Enhancing Organocatalysis by Joining Advanced Theoretical and Experimental Approaches
- Marco Masia (University of Sassari, Italy)
- Maria-Angels Carvajal (Rovira i Virgili University, Tarragona, Spain)
Since the year 2000 there has been explosive growth in the area of catalytic asymmetric synthesis now known as organocatalysis, which refers to the catalysis mediated solely by metal-free low-molecular-weight organic molecules, mainly natural or functionalized peptides. According to the prestigious journal Angewandte Chemie International Edition, organocatalysis is one of the “hot topics” in current chemistry, as witnessed by the huge number of special issues dedicated recently by important journals. 
The development of enantioselective reactions that proceed under environmentally benign conditions has grown into an extensively investigated field. On the one hand, organocatalysts are generally inexpensive and stable to moisture and air. In addition to this, they are green and sustainable. On the other hand, in the drive towards green and sustainable methodologies in the chemical laboratory, the use of water instead of organic solvents is preferred. Thus, it is not surprising that the development of organocatalysts capable of catalysing enantioselective reactions using water as the reaction medium is currently a highly sought-after goal. [2-9]
Although in the last ten years, the field has known a golden rush in experimental activities, there are still few theoretical studies on the reaction mechanisms, [10-17] what represents a limitation in the improvement of the field. In fact, the lack of knowledge on the reaction mechanisms of these organocatalytic processes obstructs the rational design of new organocatalysts with enhanced reactivity and selectivity. Furthermore, a full understanding of the role played by the peptides in the catalytic mechanism would give added insights on biological systems, particularly on enzyme catalysis.  Indeed, theoretical studies are not very abundant because in some cases technical issues characteristic of organocatalytic systems cases make the theoretical study not trivial, so methodological work is still necessary.
This workshop aims to present the most recent advances, to discuss the state of the art of the field and to enhance the exchange among theoretical and experimental communities. To our knowledge this would be the first workshop ever held on organocatalysis with a particular emphasis on the theoretical approach. We think that this meeting would boost the research activity on reaction mechanisms in organocatalysis, paving the way to new collaborative studies among the theoretical and experimental communities, and the development of new theoretical approaches and computational techniques.
Organocatalytic reactions usually take place in liquid solution and most of the time at the interface between two solvents. From the computational point of view, the study of mechanisms is highly challenging given the appearance of different time and space scales driving the reactions. A further complication is given by the fact that one or more steps of the catalytic cycle are stereo-selective, what entails the exploration of similar reaction paths and the distinction of the favored one. It seems, in fact, that the solvent plays a fundamental role in the reaction stereo-selectivity. Hence a thorough study of these reactions involves the use of state-of-the-art numerical approaches at many scales and the improvement or development of new theoretical techniques to face chemical dynamics of such complex systems.
Given these premises, the computational approaches which could come into play for the study of organocatalysis are:
1- Force Field Molecular Dynamics: this technique allows the study of structural and dynamical properties of solvents, reagents and products both in the bulk and at interfaces.  No information is given on the reaction mechanism itself, being it a quantum phenomenon, but much information could be gathered about the environment where such reactions take place.
2- ab initio Molecular Dynamics: this techniques allows for the description of the quantum degrees of freedom in the reaction. Bond breaking and bond formation could be described with different degrees of accuracy, ranging from semiempirical calculations, to Density Functional Theory and post Hartree-Fock methods (for the moment available only for small systems). 
3- Free Energy Methods: the main limitation of Molecular Dynamics lies in that the time scales for the reaction to take place could not be spanned by a simulation in reasonable computational times. To overcome this bottleneck, many techniques to accelerate the dynamics are being developed. To cite just few of them, Blue Moon Ensemble Simulations [20,21], Metadynamics  and (Temperature) Accelerated MD [23,24] would represent useful methods to tackle with organocatalysis mechanisms.
4- High-level ab initio Calculations: to our knowledge, up to now, the mechanism of most organocatalytic reactions have bee studied with high level quantum chemical calculations. [25-27] The main advantage of these techniques is that they give a highly reliable description of the electronic structure and of the energies at stake, but they are limited by the size of the system. To overcome this problem the solvent is included either explicitly (few molecules only selected by chemical intuition) or implicitly by using continuum solvent models. [28-30]
5- Photoexcitations: recent experimental advances [31-34] have shown that photoexcitation allows higher yields in organocatalysis. The study of such experimental conditions implies the application/development of very recent approaches for studying real time and real space propagation within TDDFT,  as well as the use of state-of-the-art techniques in static calculations both for TDDFT (new double hybrid functionals) and ab initio multireference methods together with implicit solvent models. [36, 37]
We would like to stress that, what has been explained above, is needed for the study of any chemical reaction or catalytic cycle at (homogeneous and heterogeneous) condensed phase, and yet interesting developments in this field have been carried out for some organometallic reactions.  However, most of chemical reactions are performed in presence of heavy metal ions and huge catalysts, what introduces further complications both for the description of the electronic structure and for the size of the systems to be simulated. The added value of organocatalysis is that it takes place with small catalysts (short aminoacids or peptides) in water; thus, not only is organocatalysis a sacred graal for green chemistry, but it represents an important (minimal system) benchmark to develop or improve techniques in the study of chemical reactions. Most of the developments made in this field would be applied also to other systems in the future.
At present, it seems that development and application of the above approaches to organocatalysis is still limited to a small niche of researchers, and that its spread to a wider experimental community is somehow damped. In this atmosphere, with our proposal we aim at gathering the researchers to focus on current research on organocatalysis, to boost the growth of the field in the theoretical community and to favor the collaborations with experimentalists.
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