Site-Selective Alkyl Dehydrogenation of a Coordinated Acylphosphine Ligand

Regio- and stereoselective alkane dehydrogenation is a difficult challenge in organometallic chemistry. Intermolecular reactions of this type typically produce numerous olefin stereo- and regioisomers. Herein, we report our initial investigations into the intramolecular dehydrogenation of a datively bound alkyl ligand, demonstrating the first example of a site-selective dehydrogenation of an unactivated acyclic alkyl group. The alkyl group is located on an acylphosphine ligand that is coordinated to a Cp*IrCl₂ monomer. A mechanistic proposal, guided by the isolation of a dimeric iridium complex and supported by computational results, is also described

Site-Selective Alkyl Dehydrogenation of a Coordinated Acylphosphine Ligand

Regio- and stereoselective alkane dehydrogenation is a difficult challenge in organometallic chemistry. Intermolecular reactions of this type typically produce numerous olefin stereo- and regioisomers. Herein, we report our initial investigations into the intramolecular dehydrogenation of a datively bound alkyl ligand, demonstrating the first example of a site-selective dehydrogenation of an unactivated acyclic alkyl group. The alkyl group is located on an acylphosphine ligand that is coordinated to a Cp*IrCl₂ monomer. A mechanistic proposal, guided by the isolation of a dimeric iridium complex and supported by computational results, is also described

The Prospect of Selective Recognition of Nerve Agents with Modular Basket-like Hosts. A Structure–Activity Study of the Entrapment of a Series of Organophosphonates in Aqueous Media

We designed, prepared, and characterized three cup-shaped cavitands <b>1</b>–<b>3</b> for trapping organophosphonates (OPR­(OR′)₂, 118–197 ų) whose shape and size correspond to G-type chemical warfare agents (132–186 ų). With the assistance of computational (molecular dynamics) and experimental (¹H NMR spectroscopy) methods, we found that host [<b>1</b>–<b>H</b>₃]³⁺ orients its protonated histamine residues at the rim outside the cavity, in bulk water. In this unfolded form, the cavitand traps a series of organophosphonates <b>5</b>–<b>13</b> (<i>K</i>_app = 87 ± 1 to 321 ± 6 M^–1 at 298.0 K), thereby placing the P–CH₃ functional group in the inner space of the host. A comparison of experimental and computed ¹H NMR chemical shifts of both hosts and guests allowed us to derive structure–activity relationships and deduce that, upon the complexation, the more sizable P–OR functional groups in guests drive organophosphonates to the northern portion of the basket [<b>1</b>–<b>H</b>₃]³⁺. This, in turn, causes a displacement of the guest’s P–CH₃ group and a contraction of the cup-shaped scaffold. The proposed induced-fit model of the recognition is important for turning these modular hosts into useful receptors capable of a selective detection/degradation of organophosphorus nerve agents

Method for the Preparation of Derivatives of Heptiptycene: Toward Dual-Cavity Baskets

We have developed a novel synthetic method that enables the preparation of functional derivatives of heptiptycene, i.e., cavitands with two juxtaposed cavities. The homocoupling of bicyclic dibromoalkenes is promoted by Pd­(OAc)₂ (10%) in dioxane (100 °C) to give cyclotrimers in 27–77% yield under optimized reaction conditions (Ph₃P, K₂CO₃, <i>n</i>-Bu₄NBr, N₂, 4 Å MS). These dual-cavity baskets show a strong π → π* absorption at 241 nm (ε = 939 000 M^–1 cm^–1), along with a subsequent fluorescence emission at 305 nm

Study of <i>para</i>-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase

Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP–AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed

Study of <i>para</i>-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase

Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP–AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed

Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents

After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (<b>C8</b>) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. <b>C8</b> displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by <b>C8</b> was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. <b>C8</b> is also effective against isopropyl phosphate-aged human AChE

Demonstration of In Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents

After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (<b>C8</b>) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. <b>C8</b> displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by <b>C8</b> was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. <b>C8</b> is also effective against isopropyl phosphate-aged human AChE