Quantum Chemical Investigation of the Formation of Spiroheterocyclic Compounds Via the (3 + 2) Cycloaddition Reaction of 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one with Diazomethane and Nitrone Derivatives

Spirocycles are important structures in drug development due to their inherent biological activity. Their complex architecture usually presents many synthetic difficulties which are efficiently resolved with detailed theoretical studies. The chemo-, regio- and stereoselectivities of the formation of spiroheterocyclic compounds via the (3 + 2) cycloaddition (32CA) reaction of 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one (A1) derivatives with diazomethane and nitrone derivative have been studied at the M06-2X/6-311G(d,p) level of theory. The reactions of diazomethane (A2) and N-methyl-C-phenyl nitrone (A3) derivatives with 1-methyl-3-(2,2,2-trifluoroethylidene)pyrrolidin-2-one derivatives (A1) occurs chemoselectively along the olefinic bond of A1 via an asynchronous one-step mechanism. Analysis of the electrophilic ( and nucleophilic ( Parr functions at the different reaction sites in A1 shows that A2 and A3 add across the atomic centers with the largest Mulliken and NBO atomic spin densities. Both electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) on the A3 molecule do not affect the observed preferred pathway in its 32CA reaction with A1 whereas the electronic and steric nature of the substituent on the A2 molecule influences the preferred pathway in the 32CA reaction of A1 and A2. The title reaction proceeds via forward electron denisity flux (FEDF), where electron density fluxes from the three-atom components (A2 and A3) to A1. The computed global electron density transfer (GEDT) values suggest that the 32CA of A1 with diazomethane is a polar reaction while the 32CA reaction of A1 with N-methyl-C-phenyl nitrone is a non-polar reaction, and an inverse relationship has been established between the polar character of the reactions and activation barriers. In all the reactions studied, the selectivities are kinetically controlled.

Insights into Elution of Anion Exchange Cartridges: Opening the Path towards Aliphatic 18F-Radiolabeling of Base-Sensitive Tracers

Aliphatic nucleophilic substitution (S_N2) with [¹⁸F]fluoride is the most widely applied method to prepare ¹⁸F-labeled positron emission tomography (PET) tracers. Strongly basic conditions commonly used during ¹⁸F-labeling procedures inherently limit or prohibit labeling of base-sensitive scaffolds. The high basicity stems from the tradition to trap [¹⁸F]fluoride on anion exchange cartridges and elute it afterwards with basic anions. This sequence is used to facilitate the transfer of [¹⁸F]fluoride from an aqueous to an aprotic organic, polar reaction medium, which is beneficial for S_N2 reactions. Furthermore, this sequence also removes cationic radioactive contaminations from cyclotron-irradiated [¹⁸O]water from which [¹⁸F]fluoride is produced. In this study, we developed an efficient elution procedure resulting in low basicity that permits S_N2 ¹⁸F-labeling of base-sensitive scaffolds. Extensive screening of trapping and elution conditions (>1000 experiments) and studying their influence on the radiochemical yield (RCY) allowed us to identify a suitable procedure for this. Four PET tracers and three synthons could be radiolabeled in substantially higher RCYs (up to 2.5-fold), even from lower precursor amounts, using this procedure. Encouraged by these results, we applied our low basicity method to the radiolabeling of highly base-sensitive tetrazines, which cannot be labeled using state-of-art direct aliphatic ¹⁸F-labeling procedures. Labeling succeeded in RCYs of up to 20%. We believe that our findings facilitate PET tracer development by opening the path towards simple and direct S_N2 ¹⁸F-fluorination of base-sensitive substrates.

Insights into Elution of Anion Exchange Cartridges: Opening the Path towards Aliphatic 18F-Radiolabeling of Base-Sensitive Tracers

