Research topic (i): Investigation, in the laboratory, of isolated molecules and small aggregates that exist in space and in the Earth’s atmosphere, and it is essential to understand fundamental aspects of the chemistry and the physics going on in these two environments. The need for an improved knowledge on these domains is urgent, considering the environmental and climate problems we face nowadays and the growing relevance of space research in general. This research sets on the revolutionary work of the ERA-Chair Holder (Professor Rui Fausto) in the field, leading to further exploring two less conventional types of chemistry: vibrationally-induced chemistry and quantum mechanical tunneling (QTM) driven chemistry (Chem. Soc. Rev., 51 (2022) 2853).

The main technique to be used in these studies is matrix isolation infrared spectroscopy. This technique joins the structural analytical power of infrared spectroscopy with the unique capabilities of the low temperature matrix isolation sampling technique, where molecules of a given substance are isolated in the solid inert environment of a frozen noble gas or N2 at temperatures close to the absolute zero. In cryogenic matrices conditions (e.g., 3−20 K) thermally activated processes become negligible for systems having barriers as low as 1 kcal mol−1, so that unstable species can be preserved for long. This allows their detailed experimental structural characterization using conventional steady-state spectroscopic techniques, like infrared spectroscopy. In addition, since thermal processes are quenched, the occurrence of chemical transformations for a matrix isolated species can only take place either upon photoexcitation or by quantum mechanical tunneling (QMT), i.e., matrix isolation creates optimal experimental conditions for accessing and directly follow these two types of chemistry and shed light on their associated physical processes (see “Tunneling in Molecules: Nuclear Quantum Effects from Bio to Physical Chemistry”, RSC, London, 2020, Chapter 1).

Professor Rui Fausto pioneered the utilization of vibrational photoexcitation to promote very selective structural changes in molecules by their in situ irradiation under matrix isolation conditions using narrowband infrared light provided by tunable laser sources (Chem. Soc. Rev., 51 (2022) 2853). Also, he has been developing very innovative research on chemical reactions proceeding by QMT, including those involving heavy atoms such as carbon or nitrogen, and in the description and understanding of the physical principles behind these processes. The work of Rui Fausto and his co-workers has been instrumental to better understand the role of QMT in chemistry, and has recently led to the discovery of new reactivity paradigms, for instance (i) the discovery of chemical reactions whose fate is controlled by QMT, superseding kinetic and thermodynamic controls and breaking the rules defined by the classical Transition State Theory (reactions that lead exclusively to a higher-energy product whose reaction path faces a higher, but narrower, energy barrier; Fig. 1), and (ii) the discovery that, contrarily to the previous thoughts, QMT processes may be efficiently controlled by introducing structural modifications in the reactant species through light-induced activation/deactivation (i.e., the discovery of optically activated QMT-based molecular switches, which have potential to became active components in molecular electronics; Fig. 2).
 

Fig. 1. Potential energy profile of tert-butylchlorocarbene (center) and its tunneling-controlled reaction to dimethylchlorocyclopropane (the tunneling product) through the higher but narrower barrier (J. Am. Chem. Soc., 116 (1994) 4123; J. Am. Chem. Soc., 139 (2017) 15276.).

Fig. 2. Optically (IR) controlled molecular switch for the H-atom tunneling reaction of triplet 2-hydroxyphenylnitrene generated in an N2 cryogenic matrix (10 K) from the azide precursor. The IR activation, via excitation of the 1st overtone of the OH stretching vibrational antenna, selectively transforms the OFF state (the anti conformer of the nitrene) into the ON state (syn conformer), allowing for the H-tunneling to take place (J. Am. Chem. Soc., 143 (2021) 8266). 

The use of narrowband laser sources to photoexcite matrix-isolated molecules was also extended to the UV/visible range, so that photochemistry resulting from electronic excitation can nowadays also be controlled in a very selective way (e.g., J. Am. Chem. Soc., 139 (2017) 17649). This appears particularly useful for in situ generation of short-living intermediates. All these types of processes are particularly relevant for atmospheric and space chemistry and physics, whose real conditions are mimicked by a matrix isolation experiment in the laboratory, and where reactions take place essentially upon light excitation (either UV/visible or infrared) or via QTM. 

