Theoretical design of new ligands to boost reaction rate and selectivity in palladium-catalyzed aromatic fluorination.

The development of palladium-catalyzed fluorination with biaryl monophosphine ligands has faced two important problems that limit its application for bromoarenes: the formation of regioisomers and insufficient catalysis for heteroaryl substrates as bromothiophene derivatives. Overcoming these problems requires more ligand design. In this work, reliable theoretical calculations were used to elucidate important ligand features necessary for achieving more rate acceleration and selectivity.

Hybrid Cluster-Continuum Method for Single-Ion Solvation Free Energy in Acetonitrile Solvent.

A new hybrid discrete-continuum approach named the cluster-continuum static approximation (CCSA) has been proposed for acetonitrile solvent. The continuum part uses the conductor-like polarizable continuum model for electrostatic and a surface area-dependent term for nonelectrostatic solvation. The CCSA includes only one explicit acetonitrile solvent molecule and a damping function, which makes the CCSA method reduce to pure continuum solvation in the case of weaker potential of mean force for solute-solvent interaction.

Bifunctional iminophosphorane organocatalyst with additional hydrogen bonding: Calculations predict enhanced catalytic performance in a michael addition reaction.

A new iminophosphorane-thiourea superbase was rationally designed and investigated as an organocatalyst for the enantioselective Michael addition reaction of nitromethane to 4-phenylbut-3-en-2-one. Starting from an iminophosphorane-thiourea organocatalyst structure already known, we have used theoretical calculations to determine the structures of transition states involved in the carbon-carbon bond formation step and carried out structural modifications to accelerate the reaction rate and to increase the enantioselectivity. The effective structural modification was adding a rigid hydroxyl group able to make an additional hydrogen bond to the transition state, producing a substantial decrease of the ΔG by 7 kcal mol.

Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation.

Context: Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane.

A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus.

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference.

S2 versus E2 reactions in a complex microsolvated environment: theoretical analysis of the equilibrium and activation steps of a nucleophilic fluorination.

The reactivity of the fluoride ion towards alkyl halides is highly dependent on the solvating environment. In polar aprotic solvents with large counter-ions is highly reactive and produces substantial E2 product, whereas in polar protic solvents leads to slow kinetics and high selectivity for S2 reactions. The use of a more complex environment with stoichiometric addition of tert-butanol to acetonitrile solvent is able to module the reactivity and selectivity of tetrabutylammonium fluoride (TBAF).

Single-ion solvation free energy: A new cluster-continuum approach based on the cluster expansion method.

Accurate calculation of the solvation free energy of single ions remains an important goal, involving development in the dielectric continuum solvation models, and statistical mechanics with explicit solvent and hybrid discrete-continuum methods. In the last case, many of the research studies involve a quasi-chemical approach using the monomer cycle or the cluster cycle to calculate the solvation free energy of single ions. In this work, a different cluster-continuum approach based on the cluster expansion method was tested for solvation of 16 cations and 32 anions in aqueous solution.

The role of intermolecular forces in ionic reactions: the solvent effect, ion-pairing, aggregates and structured environment.

The environment enclosing an ionic species has a critical effect on its reactivity. In a more general sense, medium effects are not limited to the solvent, but involve the counter ion effect (ion pairing), formation of larger aggregates and structured environment as provided by the host in the case of host-guest complexes. In this review, a general view of the medium effect on anion-molecule reactions is presented.

Nucleophilic Fluorination with KF Catalyzed by 18-Crown-6 and Bulky Diols: A Theoretical and Experimental Study.

The activation of potassium fluoride for nucleophilic fluorination of alkyl halides is an important challenge because of the high lattice energy of this salt and its low solubility in many polar aprotic solvents. Crown ethers have been used for increasing the solubilization of KF during several decades. Nevertheless, these macrocycles are not enough to produce a high reaction rate.

Theoretical free energy profile and benchmarking of functionals for amino-thiourea organocatalyzed nitro-Michael addition reaction.

