Junming Ho

Comment on the Correct Use of Continuum Solvent Models

The development of dielectric continuum solvent models 1,2 (CSMs) has facilitated the study of chemical reactions in the condensed phase in a computationally efficient manner. These methods have been parametrized to deliver accurate values of the free energies of solvation. which can be added to accurate values of the free energies in the gas-phase, to obtain the corresponding solution-phase free energy: G soln = G gas + ΔG solv + RTln(RT/P) (1) where the final term converts from the gas-phase standard state (defined by T and P) to the solution-phase standard state of 1 M. However, there are a growing number of recent studies that employ alternative approaches to evaluating G soln . This comment aims to highlight some of their shortcomings as well as clarify some potential points of confusion concerning the usage of these models.

Computational electrochemistry: prediction of liquid-phase reduction potentials

This article reviews recent developments and applications in the area of computational electrochemistry. Our focus is on predicting the reduction potentials of electron transfer and other electrochemical reactions and half-reactions in both aqueous and nonaqueous solutions. Topics covered include various computational protocols that combine quantum mechanical electronic structure methods (such as density functional theory) with implicit-solvent models, explicit-solvent protocols that employ Monte Carlo or molecular dynamics simulations (for example, Car-Parrinello molecular dynamics using the grand canonical ensemble formalism), and the Marcus theory of electronic charge transfer. We also review computational approaches based on empirical relationships between molecular and electronic structure and electron transfer reactivity. The scope of the implicit-solvent protocols is emphasized, and the present status of the theory and future directions are outlined.

pKa Calculation of Some Biologically Important Carbon Acids - An Assessment of Contemporary Theoretical Procedures.

In this study, the aqueous pKa values for 13 neutral, 10 cationic, and 5 anionic carbon acids, including amino acids, peptides, and related species have been calculated using the high level ab initio composite procedure, G3MP2+//BMK, combined with solvation energies that were calculated using the CPCM-(UAKS/UAHF), COSMO-RS, and SM6 continuum models. The pKas were further calculated using three schemes, namely the direct method and the proton exchange method as well as the inclusion of an explicit solvent water molecule. The results of this study indicate that the direct method is unsuitable for computing the pKa of carbon acids, whereas the other two schemes perform significantly better with varying degrees of success, depending on the charge of the carbon acid. Specifically, the combination of the proton exchange scheme and CPCM-UAKS model performed particularly well for neutral species, with mean absolute deviations (MADs) of ∼1 pKa unit. The ionic species were more problematic, though the combination of the proton exchange scheme and the SM6 and CPCM-UAKS models performed reasonably well for the cationic and anionic acids, respectively. The inclusion an explicit water molecule generally improved the calculated values for anionic carbon acids.

First-principles prediction of acidities in the gas and solution phase

This paper provides an overview of contemporary computational protocols toward accurate prediction of acidities in the gas and aqueous phase. The performance of various density functional theory (DFT) methods and ab initio composite procedures, such as the G3MP2(+) method, for the prediction of gas‐phase acidities of a range of neutral and cationic acids is presented. Various methods for solution pKa predictions are also reviewed where the emphasis is on thermodynamic cycle‐based methods that combine ab initio or experimental gas‐phase energies with solvation free energies from continuum solvent models. The prediction of accurate solvation free energies, especially for ionic species, represents the bottleneck for accurate pKa prediction via the direct or absolute method. The success and limitations of alternative thermodynamic cycles are discussed and some of the difficulties and future challenges associated with the applications of these methods on more complicated molecules are also highlighted.

Calculating Free Energy Changes in Continuum Solvation Models.

We recently showed for a large data set of pKas and reduction potentials that free energies calculated directly within the SMD continuum model compares very well with corresponding thermodynamic cycle calculations in both aqueous and organic solvents [ Phys. Chem. Chem. Phys. 2015 , 17 , 2859 ]. In this paper, we significantly expand the scope of our study to examine the suitability of this approach for calculating general solution phase kinetics and thermodynamics, in conjunction with several commonly used solvation models (SMD-M062X, SMD-HF, CPCM-UAKS, and CPCM-UAHF) for a broad range of systems. This includes cluster-continuum schemes for pKa calculations as well as various neutral, radical, and ionic reactions such as enolization, cycloaddition, hydrogen and chlorine atom transfer, and SN2 and E2 reactions. On the basis of this benchmarking study, we conclude that the accuracies of both approaches are generally very similar-the mean errors for Gibbs free energy changes of neutral and ionic reactions are approximately 5 and 25 kJ mol(-1), respectively. In systems where there are significant structural changes due to solvation, as is the case for certain ionic transition states and amino acids, the direct approach generally afford free energy changes that are in better agreement with experiment.

Predicting pKa in Implicit Solvents: Current Status and Future Directions

Computational prediction of condensed phase acidity is a topic of much interest in the field today. We introduce the methods available for predicting gas phase acidity and pKas in aqueous and non-aqueous solvents including high-level electronic structure methods, empirical linear free energy relationships (LFERs), implicit solvent methods, explicit solvent statistical free energy methods, and hybrid implicit–explicit approaches. The focus of this paper is on implicit solvent methods, and we review recent developments including new electronic structure methods, cluster-continuum schemes for calculating ionic solvation free energies, as well as address issues relating to the choice of proton solvation freeenergytousewithimplicitsolvationmodels,andwhetherthermodynamiccyclesarenecessaryforthecomputationof pKas. A comparison of the scope and accuracy of implicit solvent methods with ab initio molecular dynamics free energy methods is also presented. The present status of the theory and future directions are outlined.

