Elena Sáez

Na⁺ and K⁺ coordination influence protonation of [FeFe]H₂ase mimics with polyether-linked triazoles. In TFA protonated triazoles avoid K⁺, boosting TOF, while Na⁺ keeps coordination lowering activity. This insight aids in the design of HER catalysts.

Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.

An NMR comparative study of 1,2,3-triazole and triazolium anion recognition units containing sulfoxide, sulfone, and sulfoximine groups at C₄ unveils an enhancement in binding ability up to ≈1 kcal/mol in acetone-d₆ correlated with a theoretical increase of H₅ acidity. DFT calculations provide insight into binding modes in line with experimental data for these receptors.

Standard 2D NMR experiments suffer from the many t₁ increments needed for spectra with sufficient digital resolution in the indirect dimension. Despite the different methodological approaches to overcome this problem, these increments have prevented studies of fast reactions. The development of ultrafast NMR (UF‐NMR) has decisively speeded up the time scale of standard NMR to allow the study of organic reactions as they happen in real time to reveal mechanistic details. This mini‐review summarizes the results achieved in monitoring organic reactions through this exciting technique. Copyright © 2015 John Wiley & Sons, Ltd.

Ultrafast NMR spectroscopy (UF-NMR) can be used to monitor chemical reactions in real time and to provide insights into their mechanisms and the nature of the intermediates formed. Here, we have developed a 2D ¹H,³¹P UF-HMBC method and the corresponding NMR experimental setup to enable the study of a Michaelis–Arbuzov reaction at two different temperatures, 25 and 70 °C. The specific reaction studied was between triethyl phosphite and benzyl bromide to produce diethylbenzyl phosphonate. Our results show that at 70 °C the reaction takes place directly, without the detection of an intermediate by ¹H,³¹P UF-HMBC. In contrast, at 25 °C, using zinc bromide as a catalyst, our results show the formation of benzyltriethoxy phosphonium bromide as an intermediate. The experiments again show the power of UF-NMR in mechanistic studies of reactions involving various phosphorus chemical species.

Ultrafast multidimensional NMR acquisition techniques have shown promising capabilities in studies of dynamic systems in real time. The method’s characteristics have permitted the focus to be on the mechanistic details of organic reactions. The tandem UF-TOCSY/HMBC sequence applied here combines both homonuclear and heteronuclear details and therefore provides complete information about the evolution of a dynamic reaction in real time. The methodology will be applied to find an explanation of the low reactivity of alicyclic ketones such as cyclohexanone in reactions with triflic anhydride and aliphatic nitriles, which leads to bicyclic pyrimidines.

The reaction of equimolecular amounts of a nitrile and triflic anhydride or triflic acid at low temperature produces an intermediate nitrilium salt that subsequently reacts with 2 equiv of a different nitrile at higher temperature to form 2,4-disusbstituted-6-substituted 1,3,5-triazines in moderate to good yields. This synthetic procedure has also been applied to the preparation of a 1,3,5-triazine having three different substituents. The results are explained in terms of a mechanism based on the relative stability of the intermediate nitrilium salts that are formed through a reversible pathway. The formation of a substituted isoquinoline using benzyl cyanide as the second nitrile supports the postulated mechanism as well as the structure of derivatives of the proposed intermediate when the reaction is carried out in the presence of different nucleophiles other than nitriles. Theoretical calculations and the monitoring of the reaction using ¹H and ¹³C NMR spectroscopy are in agreement with the proposed mechanism pathway.

Ultrafast 2D HMBC spectroscopy permits real-time monitoring of a reaction based on the structural changes produced in a carbonyl carbon atom. This new technique was used to study the reaction of ketones, nitriles, and Tf₂O, affording relevant information about new intermediates and kinetic data.