Amino-thiourea organocatalysis is an important catalytic process for enantioselective conjugate addition reactions. The interaction of the reactants with the catalyst has a substantial effect of dispersion forces and is a challenge for a reliable description when applying density functional theory. In this report, the classical addition of acetylacetone to β-nitro-styrene catalyzed by Takemoto's catalyst in toluene was studied using the PBE functional for geometry optimization and the DLPNO-CCSD(T) benchmark method for single point energy.

Predictors of neuropsychological functioning and medication adherence in pediatric heart transplant recipients referred for neuropsychological evaluation.

Children who undergo heart transplantation are at risk for long-term neurodevelopmental sequelae secondary to heart disease and its treatment. Detailed neuropsychological profiles in clinical sample status post-pediatric heart transplantation are sparse in the literature, and there is little information regarding predictors of neuropsychological functioning or how it relates to medication adherence in this population. The present study examined these questions in a retrospective analysis of 27 pediatric heart transplantation recipients referred for clinical neuropsychological evaluation.

Free Energy Profile of a Model Palladium Catalyzed Fluorination of Aryl Bromide with Cesium Fluoride.

Addition of fluorine to aromatic rings has increased in importance in the past decade in view of the increased role of organofluorine compounds in the design of new pharmaceuticals. Palladium catalyzed nucleophilic fluorination of unactivated aryl halides using salts such as cesium fluoride was achieved with the use of bulky biaryl monophosphine ligand. Simple monophosphine palladium complexes were not able to promote this reaction, which is attributed to the difficult reductive elimination step and the formation of dimers of the PdL(Ph)(F) intermediate.

Free energy profile and microkinetic modeling of base-catalyzed conjugate addition reaction of nitroalkanes to α,β-unsaturated ketones in polar and apolar solvents.

Michael reactions involving nitroalkanes and enones are important carbon-carbon bond formation reactions. These reactions are base-catalyzed, and during the past 15 years, the asymmetric version using bifunctional amino-thiourea organocatalyst has been developed. In this work, the reaction of nitromethane and 4-phenyl-3-buten-2-one, catalyzed by the methoxide ion and piperidine as bases, was investigated by theoretical calculations.

Potassium fluoride activation for the nucleophilic fluorination reaction using 18-crown-6, [2.2.2]-cryptand, pentaethylene glycol and comparison with the new hydro-crown scaffold: a theoretical analysis.

Activation of potassium fluoride salt for selective and fast nucleophilic fluorination requires its solubilization and stabilization of the respective transition state. This goal can be achieved through control of the nano-environment around the reactants via cation or ion-pair binding catalysis. In this work, six different species were theoretically investigated as promoters and catalysts for nucleophilic fluorination: tri-tert-butanolamine, 18-crown-6, pentaethylene glycol, [2.

Infinite dilution activity coefficient from SMD calculations: accuracy and performance for predicting liquid-liquid equilibria.

Prediction of liquid-liquid phase equilibria is an important goal in the physical chemistry of solutions. Quantum chemistry methods, combined with a dielectric continuum description of the solvent, has received attention as a first principle approach. In this work, the performance of the continuum solvation model based on density (SMD) for prediction of γ in binary liquid mixtures, using 46 values of γ, was evaluated.

Cluster expansion of the solvation free energy difference: Systematic improvements in the solvation of single ions.

The cluster expansion method has been used in the imperfect gas theory for several decades. This paper proposes a cluster expansion of the solvation free energy difference. This difference, which results from a change in the solute-solvent potential energy, can be written as the logarithm of a finite series.

Mechanism of the Piperidine-Catalyzed Knoevenagel Condensation Reaction in Methanol: The Role of Iminium and Enolate Ions.

The free energy profile of the piperidine catalyzed Knoevenagel condensation reaction of acetylacetone with benzaldehyde has been obtained by theoretical calculations. The carbinolamine formation step involves catalysis by methanol solvent, and its decomposition takes place via hydroxide ion elimination without a classical transition state, leading to the iminium ion. Hydroxide ion deprotonates the acetylacetone, forming an enolate that attacks the iminium ion and leads to an addition intermediate.

