An official website of the United States government
C-H Bond dissociation energies for a unique selection of tertiary amines that are known substrates or inhibitors of monoamine oxidase have been calculated using density functional theory. These amines are unusual because they are the only tertiary amines that exhibit MAO substrate or inhibitor behavior. The unique structural feature common to these specific compounds is an sp3-hybridized CH2 moiety, which is -both to nitrogen and an C=C or C≡C. The stabilization afforded the resulting radicals by extended delocalization dramatically lowers both the C-H bond strength of the substrate (R-H → R• + H•) and pKa of the corresponding radical cation (RH•+ → R• + H+). This interplay of structure and thermodynamics may provide the driving force for an electron transfer mechanism for MAO catalysis and inhibition.
more »
« less
Why Does Monoamine Oxidase (MAO) Catalyze the Oxidation of Some Tetrahydropyridines?
Abstract Results pertaining to the mechanism of the oxidation of the tertiary amine 1‐methyl‐4‐(1‐methyl‐1‐H‐pyrrol‐2‐yl)‐1,2,3,6‐tetrahydropyridine (MMTP, a close analog of the Parkinsonism inducing compound MPTP) by 3‐methyllumiflavin (3MLF), a chemical model for the FAD cofactor of monoamine oxidase, are reported. MMTP and related compounds are among the few tertiary amines that are monoamine oxidase B (MAO−B) substrates. The MMTP/3MLF reaction is catalytic in the presence of O2and the results under anaerobic conditions strongly suggest the involvement of radical intermediates, consistent with a single electron transfer mechanism. These observations support a new hypothesis to explain the MAO‐catalyzed oxidations of amines. In general, electron transfer is thermodynamically unfavorable, and as a result, most 1° and 2° amines react via one of the currently accepted polar pathways. Steric constraints prevent 3° amines from reacting via a polar pathway. Those select 3° amines that are MAO substrates possess certain structural features (e. g., a C−H bond that is α‐ both to nitrogen and a C=C) that dramatically lower the pKaof the corresponding radical cation. Consequently, the thermodynamically unfavorable electron transfer equilibrium is driven towards products by an extremely favorable deprotonation step in the context of Le Chatelier's principle.
more »
« less
- Award ID(s):
- 2106188
- PAR ID:
- 10500082
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemBioChem
- Volume:
- 25
- Issue:
- 10
- ISSN:
- 1439-4227
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Photoredox catalysis has provided many approaches to C(sp3)–H functionalization that enable selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp3)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp3)–H functionalization.more » « less
-
Abstract We report copper(II) and copper(III) trifluoromethyl complexes supported by a pyridinedicarboxamide ligand (L) as a platform for investigating the role of electron transfer in C(sp2)−H trifluoromethylation. While the copper(II) trifluoromethyl complex is unreactive towards (hetero)arenes, the formal copper(III) trifluoromethyl complex performs C(sp2)−H trifluoromethylation of a wide range of (hetero)arenes. Mechanistic studies using the copper(III) trifluoromethyl complex suggest that the mechanism of arene trifluoromethylation is substrate‐dependent. When the thermodynamic driving force for electron transfer is high, the reaction proceeds through a previously unidentified single electron transfer (SET) mechanism, where an initial electron transfer occurs between the substrate and oxidant prior to CF3group transfer. Otherwise, a CF3radical release/electrophilic aromatic substitution (SEAr) mechanism is followed. These studies provide valuable insights into the role of strong oxidants and potential mechanistic dichotomy in Cu‐mediated C(sp2)−H trifluoromethylation.more » « less
-
Abstract Group I alkoxides are highly active precatalysts in the heterodehydrocoupling of silanes and amines to afford aminosilane products. The broadly soluble and commercially available KOtAmyl was utilized as the benchmark precatalyst for this transformation. Challenging substrates such as anilines were found to readily couple primary, secondary, and tertiary silanes in high conversions (>90 %) after only 2 h at 40 °C. Traditionally challenging silanes such as Ph3SiH were also easily coupled to simple primary and secondary amines under mild conditions, with reactivity that rivals many rare earth and transition‐metal catalysts for this transformation. Preliminary evidence suggests the formation of hypercoordinated intermediates, but radicals were detected under catalytic conditions, indicating a mechanism that is rare for Si−N bond formation.more » « less
-
Abstract The triel bond (TrB) formed between Be(CH3)2/Mg(CH3)2and TrX3(Tr=B, Al, and Ga; X=H, F, Cl, Br, and I) is investigated via the MP2/aug‐cc‐pVTZ(PP) quantum chemical protocol. The C atoms of the methyl groups in M(CH3)2are characterized by a negative electrostatic potential and act as an electron donor in a triel bond with the π‐hole above the Tr atom of planar TrX3. The interaction energy spans a wide range between −2 and −69 kcal/mol. Mg(CH3)2forms a stronger TrB than does Be(CH3)2, which comports with the more negative electrostatic potential on its methyl groups. Some of the complexes involving Mg display a high degree of transfer of the methyl group from Mg to Tr, which is accompanied by an inversion of the bridging methyl and a sizable pyramidalization of the TrX3unit. The geometries of these complexes have the properties of the long sought pentacoordinate C which has eluded identification and characterization in the past.more » « less