Accurate line shapes from sub-1 cm(-1) resolution sum frequency generation vibrational spectroscopy of α-pinene at room temperature.

Despite the importance of terpenes in biology, the environment, and catalysis, their vibrational spectra remain unassigned. Here, we present subwavenumber high-resolution broad-band sum frequency generation (HR-BB-SFG) spectra of the common terpene (+)-α-pinene that reveal 10 peaks in the C-H stretching region at room temperature. The high spectral resolution resulted in spectra with more and better resolved spectral features than those of the Fourier transform infrared, femtosecond stimulated Raman spectra in the bulk condensed phase and those of the conventional BB-SFG and scanning SFG spectroscopy of the same molecule on a surface. Experiment and simulation show the spectral line shapes with HR-BB-SFG to be accurate. Homogeneous vibrational decoherence lifetimes of up to 1.7 ps are assigned to specific oscillators and compare favorably to lifetimes computed from density functional tight binding molecular dynamics calculations. Phase-resolved spectra provided their orientational information. We propose the new spectroscopy as an attractive alternative to time domain vibrational spectroscopy or heterodyne detection schemes for studying vibrational energy relaxation and vibrational coherences in molecules at molecular surfaces or interfaces.

Rhenium(I) tricarbonyl complexes of salicylaldehyde semicarbazones: synthesis, crystal structures and cytotoxicity.

A series of N,N-disubstituted salicylaldehyde semicarbazones (SSCs), HOC(6)H(4)CHN-NHCONR(2), and their rhenium(I) tricarbonyl complexes, [ReBr(CO)(3)(SSC)], have been synthesised and characterised by IR and (1)H NMR spectroscopy. Crystallographic analysis of the complex [ReBr(CO)(3)(H(2)Bu(2))] (H(2)Bu(2)=SSC where R=Bu(n)) showed that the SSC acts as a bidentate ligand via its imino nitrogen and carbonyl oxygen atoms. The [ReBr(CO)(3)(SSC)] complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells (IC(50)=1-24μM, cf. 18μM for cisplatin), and the majority of them are virtually non-toxic against non-cancerous human fibroblasts. Apoptotic assays of [ReBr(CO)(3)(H(2)Bnz(2))] (Bnz=benzyl) revealed that it mediates cytotoxicity in MOLT-4 cells via apoptosis. The complex [ReBr(CO)(3)(H(2)Bnz(2))] reacts with guanosine by proton transfer from the phenolic OH group to N(7) of guanosine. In (CD(3))(2)SO, [ReBr(CO)(3)(H(2)Bnz(2))] undergoes facile conversion to the dimeric complex, [Re(CO)(3)(HBnz(2))](2), via bromide dissociation.

Chloroform as a Hydrogen Atom Donor in Barton Reductive Decarboxylation Reactions

The utility of chloroform as both a solvent and a hydrogen atom donor in Barton reductive decarboxylation of a range of carboxylic acids was recently demonstrated (Ko, E. J. et al. Org. Lett. 2011, 13, 1944). In the present work, a combination of electronic structure calculations, direct dynamics calculations, and experimental studies was carried out to investigate how chloroform acts as a hydrogen atom donor in Barton reductive decarboxylations and to determine the scope of this process. The results from this study show that hydrogen atom transfer from chloroform occurs directly under kinetic control and is aided by a combination of polar effects and quantum mechanical tunneling. Chloroform acts as an effective hydrogen atom donor for primary, secondary, and tertiary alkyl radicals, although significant chlorination was also observed with unstrained tertiary carboxylic acids.

The distal effect of electron-withdrawing groups and hydrogen bonding on the stability of peptide enolates.

Relative gas-phase carbon acidities have been computed for a series of acetamides, diketopiperazines, and linear dipeptides. The results show that N-electron-withdrawing substituents, protonation, and hydrogen bonding at amide nitrogen in these systems increase the acidity of both a C-H proton adjacent to the amide carbonyl and that of one proximal to the amide nitrogen. There is a good correlation between the magnitudes of the increases at the two positions, but the extent of the increase for the distal C-H adjacent to the carbonyl is greater than that for the proximal C-H, in most cases by a factor of about two. The effects on the stability of the distal enolate are shown to result from predominantly inductive affects. The size of these effects is such that protonation and hydrogen bonding at nitrogen increase the acidity of the distal C-H to almost the same extent as seen for the analogous interactions at the carbonyl oxygen. The effect is also seen in solution, where the computed aqueous pK(a) values are greater for the C-H adjacent to the amide carbonyl, by up to 13 units, and where preliminary experimental studies have shown that N-acetylation of an amide increases the rate of hydrogen-deuterium exchange via formation of the corresponding distal enolate by more than 3 orders of magnitude above the rates of exchange via the proximal enolate, of the nonacetylated amide and of diisopropylketone. The results also indicate that hydrogen bonding to amide nitrogen could be as important as bonding to oxygen in enzyme-catalyzed cleavage of alpha-C-H bonds.