& Chiral Amplification A Closer Look at Spontaneous Mirror Symmetry Breaking in Aldol Reactions Guillem Valero, Josep M. Ribó, and Albert Moyano* [a] In memory of Carlos F. Barbas III Abstract: The aldol reaction between acetone and 4-nitro- benzaldehyde run in the nominal absence of any enantiose- lective catalyst was monitored by chiral HPLC with the aid of an internal standard. The collected data show the presence of a detectable initial enantiomeric excess of the aldol prod- uct in the early stages of the reaction in about 50 % of the experiments. Only a small fraction of the reaction contained the non-racemic aldol product after 24 h. This temporary emergence of natural optical activity could be the signature of a coupled reaction network that leads to a spontaneous mirror-symmetry-breaking process, which originates at very low conversions (i.e., strongly depends on events taking place at the very first stages of the process). The reaction is not autocatalytic in the aldol product, which rules out a simple Frank-type reaction network as the source of the observed symmetry breaking. On the other hand, the isola- tion and characterisation of a double-aldol adduct suggest- ed a reaction network that involved both indirect autocataly- sis and indirect mutual inhibition between the enantiomers of the reaction product. Introduction It has long been recognised that understanding the origins of terrestrial biological homochirality (the fact that only one enan- tiomeric form of amino acids or carbohydrates can be found in living organisms) is an essential pre-requisite of any theory dealing with the origins of life on Earth. [1] In this context, physi- cal and chemical processes that take place with spontaneous mirror symmetry breaking (SMSB) are usually invoked as a pos- sible source of the homochirality of biomolecules. [2] The possi- bility of chemical reactions that start from achiral reagents, and can lead to an essentially homochiral (i.e., enantiomerically homogeneous) product by amplification of a very tiny enantio- meric imbalance was theoretically predicted by Frank in 1953. [3] In this seminal paper, Frank proposed that SMSB would be readily achieved for a reaction network composed of an irreversible asymmetric autocatalysis (i.e., a reaction in which the chiral product L (or D) enantioselectively catalyses its own formation from an achiral compound, M) coupled with an irre- versible mutual inhibition reaction between the product enan- tiomers L and D (Scheme 1). The original Frank model predicts that a homochiral stationary state (i.e., a state in which all of the molecules of the chiral product have the same absolute configuration) will eventually be reached if the concentration of the initial achiral reagent(s) M is held constant. Later, generalisation of the Frank model showed that in any (not necessarily irreversible) reaction network in which the two enantiomers of a chiral autocatalytic species are enantioselec- tively generated from achiral reactants and react in a heterochi- ral fashion to give a catalytically inactive product, a critical con- centration value of the achiral reactants can always be found. Above this concentration the racemic stationary state becomes unstable, so a very small enantiomeric excess (ee) of the chiral product (that may arise spontaneously by random fluctuations around the racemic composition) will drive the system to a thermodynamically more stable non-racemic (but not necessarily homochiral) stationary state. [4, 5] The confinement of a Frank-type reaction network in a closed system (i.e., a system that can only exchange thermal energy with its surroundings, so that the starting achiral mate- rial M is consumed and the inhibition product P remains in the system) will inevitably lead to an equilibrium racemic state, [5, 6] because of the restrictions imposed by the principle of micro- Scheme 1. Frank model for SMSB in chemical reactions. [a] G. Valero, Prof. Dr. J. M. Ribó, Prof. Dr. A. Moyano Departament de Química Orgànica Universitat de Barcelona, Facultat de Química C. Martí I Franqus 1-11, 08028-Barcelona, Catalonia (Spain) E-mail : amoyano@ub.edu Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201404497. Chem. Eur. J. 2014, 20, 1 – 15  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 && These are not the final page numbers! ÞÞ Full Paper DOI: 10.1002/chem.201404497