In this ERA-chair the studies generally described above will be taken to a higher level of sophistication. Processes like conformational isomerizations, sigmatropic reactions, radical abstractions, and carbene and nitrene reactions, for long-living chemical species that have been detected in atmosphere (in particular those resulting from atmosphere anthropogenic pollution, like volatile organic compounds or nitrogen oxides and small aggregates of these species with themselves or water, for example) or shown to be present in space (like cyanides, small aldehydes and ketones, carbodiimides, ketenes, amines, amino acids, etc) as well as for short-living intermediates formed from these species as result of light-induced reactions or QMT (as nitrenes, carbenes, radicals, azirines, etc) will be investigated. Some innovative/state-of-the-art concepts, based on QMT and vibrationally-induced chemistry, will be developed in the project and applied to diverse reactions:

(i) Vibrationally-activated tunneling: We will use vibrational excitation as a powerful strategy to compress energy barriers (shorten reaction distances) and, in this way, increase QMT probability. Thus, vibrational modes associated with the relevant reaction coordinates in the target reactant molecules will be pumped with tunable IR light to test for vibrational activated tunneling processes. In this way, the preferred reaction pathways can be optically controlled, superseding the predictions of the classical TST. In some cases, new reaction paths can become accessible, thus allowing to achieve products resulting exclusively from tunneling control.

(ii) Optical conformational control of proton tunneling: We will use an elegant experimental scheme to achieve control of proton tunneling based on conformation manipulation of an H donor moiety in the vicinity of the reactive center. Tunable IR laser light set up at the OH, SH or NS stretching overtones, for example, will be used to control the conformation of the H-donor located in the vicinity of a nitrene or carbene center (generated in situ by UV/Vis narrowband selective excitation of a matrix-isolated precursor), thus allowing to switch on and off the tunneling reaction. Rui Fausto’s pioneer work on this field (see Fig. 2; J. Am. Chem. Soc., 143 (2021) 8266) and experience on controlling conformational states of molecules put us in a privileged position to successfully use this strategy for the first time in a systematic way.

(iii) Isotope controlled vibrationally-induced and tunneling-driven reactions: We hypothesize that in molecular systems with two possible reaction products, it will be possible to produce one or the other exclusively, depending only on the isotopic composition. For instance, as reported by Rui Fausto and co-workers for p-amino-benzazirine two competitive (C vs. N) QMT reactions take place at cryogenic conditions (J. Am. Chem. Soc. 141 (2019) 14340). Due to the fact that tunneling probability decreases exponentially with the square root of the moving mass, the presence of ¹⁵N or ¹³C in the tree-membered ring will potentially make the carbon or the nitrogen QMT the selected pathway, respectively. For vibrationally-induced reactions, the different coupling of the excited vibrational coordinate (e.g., N-H vs. N-D, or C-H vs. C-D, for example) with other internal degrees of freedom in a molecule may also lead to different preferred reactions for the light and heavy isotopologue. These new reactivity strategies can be expected to appear as breakthrough methods, for example for isotopic enrichment in organic synthesis.

Research topic (ii): The second major subject to be addressed within the research activities of Spectroscopy@IKU is the study of solid-state polymorphism in molecular crystals, i.e., the property exhibited by some molecules (potentially by all molecules) to give rise to different crystalline forms, which present different physical and chemical properties, as well as, very often, different biological activities (Comm. Chem. - Nature, 3 (2020) 34).

