Effects of substituents on the stabilities of phosphonyl radicals and their hydroxyphosphinyl tautomers

High-level ab initio quantum chemical methods have been used to calculate the radical stabilization energies (RSEs) of phosphonyl radicals XYP(=O)· bearing a range of substituents X and Y. The main influences on these radicals' stabilities are σ-effects. Due to the high positive charge on phosphorus, σ-withdrawal is destabilizing, and σ-donation is stabilizing. The pyramidal geometry at phosphorus minimizes the effect of stabilization by π-delocalization, while the potentially stabilizing effect of lone-pair donation is outweighed by concomitant σ-withdrawal. Thus, the calculated RSEs of phosphonyl radicals XHP(=O)· increase in the order X = F < MeN < MeO < CF < Bu < MeN < NC < H < Ph < MeS < MeSi. The tautomeric hydroxyphosphinyl radicals X(OH)P· exhibit a different set of substituent effects, with RSEs increasing in the order X = CF < MeN < MeN < MeO < Bu < H < MeS < MeSi < F < NC < Ph. In these radicals, both the σ- and π-properties of the X substituent influence stability, in tandem with those of the OH group. A comparison of the absolute enthalpies of isomeric phosphonyl and hydroxyphosphinyl radicals indicates that the hydroxyphosphinyl radicals X(OH)P· are more stable than the phosphonyl radicals XYP(=O)·. This is not a common situation in phosphorus chemistry. It is primarily attributed to the greater phosphorus p character of the singly occupied molecular orbital (SOMO) in the hydroxyphosphinyl radicals compared with the phosphonyl tautomers. As in closed-shell phosphorus species, the magnitude of the effect is modulated by the electronegativity of the substituent X

Containing ecstasy: Analytical tools for profiling an illegal drug market - NDLERF Report

Analytical tools for illegal market profiling • There is no one analytical tool to profile illegal drug markets; rather, a combination of methods are appropriate for different drug markets and different market participants. • For the ecstasy market, data indicative of organisational activity, such as arrests, and health outcomes such as deaths, hospitalizations and occasions of specialist treatment, provide only limited market intelligence, as the majority of ecstasy consumers and suppliers do not come into contact with police or health agencies. • A market cannot be understood by focusing solely on supply-side activities; the attitudes and behaviours of consumers and regulators also determine market mechanisms and outcomes. • In Australia, changing consumer patterns of ecstasy use are one of the most accessible sources of intelligence about the state of the market. • Population surveys set the baseline for the prevalence of ecstasy use and the characteristics of ecstasy consumers. • Surveys of special populations provide richer detail of consumer attitudes, knowledge and market behaviors. Such open source intelligence also provides early warning systems for change in the market. • Profiling the supply chain for ecstasy and the behavior of suppliers are inherently diffi cult because of the hidden, illegal nature of their market activities

Opposing auxiliary conformations produce the same torquoselectivity in an oxazolidinone-directed Nazarov cyclization

Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180 flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3-5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (N-acyloxazolidinone) paradigm

An ab initio guide to structure-reactivity trends in reversible addition fragmentation chain transfer polymerization

The effects of substituents on the addition-fragmentation reaction, P · + S=C(Z)SR → PSC·(Z)SR → PSC(Z)=S + R·, of the reversible addition fragmentation chain transfer (RAFT) process have been studied via high-level ab initio calculations. A number of simple isodesmic quantities are introduced in order to rank the stabilities of the RAFT agents and the RAFT-adduct radicals, together with the efficiency of addition-fragmentation and of the overall chain transfer process. The stabilities of me RAFT agents and RAFT-adduct radicals are mainly affected by the Z group, while the chain transfer efficiency depends mainly on the R group. The rankings can be used as a first-reference guide for selecting an R and Z group for a given polymerization

Exploring drug use: prevalence and patterns of drug use among emergency department patients

