Noorduin et al. (Nature Chemistry, 2009) demonstrated that irradiating an acetonitrile solution of racemic N-(2-methylbenzylidene)phenylglycine amide with left- or right-handed circularly polarized ultraviolet light, followed by abrasive grinding of the racemic crystal slurry under in-solution racemization, converts the solid completely into one crystal handedness (an enantiopure solid phase), fully determined by the rotation sense of the light. The authors proposed that the direction arises from minute amounts of chiral photoproducts that may act as tailor-made crystal-growth inhibitors, but their supplementary information records that the photoproduct mixture is complex and that only an achiral photo-oxidation product, N-benzoyl-2-methylbenzamide, could be isolated and identified — it cannot be the directing agent. The chemical identity, in-situ concentration, and formation pathway of the actual chiral directing species remain unknown; the supplementary information reports one outcome-level test of the authors' leading candidate class — synthesized cyclic imidazolidinone additives, added exogenously, directed the deracemization following the 'rule of reversal' — but the in-situ species were not identified and no crystal-growth-rate, crystal-morphology, or adsorption measurements under the irradiation and grinding conditions were reported. No later work has identified the photoproducts or directly tested the mechanism in this system under its in-situ conditions; later literature clarified the physics of attrition-enhanced deracemization, additive effects in related systems with designed chiral additives, and circularly-polarized-light chirality induction in other substrates, while reviews of prebiotic homochirality still lack a quantitative natural-CPL account of this sequence. The problem is open.

Background

Many biological molecules occur in nature in only one of two mirror-image forms, a property called homochirality, and how this single-handedness arose is a long-standing open question. Circularly polarized light (CPL) — light whose electric-field vector rotates in a left- or right-handed helix along the propagation direction, making it a genuinely chiral physical stimulus — is emitted with small degrees of polarization from star-forming regions and has long been considered a candidate source of the initial chiral bias on early Earth. The obstacle is magnitude: irradiating racemic molecules with CPL typically produces enantiomeric excesses (ee, the relative imbalance between the two mirror-image forms, or enantiomers) of only fractions of a percent to a few percent, whereas biology is essentially enantiopure. Some amplification mechanism is therefore required between a small CPL-induced bias and complete homochirality.

Noorduin et al. (Nature Chemistry 1:729–732, 2009) connected a tiny CPL-induced chemical bias to a powerful solid-state amplifier. Their substrate, called compound 1 in the paper, is N-(2-methylbenzylidene)-phenylglycine amide — an imine derivative of the amino-acid phenylglycine that crystallizes from acetonitrile as a conglomerate, i.e. as a physical mixture of separate R and S crystals rather than a mixed racemic compound, and that racemizes in solution when a strong base (DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene) is added. Such conglomerates undergo attrition-enhanced deracemization (also called Viedma ripening): abrasive grinding of the racemic crystal slurry under solution racemization, through repeated growth and dissolution of crystal fragments, converts the system completely into crystals of a single handedness — normally to a randomly chosen one. Noorduin et al. first irradiated solutions of 1 with CPL — the source describes the light as filtered through a 300–400 nm filter and, elsewhere, as circularly polarized light of 310 nm wavelength with a power of approximately 0.35 mW — at wavelengths where the two enantiomers differ in the sign of their circular dichroism (the difference in absorption of left- versus right-handed CPL), generating a minute amount of chiral photoproducts. Adding racemic solid, DBU, and glass beads and then grinding converted the slurry completely into one enantiomorph: in all cases l-CPL resulted in an (S)-solid phase and r-CPL gave an (R)-solid phase. The controls were not random: in more than 100 earlier deracemization experiments starting from racemic 1 without CPL irradiation, the outcome always evolved to (R)-1, and the supplementary information reports that the experiments with linearly polarized light likewise all evolved to an enantiopure (R)-1 solid phase — results the authors interpreted to mean that minute levels of chiral impurities overruled the expected randomness. The direction by the rotation sense of the CPL therefore stands against this systematic (R) baseline, most sharply in the left-handed-CPL experiments, which reverse it. Irradiation of solid-free solution still directed the later deracemization, so the directing agent is a solution-borne species that survives the racemizing conditions.

The mechanistic account the authors propose is indirect and hedged. In their picture, enantioselective absorption of CPL by one enantiomer forms a chiral, non-racemizable photoproduct (denoted R* or S*) that may act as a 'tailor-made' crystal-growth inhibitor — a concept introduced by Addadi, Weinstein, Gati, Weissbuch, and Lahav (J. Am. Chem. Soc. 104:4610–4617, 1982): an additive structurally related to the crystallizing compound adsorbs preferentially onto the faces of crystals of the same absolute configuration and retards their growth (the 'rule of reversal'), so selective inhibition of one enantiomorph's growth steers the grinding process toward the other. The paper's supplementary information, however, states that the photoproduct fraction is a complex mixture formed in low yield, of which only one species — the achiral photo-oxidation product N-benzoyl-2-methylbenzamide — could be isolated and identified, and that this achiral compound cannot be the directing agent. The same supplementary information reports a test of the authors' leading candidate class: chiral cyclic products of 1 — the diastereomeric 2-(2-methylphenyl)-5-phenyl-imidazolidin-4-ones — are known to form easily and correspond to minute peaks in the HPLC traces of the irradiated solutions, and when two such cyclic products were synthesized and added as exogenous additives to deracemization experiments, they indeed directed the outcome, with the handedness of the outcome following the rule of reversal. That experiment, however, used prepared additives at concentrations far above the trace in-situ photoproduct fraction rather than the in-situ species themselves, and no crystal-growth-rate, crystal-morphology, or adsorption measurements bearing on the inhibition hypothesis were reported; the structures, in-situ concentrations, and formation pathways of the photoproducts that actually direct the reaction were not determined. The paper also framed the result as a possible prebiotic scenario, arguing that even if such processes are very slow in nature, ultimately single chirality will be achieved over time; it did not quantitatively assess whether the sequence can operate under natural CPL intensities, spectra, and timeframes or generalize to other prebiotically relevant molecules and crystal systems — a program-level question that belongs to the wider origin-of-homochirality literature rather than to the source's open item.

Later work, reviewed below, has clarified the physics of attrition-enhanced deracemization and the effects of designed chiral additives in related systems, and has continued CPL chirality induction in other substrates, but has not returned to the identity or the growth-inhibition mechanism of the CPL photoproducts of compound 1.

Problem Statement

From Noorduin et al. (Nature Chemistry 1:729–732, 2009): establish the molecular basis of circularly-polarized-light-directed complete deracemization of N-(2-methylbenzylidene)-phenylglycine amide. The load-bearing mechanistic core consists of two linked questions: (1) determine the chemical identity of the chiral photoproduct(s) generated upon UV CPL irradiation of compound 1 in acetonitrile (the source describes the irradiation as filtered through a 300–400 nm filter and, elsewhere, as circularly polarized light of 310 nm wavelength, approximately 0.35 mW, at the circular-dichroism band where the two enantiomers differ in sign) that act as the directing agents in the subsequent attrition/racemization deracemization — the molecular structures of the in-situ directing species, and whether the direction is due to a single species or to a joint action of a mixture (the source work isolated only an achiral oxidation product, which cannot direct deracemization, and its rule-of-reversal additive test used synthesized cyclic candidates rather than the identified in-situ species); and (2) establish the mechanism by which the identified species stereoselectively direct the deracemization toward one crystal enantiomorph, testing directly the proposed tailor-made crystal-growth-inhibitor ('rule of reversal') account. This is the source's own open item: "The precise nature of the growth inhibitor remains a topic for further research."

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