Roles of Guanidines in Recent Cycloaddition Reactions Petar Štrbac, Davor Margetić, Anamarija Briš Reactions, 2026 Guanidines are structurally unique, highly basic, nitrogen-containing organic compounds with strong hydrogen-bonding ability and biological activity, providing valuable functionality in medicinal chemistry, organocatalysis, and materials science. Among modern strategies for assembling guanidine-containing molecules, cycloaddition reactions have emerged as powerful tools due to their efficiency, stereoselectivity, and ability to rapidly build molecular complexity. Recent innovations have expanded cycloaddition methodologies for generating guanidine functionalities, incorporating guanidine-containing substrates, and using guanidine-based catalysts. This review summarizes these advances and highlights the current trends in guanidine-related cycloaddition chemistry.
Direct Analysis of Complex Reaction Mixtures: Formose Reaction Anamarija Briš, Mathieu G. Baltussen, Guilherme L. Tripodi, Wilhelm T. S. Huck, Pietro Franceschi, et al. Angewandte Chemie International Edition, 2024 Complex reaction mixtures, like those postulated on early Earth, present an analytical challenge because of the number of components, their similarity, and vastly different concentrations. Interpreting the reaction networks is typically based on simplified or partial data, limiting our insight. We present a new approach based on online monitoring of reaction mixtures formed by the formose reaction by ion‐mobility‐separation mass‐spectrometry. Monitoring the reaction mixtures led to large data sets that we analyzed by non‐negative matrix factorization, thereby identifying ion‐signal groups capturing the time evolution of the network. The groups comprised ≈300 major ion signals corresponding to sugar‐calcium complexes formed during the formose reaction. Multivariate analysis of the kinetic profiles of these complexes provided an overview of the interconnected kinetic processes in the solution, highlighting different pathways for sugar growth and the effects of different initiators on the initial kinetics. Reconstructing the network's topology further, we revealed so far unnoticed fast retro‐aldol reaction of ketoses, which significantly affects the initial reaction dynamics. We also detected the onset of sugar‐backbone branching for C6 sugars and cyclization reactions starting for C5 sugars. This top‐down analytical approach opens a new way to analyze complex dynamic mixtures online with unprecedented coverage and time resolution.
Hydrogen-Bonding Secondary Coordination Sphere Effect on CO2 Reduction Anamarija Briš, Davor Margetić Organics, 2023 Great efforts of the scientific community are focused on the development of catalysts for the reduction of carbon dioxide (CO2) to useful molecules such as carbon monoxide, formic acid, methanol, ethanol, methane, ethylene, or acetate. Various metal porphyrin complexes were synthesized and studied to develop highly active and selective catalysts. While the substituents on the porphyrin core (the primary coordination sphere) determine the reactivity of the metal, the introduction of the secondary coordination is important for the binding and activation of CO2. In this review, selected examples of iron porphyrin catalysts with a secondary coordination sphere capable of stabilizing intermediates of the CO2 reduction process by hydrogen bonding are presented.
N,N′-Di-Boc-2H-Isoindole-2-carboxamidine—First Guanidine-Substituted Isoindole Petar Štrbac, Anamarija Briš, Davor Margetić Molecules, 2022 Synthesis of N,N′-Di-Boc-2H-isoindole-2-carboxamidine, the first representative of isoindoles containing guanidine functionality, was carried out. The cycloaddition reactivity of this new Diels–Alder heterodiene was studied and the title compound was employed as a cycloaddition delivery reagent for guanidine functionality. Higher reactivity was found in comparison with the corresponding pyrrole derivative. Substitution with fluorine or guanidine functionality does not change the reactivities of isoindoles, and these findings are in good accord with computational results.
Monitoring Reaction Intermediates to Predict Enantioselectivity Using Mass Spectrometry** Roelant Hilgers, Sin Yong Teng, Anamarija Briš, Aleksandr Y. Pereverzev, Paul White, et al. Angewandte Chemie International Edition, 2022 Enantioselective reactions are at the core of chemical synthesis. Their development mostly relies on prior knowledge, laborious product analysis and post-rationalization by theoretical methods. Here, we introduce a simple and fast method to determine enantioselectivities based on mass spectrometry. The method is based on ion mobility separation of diastereomeric intermediates, formed from a chiral catalyst and prochiral reactants, and delayed reactant labeling experiments to link the mass spectra with the reaction kinetics in solution. The data provide rate constants along the reaction paths for the individual diastereomeric intermediates, revealing the origins of enantioselectivity. Using the derived kinetics, the enantioselectivity of the overall reaction can be predicted. Hence, this method can offer a rapid discovery and optimization of enantioselective reactions in the future. We illustrate the method for the addition of cyclopentadiene (CP) to an α,β-unsaturated aldehyde catalyzed by a diarylprolinol silyl ether.
Gas-phase basicity of cyclic guanidine derivatives - a DFT study Anamarija Briš, Zoran Glasovac, Davor Margetić New Journal of Chemistry, 2021 Density functional theory calculations (B3LYP) were employed in the study of gas-phase basicity (GB) and pKa of three different types of cyclic guanidines differing in the number of nitrogen atoms incorporated in rings.
Mechanochemical Friedel-crafts acylations Mateja Đud, Anamarija Briš, Iva Jušinski, Davor Gracin, Davor Margetić Beilstein Journal of Organic Chemistry, 2019 Friedel–Crafts (FC) acylation reactions were exploited in the preparation of ketone-functionalized aromatics. Environmentally more friendly, solvent-free mechanochemical reaction conditions of this industrially important reaction were developed. Reaction parameters such as FC catalyst, time, ratio of reagents and milling support were studied to establish the optimal reaction conditions. The scope of the reaction was explored by employment of different aromatic hydrocarbons in conjunction with anhydrides and acylation reagents. It was shown that certain FC-reactive aromatics could be effectively functionalized by FC acylations carried out under ball-milling conditions without the presence of a solvent. The reaction mechanism was studied by in situ Raman and ex situ IR spectroscopy.