The results of this provide important evidence of the very high levels of drug and alcohol use observed in people who attend hospital emergency departments, and at the same time illustrate the close association between recent usage of drugs and hospital presentation. While the results cannot confirm a causal link between illicit drug use and accidents or injuries (for example, overdose), they do suggest that certain forms of drug use can lead to adverse health consequences for some individuals. Furthermore, they reveal evidence of a range of risk-taking behaviours associated with drug use, such as driving a motor vehicle under the influence of drugs or alcohol, which have clear implications for public health and public safety across Queensland

Mapping the Interactions of I2, I., I−, and I+ with Alkynes and Their Roles in Iodocyclizations

A combination of experiment and theory has been used to explore the mechanisms by which molecular iodine (I2 ) and iodonium ions (I(+) ) activate alkynes towards iodocyclization. Also included in the analysis are the roles of atomic iodine (I(.) ) and iodide ion (I(-) ) in mediating the competing addition of I2 to the alkyne. These studies show that I2 forms a bridged I2 -alkyne complex, in which both alkyne carbons are activated towards nucleophilic attack, even for quite polarized alkynes. By contrast, I(+) gives unsymmetrical, open iodovinyl cations, in which only one carbon is activated toward nucleophilic attack, especially for polarized alkynes. Addition of I2 to alkynes competes with iodocyclization, but is reversible. This fact, together with the capacity of I2 to activate both alkyne carbons towards nucleophilic attack, makes I2 the reagent of choice (superior to iodonium reagents) for iodocyclizations of resistant substrates. The differences in the nature of the activated intermediate formed with I2 versus I(+) can also be exploited to accomplish reagent-controlled 5-exo/6-endo-divergent iodocyclizations

Opposing Auxiliary Conformations Produce the Same Torquoselectivity in an Oxazolidinone-Directed Nazarov Cyclization

Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3–5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R⁴ and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (<i>N</i>-acyloxazolidinone) paradigm

Mechanisms of carbonyl activation by BINOL N-triflylphosphoramides: enantioselective nazarov cyclizations

BINOL N-triflylphosphoramides are versatile organocatalysts for reactions of carbonyl compounds. Upon activation by BINOL N-triflylphosphoramides, divinyl ketones undergo rapid and highly enantioselective (torquoselective) Nazarov cyclizations, making BINOL N-triflylphosphoramides one of the most important classes of catalysts for the Nazarov cyclization. However, the activation mechanism and the factors that determine enantioselectivity have not been established until now. Theoretical calculations with ONIOM and M06-2X are reported which examine how BINOL N-triflylphosphoramides activate divinyl ketones and control the torquoselectivity of the cyclization. Unexpectedly, the computations reveal that the traditionally accepted mechanisms for these catalysts (i.e., NH⋯O=C hydrogen bonding or proton transfer) are not the dominant activation mechanisms. Instead, the active catalyst is a less-stable tautomer of the phosphoramide containing a P(=NTf)OH group. Proton transfer from the catalyst to the substrate occurs concomitantly with ring closure. The enantioselectivities of Nazarov cyclizations of three different classes of divinyl ketones are shown to depend on a combination of factors, including catalyst distortion, the degree of proton transfer, intramolecular substrate stabilization, and intermolecular noncovalent interactions between the substrate and catalyst in the transition state, all of which relate to how well the cyclizing divinyl ketone fits into the chiral binding pocket of the catalyst

Asymmetric synthesis of multiple quaternary stereocentre-containing cyclopentyls by oxazolidinone-promoted Nazarov cyclizations

Carbometalation of oxazolidinone (Ox)-substituted ynamides is used to generate highly substituted Ox-divinyl (and aryl vinyl) ketones for use in Nazarov cyclizations. The Ox-group serves as a remarkably effective chiral activating group, enabling the torquoselective Nazarov cyclization of these sterically congested substrates to be performed under mild conditions. It also serves as a charge-stabilizing group in the intermediate oxyallyl cation, suppressing undesired [1,2]-sigmatropic shifts of neighboring substituents and facilitating the regio- and stereoselective incorporation of nucleophiles to yield cyclopentanoids containing up to three contiguous all-carbon quaternary (4°) stereocentres