The universal expression for the amplitude square in quantum electrodynamics

The universal expression for the amplitude square |u_f M u_i|^2 for any matrix of interaction M is derived. It has obvious covariant form. It allows the avoidance of calculation of products of the Dirac's matrices traces and allows easy calculation of cross-sections of any different processes with polarized and unpolarized particles.Comment: 4 page

Data-driven derivation of molecular substructures that enhance drug activity in Gram-negative bacteria

[Image: see text] The complex cell envelope of Gram-negative bacteria creates a formidable barrier to antibiotic influx. Reduced drug uptake impedes drug development and contributes to a wide range of drug-resistant bacterial infections, including those caused by extremely resistant species prioritized by the World Health Organization. To develop new and efficient treatments, a better understanding of the molecular features governing Gram-negative permeability is essential. Here, we present a data-driven approach, using matched molecular pair analysis and machine learning on minimal inhibitory concentration data from Gram-positive and Gram-negative bacteria to uncover chemical features that influence Gram-negative bioactivity. We find recurring chemical moieties, of a wider range than previously known, that consistently improve activity and suggest that this insight can be used to optimize compounds for increased Gram-negative uptake. Our findings may help to expand the chemical space of broad-spectrum antibiotics and aid the search for new antibiotic compound classes

<i>In Situ </i>Studies of Arylboronic Acids/Esters and R₃SiCF₃ Reagents: Kinetics, Speciation, and Dysfunction at the Carbanion–Ate Interface

[Image: see text] Reagent instability reduces the efficiency of chemical processes, and while much effort is devoted to reaction optimization, less attention is paid to the mechanistic causes of reagent decomposition. Indeed, the response is often to simply use an excess of the reagent. Two reaction classes with ubiquitous examples of this are the Suzuki–Miyaura cross-coupling of boronic acids/esters and the transfer of CF(3) or CF(2) from the Ruppert–Prakash reagent, TMSCF(3). This Account describes some of the overarching features of our mechanistic investigations into their decomposition. In the first section we summarize how specific examples of (hetero)arylboronic acids can decompose via aqueous protodeboronation processes: Ar–B(OH)(2) + H(2)O → ArH + B(OH)(3). Key to the analysis was the development of a kinetic model in which pH controls boron speciation and heterocycle protonation states. This method revealed six different protodeboronation pathways, including self-catalysis when the pH is close to the pK(a) of the boronic acid, and protodeboronation via a transient aryl anionoid pathway for highly electron-deficient arenes. The degree of “protection” of boronic acids by diol-esterification is shown to be very dependent on the diol identity, with six-membered ring esters resulting in faster protodeboronation than the parent boronic acid. In the second section of the Account we describe (19)F NMR spectroscopic analysis of the kinetics of the reaction of TMSCF(3) with ketones, fluoroarenes, and alkenes. Processes initiated by substoichiometric “TBAT” ([Ph(3)SiF(2)][Bu(4)N]) involve anionic chain reactions in which low concentrations of [CF(3)](−) are rapidly and reversibly liberated from a siliconate reservoir, [TMS(CF(3))(2)][Bu(4)N]. Increased TMSCF(3) concentrations reduce the [CF(3)](−) concentration and thus inhibit the rates of CF(3) transfer. Computation and kinetics reveal that the TMSCF(3) intermolecularly abstracts fluoride from [CF(3)](−) to generate the CF(2), in what would otherwise be an endergonic α-fluoride elimination. Starting from [CF(3)](−) and CF(2), a cascade involving perfluoroalkene homologation results in the generation of a hindered perfluorocarbanion, [C(11)F(23)](−), and inhibition. The generation of CF(2) from TMSCF(3) is much more efficiently mediated by NaI, and in contrast to TBAT, the process undergoes autoacceleration. The process involves NaI-mediated α-fluoride elimination from [CF(3)][Na] to generate CF(2) and a [NaI·NaF] chain carrier. Chain-branching, by [(CF(2))(3)I][Na] generated in situ (CF(2) + TFE + NaI), causes autoacceleration. Alkenes that efficiently capture CF(2) attenuate the chain-branching, suppress autoacceleration, and lead to less rapid difluorocyclopropanation. The Account also highlights how a collaborative approach to experiment and computation enables mechanistic insight for control of processes

The problem of racemization in drug discovery and tools to predict it

Introduction: Racemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated. Areas covered: Herein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and the authors review methods to predict racemization risk. Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk. Expert opinion: It is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline

Constraining slow-roll inflation with WMAP and 2dF

We constrain slow-roll inflationary models using the recent WMAP data combined with data from the VSA, CBI, ACBAR and 2dF experiments. We find the slow-roll parameters to be $0 < \epsilon_1 < 0.032$ and $\epsilon_2 + 5.0 \epsilon_1 = 0.036 \pm 0.025$. For inflation models $V \propto \phi^{\alpha}$ we find that $\alpha< 3.9, 4.3$ at the 2$\sigma$ and $3\sigma$ levels, indicating that the $\lambda\phi^4$ model is under very strong pressure from observations. We define a convergence criterion to judge the necessity of introducing further power spectrum parameters such as the spectral index and running of the spectral index. This criterion is typically violated by models with large negative running that fit the data, indicating that the running cannot be reliably measured with present data.Comment: 8 pages RevTeX4 file with six figures incorporate

Asymmetric synthesis of heterocyclic chloroamines and aziridines by enantioselective protonation of catalytically generated enamines

L.A.M. and J.W.B.F. thank EPSRC for postdoctoral funding (EP/S027165/1; EP/R025754/1). J.W.B.F. thanks the Leverhulme Trust for postdoctoral funding (RPG-2018-362). M.W.A. thanks the University of St Andrews for a PhD studentship.We report a method for the synthesis of chiral vicinal chloroamines via asymmetric protonation of catalytically generatedprochiral chloroenamines using chiral Brønsted acids. The processis highly enantioselective, with the origin of asymmetry and catalystsubstituent effects elucidated by DFT calculations. We show theutility of the method as an approach to the synthesis of a broadrange of heterocycle-substituted aziridines by treatment of thechloroamines with base in a one-pot process, as well as the utility ofthe process to allow access to vicinal diamines.Publisher PDFPeer reviewe

Et3SiH + KOtBu provide multiple reactive intermediates that compete in the reactions and rearrangements of benzylnitriles and indolenines

The combination of potassium tert-butoxide and triethylsilane is unusual because it generates multiple different types of reactive intermediates simultaneously that provide access to (i) silyl radical reactions, (ii) hydrogen atom transfer reactions to closed shell molecules and to radicals, (iii) electron transfer reductions and (iv) hydride ion chemistry, giving scope for unprecedented outcomes. Until now, reactions with this reagent pair have generally been explained by reference to one of the intermediates, but we now highlight the interplay and competition between them