtaining order through self-organization, is not a particularly powerful way to separate mixtures of organic chemicals into their constituents. Normally, an organic compound must be relatively pure before crystallization occurs. That salts crystallize better may explain why crystals are more common in the mineral world than in the organic world. Even organic salts can have problems in crystallizing from an impure mixture.

Those facts generate the central problem in prebiotic chemistry. Spontaneous self-organization is not known to be an intrinsic property of most organic matter, at least as observed in the laboratory. It can be driven only by an external source of free energy that is coupled to the organic system.

5.4.1
Nucleophilic and Electrophilic Reactions Can Destroy as Well as Create

As described above, formidable chemical obstacles oppose the abiotic synthesis of such biopolymers as RNA, DNA, and protein despite their prominence in life today. Numerous degradative processes would also hinder any event of that kind. The same inherent reactivities that generate organic molecules can convert them into complex mixtures. An example can be seen in the processes that might have generated the sugar ribose, a key component of RNA and DNA, under prebiotic conditions. A reaction called the formose reaction is known to produce ribose by converting formaldehyde in the presence of calcium hydroxide into several sugars, including ribose.25-27

The formose reaction exploits the natural electrophilicity of formaldehyde and the natural nucleophilicity of the enediolate of glycolaldehyde, a carbohydrate that has been detected in interstellar clouds.28 That species reacts as a nucleophile with formaldehyde (acting as an electrophile) to yield glyceraldehyde. Reaction of glyceraldehyde with a second equivalent of the enediolate generates a pentose sugar (ribose, arabinose, xylose, or lyxose, depending on stereochemistry). A curved-arrow mechanism describes this process in Figure 5.1.

Despite the reactivity inherent in glycolaldehyde and formaldehyde, the formose reaction does not offer a compelling source of prebiotic ribose. Under typical formose reaction conditions, ribose not only forms but also decomposes. In the presence of calcium hydroxide, ribose is rapidly converted to a mixture of organic species; this mixture has never been thoroughly characterized, but it does not appear to contain much ribose, and it is not an auspicious precursor of life. The further reaction of ribose in the presence of calcium hydroxide occurs because ribose itself has both electrophilic and nucleophilic sites, respectively, at the aldehyde carbon and at the carbon directly bonded to the aldehyde (after enolization—see Figure 5.1). Molecules having both reactivities tend, as expected, to polymerize as the nucleophilic sites and electrophilic sites react with each other, with more formaldehyde, with water, or with other electrophiles in the increasingly complex mixture. Those reactivities undoubtedly cause the rapid destruction of the ribose formed under formose conditions. On the basis of those reactivities, Larralde, Robertson, and Miller concluded that “ribose and other sugars were not components of the first genetic material.”29

A solution to the instability of ribose has been offered by Eschenmoser, Arrhenius, and others. It has focused on the generation of sugar phosphates, which have long been known to be more stable to degradation under alkaline conditions. A possible mechanism for forming them is shown in Figure 5.2.

For those reasons, some have suggested that life may have begun with an alternative organic compound as a genetic material, not RNA, but have been based on molecules that are less fragile.30 They are commonly suggested to be molecules that do not have carbohydrates in their backbones. Underlying that concept is the notion



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