Cocatalytic Activity of the Furfuryl and Oxanorbornane-Substituted Guanidines in the Aldol Reaction Catalyzed by (S)-Proline.

This work investigated the cocatalytic activity of recently prepared guanidinium salts containing an oxanorbornane subunit in an (S)-proline-catalyzed aldol reaction. The activity was interpreted by the diastereoselectivity of the reaction (anti/syn ratio) and for the most interesting polycyclic guanidinium salt, the enantioselectivity of the reaction was determined. The results indicated a negative impact on the oxanorbornane unit if present as the flexible substituent. For most of the tested aldehydes, the best cocatalysts provided enantioselectivities above 90% and above 95% at room temperature and 0 °C, respectively, culminating in >99.5% for 4-chloro- and 2-nitrobenzaldehyde as the substrate. The barriers for forming four possible enantiomers were calculated and the results for two anti-enantiomers are qualitatively consistent with the experiment. Obtained results suggest that the representatives of furfurylguanidinium and rigid polycyclic oxanorbornane-substituted guanidinium salts are good lead structures for developing new cocatalysts by tuning the chemical space around the guanidine moiety.

A DFT Investigation of the Reactivity of Guanidinium Salts in Tandem aza-Michael Addition/Intramolecular Cyclization.

A proposed mechanism of the reaction of guanidinium chlorides with dimethyl acetylenedicarboxylate in a tandem aza-Michael addition reaction/intramolecular cyclization was investigated by DFT M06-2X and B3LYP computational approaches. The energies of the products were compared against the G3, M08-HX, M11, and wB97xD data or experimentally obtained product ratios. The structural diversity of the products was interpreted by the concurrent formation of different tautomers formed in situ upon deprotonation with a 2-chlorofumarate anion. A comparison of relative energies of the characteristic stationary points along the examined reaction paths indicated that the initial nucleophilic addition is energetically the most demanding process. The overall reaction is strongly exergonic, as predicted by both methods, which is primarily due to methanol elimination during the intramolecular cyclization step producing cyclic amide structures. Formation of a five-membered ring upon intramolecular cyclization is highly favored for the acyclic guanidine, while optimal product structure for the cyclic guanidines is based on a 1,5,7-triaza [4.3.0]-bicyclononane skeleton. Relative stabilities of the possible products calculated by the employed DFT methods were compared against the experimental product ratio. The best agreement was obtained for the M08-HX approach while the B3LYP approach provided somewhat better results than the M06-2X and M11 methods.

Anion-Controlled Synthesis of Novel Guanidine-Substituted Oxanorbornanes.

The cycloaddition of simple alkyl-substituted guanidine derivatives is an interesting approach toward polycyclic superbases and guanidine-based organocatalysts. Due to the high nucleophilicity of guanidines, an aza-Michael reaction with dienophiles is more common and presents a huge obstacle in achieving the desired synthetic goal. Our preliminary investigations indicated that the proton could act as a suitable protecting group to regulate the directionality of the reaction. To investigate the role of the protonation state and type of anion, the reactivity of furfuryl guanidines with dimethyl acetylenedicarboxylate was explored. Furfuryl guanidines showed a strong reaction dependence on the nucleophilicity of the counterion and the structure of guanidine. While the reaction of DMAD with the guanidinium halides provided products of an aza-Michael addition, Diels-Alder cycloaddition occurred if non-nucleophilic hexafluorophosphate salts were used. Depending on the structure and the reaction conditions, oxanorbornadiene products underwent subsequent intramolecular cyclization. A tendency toward intramolecular cyclization was interpreted in terms of the pKa of different positions of the guanidine functionality in oxanorbornadienes. New polycyclic guanidines had a slightly decreased pKa in acetonitrile and well-defined geometry suitable for the buildup of selective sensors.

Benzoylguanidines as Anion-Responsive Systems.

A series of benzoylguanidinium salts was prepared and the changes in UV/Vis spectra, triggered by the presence of anions, were investigated. All compounds undergo deprotonation with basic anions like dihydrogenphosphate and acetate in acetonitrile. The most pronounced spectral changes were obtained by deprotonation of N1 -benzoyl-N3 -(p-nitrophenyl) guanidinium chloride which shows the naked-eye visible color change from colorless to yellow. Measured pKa (BH+ ) in acetonitrile ranges from 12-16, which is comparable to the pyridinium cations. The proton transfer equilibria were also tested in acetonitrile/water mixture where all but the most acidic derivatives showed pKa (BH+ ) of 4-6 units which corresponds to apparent association constants of 104 -106  dm3 mol-1 . UV/Vis spectra of neutral and protonated forms were modelled by the TD-DFT approach using CAM-B3LYP and PBE0 functionals and compared to CC2 results. In the case of CAM-B3LYP, a parameter ω, defining amount of long-range exchange correction, was varied to achieve the best agreement with the experimental spectra. The optimized ω parameters are 0.10 a0 -1 for neutral benzoylguanidines and 0.20 a0 -1 for neutral nitrobenzoyl and protonated systems. The larger ω parameter in the latter is ascribed to more pronounced charge transfer character of the HOMO-LUMO transition - the one responsible for the lowest energy absorption band.