Formamide reaction network in gas phase and solution via a unified theoretical approach: Toward a reconciliation of different prebiotic scenarios

Increasing experimental and theoretical evidence points to formamide as a possible hub in the complex network of prebiotic chemical reactions leading from simple precursors like H₂, H₂O, N₂, NH₃, CO, and CO₂ to key biological molecules like proteins, nucleic acids, and sugars. We present an in-depth computational study of the formation and decomposition reaction channels of formamide by means of ab initio molecular dynamics. To this aim we introduce a new theoretical method combining the metadynamics sampling scheme with a general purpose topological formulation of collective variables able to track a wide range of different reaction mechanisms. Our approach is flexible enough to discover multiple pathways and intermediates starting from minimal insight on the systems, and it allows passing in a seamless way from reactions in gas phase to reactions in liquid phase, with the solvent active role fully taken into account. We obtain crucial new insight into the interplay of the different formamide reaction channels and into environment effects on pathways and barriers. In particular, our results indicate a similar stability of formamide and hydrogen cyanide in solution as well as their relatively facile interconversion, thus reconciling experiments and theory and, possibly, two different and competing prebiotic scenarios. Moreover, although not explicitly sought, formic acid/ammonium formate is produced as an important formamide decomposition byproduct in solution.Very different environments have been suggested as possible cradles for the emergence of biomolecules, including a primordial liquid soup (1), rarified gaseous interstellar clouds (2, 3), liquid–solid interfaces at hydrothermal conditions (4), and the extreme case of impact sites of meteorites and comets (5). Biochemically relevant reactions can be fueled by a range of different energy sources, and a large number of possible chemical reactions and reaction paths are suggested to have played an important role in the process leading simple molecules to form small organic molecules and, from them, biological monomers and polymers.Among such small organic molecules, formamide is assuming an ever more central role in prebiotic chemistry research, as recently shown in experiments mimicking some of those origins of life scenarios, such as laser sparks (6), UV light (7), proton irradiation (8), or shock waves (as in meteorite impacts) (9). The main reason for such strong interest in formamide, besides its ubiquitousness in the solar system, is its chemical flexibility: it can be formed from (or, conversely, dissociated into) different molecular species that represent fundamental building blocks, including H₂, H₂O, NH₃, CO, HCN, HNCO, and HCOOH (10, 11). The barriers for these different processes lie in a relatively narrow range, providing many synthetic directions. Additionally, as has been also showed experimentally and computationally, formamide could give rise to all classes of biomolecular monomers, from amino acids to nucleic acids to sugars (12, 13).For example, inspired by the classic Miller experiments, recent ab initio MD (AIMD) simulations demonstrated that an intense electric field can induce the barrierless (spontaneous) formation of formamide and formic acid from a CH₄, CO, NH₃, H₂O, and N₂ mixture in the condensed phase, and under the same conditions, formamide in turn gives birth to more complex organic molecules including glycine (14). In this context, understanding the thermodynamics (free energy differences) and kinetics implied in basic reactions of prebiotic relevance is key to assess the likelihood of the different scenarios put forward in the literature. Computational approaches are a formidable complement to experiments in this field because they exploit the fundamental laws of quantum mechanics to study chemical reactions, interpret experimental results, and predict novel mechanisms.However, contemporary computational physical chemistry is dominated by gas-phase calculations at zero temperature, with effects due to temperature, pressure, and chemical environment relegated to approximated extrapolations. For instance, our knowledge of reaction dynamics in condensed phases is far from complete (15, 16), despite the fact that water is a polyvalent molecule, known to participate also in formamide chemistry under different roles, including as a stabilizer through hydrogen bonds, as an efficient acid–base bifunctional catalyst, and as a coreactant (17). Additional effects should also be considered, including vibrational energy dissipation upon birth of exothermic products or solute trapping into finite-lifetime cages affecting its diffusion and reactivity (16, 18, 19). The large number of possible configurations [already including few water molecules (17)] together with the strong anharmonicity of liquids naturally calls for methods like MD that include from the start the finite-temperature dynamics. From a prebiotic perspective, it is necessary to have a comparative understanding of reaction networks in different environments (gas or condensed phase, with different solvents and also interfaces with minerals) and at different conditions (T, P, irradiation, shock waves, etc.), eventually embracing also nonequilibrium scenarios, for their role in the emergence of life.The overwhelming gap between the (long) time scale of reactive events and the (short) time scale of ab initio MD simulations can be effectively overcome using the available enhanced sampling techniques, including metadynamics (20) and transition path sampling (21). Despite this, the widespread adoption of MD simulations in the study of chemical reactions has so far been slowed down by the lack of standard, general purpose formulations of reaction coordinates. In particular, it is challenging to design coordinates that fully include the important role of the solvent degrees of freedom (22–24) and that are general enough to be applied to a palette of diverse reaction mechanisms.Here we propose a novel free energy calculation approach able to address in a general way a wide range of chemical reaction mechanisms in solution. The method deals in the same formal way (namely, in the same space of coordinates) with gas-phase and solutions, allowing for the first time to our knowledge a direct comparison of the two environments and an easy assessment of the effects of a given solvent on reaction pathways. We exploit the unique advantages of our new approach to reconstruct in detail the multiple formation/decomposition mechanisms of formamide and to disclose the sizable qualitative and quantitative difference of solution chemistry with respect to gas phase. In this way we unveil a reaction network of remarkable complexity that sheds further light on fundamental prebiotic reactions and will serve as the basis of a future comparative understanding of different scenarios for the emergence of biological molecules.