Calculated methyl anion affinities are known to correlate with experimentally determined Mayr E parameters for individual organic functional group classes but not between neutral and cationic organic electrophiles. We demonstrate that methyl anion affinities calculated with a solvation model (MAA*) give a linear correlation with Mayr E parameters for a broad range of functional groups. Methyl anion affinities (MAA*), plotted on the log scale of Mayr E, provide insights into the full range of electrophilicity of organic functional groups. On the Mayr E scale, the electrophilicity toward the methyl anion spans 180 orders of magnitude. Article pubs.acs.org/joc
Methyl cation affinities are calculated for the canonical nucleophilic functional groups in organic chemistry. These methyl cation affinities, calculated with a solvation model (MCA*), give an emprical correlation with the Ns N term from the Mayr equation under aprotic conditions when they are scaled to the Mayr reference cation (4-MeOC 6 H 4 ) 2 CH + (Mayr E = 0). Highly reactive anionic nucleophiles were found to give a separate correlation, while some ylides and phosphorus compounds were determined to give a poor correlation. MCA*s are estimated for a broad range of simple molecules representing the canonical functional groups in organic chemistry. On the basis of a linear correlation, we estimate the range of nucleophilicities of organic functional groups, ranging from a C−C bond to a hypothetical tert-butyl carbanion, toward the reference electrophile to be about 50 orders of magnitude.
The facile synthesis of functionalized azetidines has been an ongoing challenge. Here, we report a general method to directly alkylate 1-azabicyclo[1.1.0]butane (ABB) with organometal reagents in the presence of Cu(OTf) 2 to rapidly prepare bis-functionalized azetidines. This method allows for the preparation of azetidines bearing alkyl, allyl, vinyl, and benzyl groups. This catalyst system was extended to aziridines and spirocycles. Several building blocks and druglike compounds were prepared in rapid fashion and in good yield.
The chemo/regioselective H-D exchange of amino acids and synthetic building blocks by an environmentally benign Pd/C-Al-D2O catalytic system is described. Due to the importance of isotope labeled compounds in medicinal chemistry and structural biology, notably their use as improved drug candidates and biological probes, the efficient and selective deuteration methods are of great interest. The approach is based on selective H-D exchange reactions where the deuterium source is simple D2O. D2 gas is generated in situ from the reaction of aluminum and D2O, while the commercially available palladium catalyst assists the H-D exchange reaction. The high selectivity and efficiency, as well as the simplicity and safe nature of the procedure make this method an environmentally benign alternative to current alternatives.
While deuterium (D) is barely different from its most abundant isotope hydrogen (H), the additional neutron makes a significant difference in the properties of deuterated compounds. While metabolic enzymes easily transform drug molecules to metabolites that the body can excrete, the introduction of deuterium to drugs appears to strengthen the resistance of drugs toward metabolism. The higher the stability, the longer the drug can work, which may result in lower dosage, therefore less side effects. In fact, the carbon‐deuterium bond is known to be six‐ten times stronger than its C‐H counterpart. There are several known methods for the introduction of deuterium to organic compounds; most methods, however, do not conform to the recent expectations and standards of sustainable synthesis. In order to develop an environmentally benign deuteration method we have turned our attention to the Al‐H2O system that is commonly applied for hydrogenation reactions. Replacing the H2O with its deuterated version D2O this hydrogen generating system can be turned to an easy and safe source of deuterium. The application of either the commercially available Ni‐Al alloy or Al only in conjunction with common hydrogenation catalysts, such as Pd or Pt, for the H‐D exchange of compounds with reactive C‐H bonds can be easily performed, while yielding no harmful byproducts. The low reactivity of the aluminum metal can be significantly enhanced by the application of ultrasonic irradiation. The H‐D exchange reaction can be carried out under relatively mild conditions; in more difficult cases the application of microwave irradiation yields the final products in a 1 h reaction. The success of the method was demonstrated by applying a broad variety of compounds from essential amino acids to actual drug compounds. By generating stronger bonds, the drugs would be able to remain active for an extended period of time, allowing the use of lower amounts, thus significantly improve the safety of their use.
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