A veteran origin-of-life researcher died last October: Leslie E. Orgel of the Salk Institute for Biological Studies.  Orgel had co-authored Origins of Life on the Earth (1973) with Stanley Miller, the man whose spark-discharge experiment launched the modern origin-of-life craze in the 1950s (05/02/2003).  Orgel worked in the field for decades and was familiar with all the different approaches. The following quotes are his main criticism of organic chemistry.

1. Could is not good enough:  “It must be recognized that assessment of the feasibility of any particular proposed prebiotic cycle must depend on arguments about chemical plausibility, rather than on a decision about logical possibility.”  To claim a chemical reaction is possible does not mean it will ever happen.  What are the specific reactants?  How efficient are they?  Researchers must present ideas that are chemically plausible, not just possible.
2. Paper is not good enough:  “It is a catalytic cycle in which a complicated sequence of enzymatic reactions is used to bring about indirectly a reaction that looks simple on paper, but is not easily achieved in practice.”  A researcher needs to think about chemical cofactors required, and the possibility of damaging cross-reactions, for instance, or whether reactions in a cycle are likely to proceed in a realistic time frame.
3. Time is not enough:  A metabolic cycle on the primitive earth may have had eons longer to work than a chemist in a lab.  “However, the identification of a cycle of plausible prebiotic reactions is a necessary but not a sufficient step toward the formulation of a plausible self-organizing prebiotic cycle.”
4. Where are the exits?  Every step in a metabolic cycle needs to be efficient enough to keep the whole cycle going.  “The cycle could not survive if side reactions funneled off more than half of the cycle components irreversibly, because then the concentration of the cycle components would decline exponentially to zero.”
5. Weakest link breaks the chain:  A researcher might be able to propose that each step in a metabolic cycle, say the 11 steps in the reverse citric acid cycle, is plausible in a prebiotic environment.  “However, the reactions are not independent because each reaction is pulled toward completion by the use of its product as the input for the subsequent reaction of the cycle.” 
6. Don’t forget thermodynamics:  Because reactions are reversible, it is likely the input of a step will be depleted.  “Whatever the original input, one would finish with an equilibrium mixture, the composition of which is determined by thermodynamics.”  Equilibrium means you are at a standstill and nothing more will happen.
7. Not all reactions are created equal:  Orgel lists seven reactions in the reverse citric acid cycle (one popular scenario for a self-organizing metabolic scenario) that are completely different.  “The reverse citric acid cycle involves a number of fundamentally different kinds of chemical transformations,” he said; “At the very least, six different catalytic activities would have been needed to complete the reverse citric acid cycle.”  What would this require: six different environments on the early earth?  This “could be argued, but with questionable plausibility,” he remarked.
8. Beware of thieves:  Damaging side reactions are often more likely to occur than the desired ones.  Orgel gives examples, such as difficult carboxylation reactions.  “This reaction would move material irreversibly out of the cycle, so one must postulate a specific catalyst that discriminates between succinic and malic acid.”
9. Inspectors required:   Biological enzymes in living cells are experts at discriminating between similar substrates.  The same cannot be assumed in a prebiotic environment: “One needs, therefore, to postulate highly specific catalysts for these reactions.  It is likely that such catalysts could be constructed by a skilled synthetic chemist, but questionable that they could be found among naturally occurring minerals or prebiotic organic molecules.”
10. Minerals are not enough:  Clay surfaces and other substrates have been popular ingredients in metabolic cycle scenarios.  The necessary reactions might occur on these natural lab tables, they say.  Orgel discusses two leading scenarios.  “While the details of the two proposals are different, the difficulty of achieving all of the required reactions while avoiding all of the likely side reactions seems at least as formidable” in both of them.
11. Hand-waving is not enough:  Orgel criticizes a recent proposal by Wachtershauser that describes self-organization by “metabolic reproduction, evolution, and inheritance by ligand feedback.”  Suggestive words.  “Unfortunately he never explains, even in outline, how this mechanism could lead to the synthesis of the aminoacyl-nucleotide conjugates that seem to be an essential feature of the proposal.”
12. One example is not enough:  “The only autocatalytic cycle that has been demonstrated experimentally is that involved in the formose reaction—the polymerization of formaldehyde to give a notoriously complex mixture of products, including ribose, the organic component of the backbone of RNA.”  Well, this must be the path to explore!  Indeed, researchers have explored this path since it was discovered in the 19th century.  Is it the holy grail?  Not exactly; the mix must be seeded with certain impurities to get started, and “Despite some successes, it is still not possible to channel the formose reaction in such a way as to produce ribose in substantial yield.”
        Ribose, of course, is one of the most difficult essential parts of RNA to imagine forming on the prebiotic earth – especially in the presence of water (see Benner, 11/05/2004).  The proposed hopeful cycles, unfortunately, produce a host of other unhelpful reaction products.
13. Simple is not enough:  Orgel begins a section on “Cycles and the Evolution of Complexity.”  Assume a cycle begins.  That does not mean that complexity will evolve.  “A cycle ... does not seem capable of evolving in any interesting way without becoming more complex.”  The scenarios that suggest a substantial amount of “information content” will emerge from a simple cycle, with genetic macromolecules coming in late to add stability, are little more than “intuitions” – not schemes that can be examined critically.
14. Variation is not enough:  Suggesting that a change in temperature or concentration is a form of evolution is a play on words.  For instance, “one could not usefully claim that the dependence of the rate of a reaction such as ester hydrolysis on reaction conditions is a form of evolution.”  At some point you have to add complexity to the picture.  “The evolution of any substantial additional complexity of a cycle, therefore, must depend on the appending of further reaction sequences to those present in the core cycle.”
15. The law of diminishing returns:  “Given the difficulty of finding an ensemble of catalysts that are sufficiently specific to enable the original cycle, it is hard to see how one could hope to find an ensemble capable of enabling two or more.”  The further the scenario gets from the original simple cycle, the more the problems arise.  Orgel has heard many proposals in his career.  None of them “explains how a complex interconnected family of cycles capable of evolution could arise or why it should be stable.”