CMIRS Solvation Model for Methanol: Parametrization, Testing, and Comparison with SMD, SM8, and COSMO-RS.

The new continuum solvation model, composite method for implicit representation of solvent (CMIRS), proposed by Pomogaeva and Chipman and implemented in GAMESS was parametrized for methanol solvent, with the aim of using it for ionic reactions in solution. The model was tested for predicting single-ion solvation free energy, pK of acids and protonated bases, and the activation free-energy barriers of S2 and SAr reactions in methanol. A comparison was performed with other continuum models, such as SMD, SM8, and COSMO-RS.

Theoretical Design and Calculation of a Crown Ether Phase-Transfer-Catalyst Scaffold for Nucleophilic Fluorination Merging Two Catalytic Concepts.

Fluorinated organic molecules are playing an increased role in the area of pharmaceuticals and agrochemicals. This fact demands the development of efficient catalytic fluorination processes. In this paper, we have designed a new crown ether with four hydroxyl groups strategically positioned.

Cluster-continuum quasichemical theory calculation of the lithium ion solvation in water, acetonitrile and dimethyl sulfoxide: an absolute single-ion solvation free energy scale.

Absolute single-ion solvation free energy is a very useful property for understanding solution phase chemistry. The real solvation free energy of an ion depends on its interaction with the solvent molecules and on the net potential inside the solute cavity. The tetraphenyl arsonium-tetraphenyl borate (TATB) assumption as well as the cluster-continuum quasichemical theory (CC-QCT) approach for Li(+) solvation allows access to a solvation scale excluding the net potential.

The role of ammonia oxide in the reaction of hydroxylamine with carboxylic esters.

Theoretical calculations indicate that hydroxylamine can exist in both neutral and zwitterionic (ammonia oxide) forms in aqueous solution, the former being 3.5 kcal mol(-1) more stable. In this report, we have studied the reaction mechanism of hydroxylamine with phenyl acetate and analyzed the role of the zwitterionic isomer.

Monitoring lipase/esterase activity by stopped flow in a sequential injection analysis system using p-nitrophenyl butyrate.

Lipases and esterases are biocatalysts used at the laboratory and industrial level. To obtain the maximum yield in a bioprocess, it is important to measure key variables, such as enzymatic activity. The conventional method for monitoring hydrolytic activity is to take out a sample from the bioreactor to be analyzed off-line at the laboratory.

Executive Function Performance for Children With Epilepsy Localized to the Frontal or Temporal Lobes.

Research with adults with epilepsy consistently indicates deficits in executive function (EF). There is less research specific to children with epilepsy and EF. The purpose of this study was to consider EF deficits in children with complex partial epilepsy and complex partial with secondary generalization epilepsy with onset localized to the frontal or temporal lobes.

Performance of the SMD and SM8 models for predicting solvation free energy of neutral solutes in methanol, dimethyl sulfoxide and acetonitrile.

The continuum solvation models SMD and SM8 were developed using 2,346 solvation free energy values for 318 neutral molecules in 91 solvents as reference. However, no solvation data of neutral solutes in methanol was used in the parametrization, while only few solvation free energy values of solutes in dimethyl sulfoxide and acetonitrile were used. In this report, we have tested the performance of the models for these important solvents.

What is the future of training in surgery? Needs assessment of national stakeholders.

Background: The Curriculum Committee of the American College of Surgeons-Accredited Educational Institutes conducted a need assessment to (1) identify gaps between ideal and actual practices in areas of surgical care, (2) explore educational solutions for addressing these gaps, and (3) shape a vision to advance the future of training in surgery.

Methods: National stakeholders were recruited from the committee members' professional network and interviewed via telephone. Interview questions targeted areas for improving surgical patient care, optimal educational solutions for training in surgery including simulation roles, and entities that should primarily bear training costs.