Aliphatic nucleophilic substitution (S_N2) with [¹⁸F]fluoride is the most widely applied method to prepare ¹⁸F-labeled positron emission tomography (PET) tracers. Strongly basic conditions commonly used during ¹⁸F-labeling procedures inherently limit or prohibit labeling of base-sensitive scaffolds. The high basicity stems from the tradition to trap [¹⁸F]fluoride on anion exchange cartridges and elute it afterwards with basic anions. This sequence is used to facilitate the transfer of [¹⁸F]fluoride from an aqueous to an aprotic organic, polar reaction medium, which is beneficial for S_N2 reactions. Furthermore, this sequence also removes cationic radioactive contaminations from cyclotron-irradiated [¹⁸O]water from which [¹⁸F]fluoride is produced. In this study, we developed an efficient elution procedure resulting in low basicity that permits S_N2 ¹⁸F-labeling of base-sensitive scaffolds. Extensive screening of trapping and elution conditions (>1000 experiments) and studying their influence on the radiochemical yield (RCY) allowed us to identify a suitable procedure for this. Four PET tracers and three synthons could be radiolabeled in substantially higher RCYs (up to 2.5-fold), even from lower precursor amounts, using this procedure. Encouraged by these results, we applied our low basicity method to the radiolabeling of highly base-sensitive tetrazines, which cannot be labeled using state-of-art direct aliphatic ¹⁸F-labeling procedures. Labeling succeeded in RCYs of up to 20%. We believe that our findings facilitate PET tracer development by opening the path towards simple and direct S_N2 ¹⁸F-fluorination of base-sensitive substrates.

Unravelling the strain-promoted [3+2] cycloaddition reactions of phenyl azide with cycloalkynes from the molecular electron density theory perspective

The increase of the strain not only increases the reaction rate and the exothermic character of these reactions, but also changes the mechanism for the small cycloalkynes from a non-polar to a polar reaction.

Catalytic Oxidation of Thiophenes with Air and PW/SBA-15

Catalytic oxidation is considered a viable method for reducing the sulphur level of transportation fuels and H2O2 is usually used as the oxidant. For this reason, it is essential that any extraction operation must remove the oxidation product from the fuel. A new oxidation method is studied in the present work. Instead of H2O2, air was used as the oxidant and phosphotungstic acid (PW) was used as the catalyst; the latter was imbedded in the pore spaces of the mesoporous silica material SBA-15 to form a PW/SBA-15 composite. The oxidation reaction occurred in the pore spaces of the composite and the polar reaction products were immediately adsorbed there. As a consequence, there was no need for a subsequent exaction operation. Desulphurization experiments were carried out using a model fuel composed of n-octane and thiophene. The content of thiophene was reduced from 2000 ppmw to less than 1 ppmw at 50°C and ambient pressure. The saturated PW/SBA-15 composite was regenerated at 350°C by using a nitrogen flow for 4 h. Such conditions allowed the catalytic activity to be recovered.

Nitrogen and Sulfur Transferases

Unlike other group transfer reactions in biochemistry, the actions of nitrogen transferring enzymes do not follow a single unifying chemical principle. Nitrogen-transferring enzymes catalyze aminotransfer, amidotransfer, and amidinotransfer. An aminotransferase catalyzes the transfer of the NH2 group from a primary amine to a ketone or aldehyde. An amidotransferase catalyzes the transfer of the anide-NH2 group from glutamine to another group. These reactions proceed by polar reaction mechanisms. Aminomutases catalyze 1,2-intramolecular aminotransfer, in which an amino group is inserted into an adjacent C—H bond. The action of lysine 2,3-aminomutase, described in chapter 7, is an example of an aminomutase that functions by a radical reaction mechanism. Tyrosine 2,3-aminomutase also catalyzes the 2,3-amino migration, but it does so by a polar reaction mechanism. In this chapter, we consider NH2-transferring enzymes that function by polar reaction mechanisms. Transaminases or aminotransferases are the most extensively studied pyridoxal-5'-phosphate (PLP)–dependent enzymes, and many aminotransferases catalyze essential steps in catabolic and anabolic metabolism. In the classic transaminase reaction, aspartate aminotransferase (AAT) catalyzes the fully reversible reaction of L-aspartate with α-ketoglutarate according to fig. 13-1 to form oxaloacetate and L-glutamate. Like all aminotransferases, AAT is PLP dependent, and PLP functions in its classic role of providing a reactive carbonyl group to function in facilitating the cleavage of the α-H of aspartate and the departure of the α-amino group of aspartate for transfer to α-ketoglutarate (Snell, 1962). PLP in the holoenzyme functions in essence to stabilize the α-carbanions of L-aspartate or L-glutamate, the major biological role of PLP discussed in chapter 3. The functional groups of the enzyme catalyze steps in the mechanism, such as the 1,3-prototropic shift of the α-proton to C4' of pyridoxamine 5'-phosphate (PMP). The steady-state kinetics corresponds to the ping pong bi bi mechanism shown at the bottom of fig. 13-1. This mechanism allows L-aspartate to react with the internal aldimine, E=PLP in fig. 13-1, to produce an equivalent of oxaloacetate, with conversion of PLP to PMP at the active site (E.PMP), the free, covalently modified enzyme in the ping pong mechanism.