Polymorphism is a hot topic in materials sciences and is felt as one of the most critical subjects needing further urgent development by the industrial sector, especially by the pharmaceutic industry. Just to mention a classic illustrative example of the impact of polymorphism on the pharmaceutical industry, it appears appropriate to refer here the “ritonavir case” (Chem. World, April (2007) 64). Ritonavir is a peptidomimetic drug used to treat HIV-1 infection that was introduced in the market in 1996. Two years later, a lower energy, more stable polymorph (form II) was identified to be formed spontaneously from the (at the time) sole known polymorph (form I), causing slowed dissolution of the marketed dosage of the drug and compromising its oral bioavailability. This event forced the removal of the oral capsule formulation from the market and caused billions loss Euros in sales, besides extra development costs for finding a way to preclude the undesired spontaneous conversion of ritonavir polymorph I into polymorph II. Many other examples showing the fundamental importance of polymorphism in drugs design and formulation can be found in the scientific literature.

Spectroscopy is instrumental to identify and characterize new polymorphs of a given compound, in particular infrared and Raman spectroscopies, but also, frequently, UV/visible spectroscopy. Complementary analytical methods are also important in the investigation of polymorphism, such as differential scanning calorimetry (DSC; for thermal characterization of the polymorphs and phase transitions) and X-ray diffraction (XRD; single crystal XRD for detailed structure determinations, and powder XRD for general characterization of different phases).
Two main problems will be tackled by the Spectroscopy@IKU research team, which can be addressed using similar experimental approaches. The first is the study of polymorphism of pure compounds (one component systems). The second is the preparation of polymorphs of cocrystals, which are crystals formed by at least two different components that are nowadays a topic of intensive research, in particular when they are constituted by substances of pharmacological interest, since in this case cocrystals have the potential to join in the same material the intrinsic biological activities of the components (for example, a molecule that is an anti-inflammatory and another one that is an antibiotic can be delivered together and directed simultaneously to the proper local in the body where they can act synergistically). 

A new general approach for polymorphs screening will be implemented, which relies in the development of novel versatile sampling strategies for crystals/cocrystals generation from compounds initially in their gas phase. For that goal, a special novel Raman cell will be developed that allows fine control of temperature, pressure, viscosity and nature of dispersive media for the crystals (or cocrystals) precursors, and relative concentrations and surface contact area of the components and coformers, which also allows simultaneous spectroscopic probing. 
These experiments will take advantage of Prof. Rui Fausto’s wide experience on solid state polymorphism and in the development of specialized sampling devices for spectroscopy and of new protocols for experimental design (in particular in low temperature spectroscopy). The versatility of the planed groundbreaking experimental design allows expecting that the series of studies to be carried out will also allow to elucidate relevant mechanistic details of the physics underground the processes of (co)crystalization and polymorphs’ formation/selection, still fields rather unexplored hitherto.

Theoretical and computational approaches: The experimental work to be developed will be solidly grounded on modern theoretical and computational methods. For the isolated molecules, the Density Functional Theory approach will be used as standard technique for prediction of vibrational spectra as well as for calculation of molecular structures and relative energies, since it has been proved to be particularly successfully in the calculation of these types of data. Time-Dependent DFT (TD-DFT) will be used as standard for computation of electronic spectra. More advanced post Hartree-Fock methods (e.g., coupled clusters, Moller-Plesset perturbation, configurations interaction, etc.) will be used whenever required or advisable. All these types of calculations can be performed using commercial software, like GAUSSIAN, GAMESS or SPARTAN, for example. For crystalline systems, contemporary fully-periodic quantum chemical calculations will be applied, as implemented in the CRYSTAL program. When necessary, spectroscopic data analysis will be undertaken with help of chemometrics methods for data dimension reduction, pattern recognition, and classification (e.g., principal component analysis, partial least squares with discriminant analysis, hierarchical clustering, etc), available in UNSCRAMBLER. All the mentioned computer programs and other relevant software for molecular modelling (e.g., ChemCraft, MultiWFN, Gaussview), spectra analysis (e.g., OMNIC, SpectraGryph, GRAMS, LabView) and crystal structure analysis (Crystal Explorer) will be available to the Spectroscopy@IKU researchers (most of them are already available at IKU Labs). Calculations will be done using the IKU High Performance Computer Laboratory (HPC Lab).