The techniques and thought processes of the field of physical organic chemistry, focused on small organic molecule structure and reactivity, have been taken up by numerous other fields, including, but not limited to, sensor design, organometallics, organic materials, organocatalysis, and supramolecular chemistry. The unifying principles of each field stem from physical organic chemistry pursuits. The insights, terminology, and lessons, as well as the experimental and computational techniques of physical organic chemistry currently permeate nearly all fields of organic chemistry. Thus, although the number of individuals that call themselves physical organic chemists is dwindling, we should recognize this as the inevitable outcome, revealing the strength of the discipline—it is so powerful that all areas of organic chemistry have adopted it, and therefore, we are all physical organic chemists at heart. This manuscript sets forth to highlight this conclusion by showing how several recent studies in fields not historically recognized as physical organic can be described as being so. The message is upbeat; organic chemists have a common background and language that emanates from physical organic chemistry, irrespective of the titles we each associate ourselves with.

Differential sensing (DS) methods traditionally use spatially arrayed receptors and optical signals to create score plots from multivariate data which classify individual analytes or complex mixtures. Herein, a new approach is described, in which nucleic acid sequences and sequence counts are used as the multivariate data without the necessity of a spatial array. To demonstrate this approach to DS, previously selected aptamers, identified from the literature, were used as semi-specific receptors, Next-Gen DNA sequencing was used to generate data, and cell line differentiation was the test-bed application. The study of a principal component analysis loading plot revealed cross-reactivity between the aptamers. The technique generates high-dimensionality score plots, and should be applicable to any mixture of complex and subtly different analytes for which nucleic acid-based receptors exist.

N-Alkyl ammonium resorcinarene chlorides, stabilized by an intricate array of hydrogen bonds leading to a cavitand-like structure, bind amides. The molecular recognition occurs through intermolecular hydrogen bonds between the carbonyl oxygen and the amide hydrogen of the guests and the cation–anion circular hydrogen-bonded seam of the hosts, as well as through CH⋅⋅⋅π interactions. The N-alkyl ammonium resorcinarene chlorides cooperatively bind a series of di-acetamides of varying spacer lengths ranging from three to seven carbons. Titration data fit either a 1:1 or 2:1 binding isotherm depending on the spacer lengths. Considering all the guests possess similar binding motifs, the first binding constants were similar (K₁: 10² M⁻¹) for each host. The second binding constant was found to depend on the upper rim substituent of the host and the spacer length of the guests, with the optimum binding observed with the six-carbon spacer (K₂: 10³ M⁻²). Short spacer lengths increase steric hindrance, whereas longer spacer lengths increase flexibility thus reducing cooperativity. The host with the rigid cyclohexyl upper rim showed stronger binding than the host with flexible benzyl arms. The cooperative binding of these divalent guests was studied in solution through ¹H NMR titration studies and supplemented by diffusion-ordered spectroscopy (DOSY), X-ray crystallography, and mass spectrometry.

A receptor assembly composed of iron(II) triflate and pyridine-2,6-dicarbaldehyde was used to determine the enantiomeric excess (ee) of alpha-chiral primary amines using circular dichroism spectroscopy. The alpha chiral amines condense with the dialdehyde to form a diimine, which forms a 2:1 octahedral complex with iron(II). The ee values of unknown concentrations of alpha-chiral amines were determined by constructing calibration curves for each amine and then measuring the ellipticity at 600 nm. This improves our previously reported assay for ee determination of chiral primary amines by further increasing the wavelength at which CD is measured and reducing the absolute error of the assay. Chirality 27:294–298, 2015. 2015 Wiley Periodicals, Inc.

Differential sensing (DS) methods traditionally use spatially arrayed receptors and optical signals to create score plots from multivariate data which classify individual analytes or complex mixtures. Herein, a new approach is described, in which nucleic acid sequences and sequence counts are used as the multivariate data without the necessity of a spatial array. To demonstrate this approach to DS, previously selected aptamers, identified from the literature, were used as semi-specific receptors, Next-Gen DNA sequencing was used to generate data, and cell line differentiation was the test-bed application. The study of a principal component analysis loading plot revealed cross-reactivity between the aptamers. The technique generates high-dimensionality score plots, and should be applicable to any mixture of complex and subtly different analytes for which nucleic acid-based receptors exist.

Asymmetric hydrogenation of unprotected NH imines catalyzed by rhodium/bis(phosphine)-thiourea provided chiral amines with up to 97 % yield and 95 % ee. ¹H NMR studies, coupled with control experiments, implied that catalytic chloride-bound intermediates were involved in the mechanism through a dual hydrogen-bonding interaction. Deuteration experiments proved that the hydrogenation proceeded through a pathway consistent with an imine.

Five SOX peptides are used to classify the MAPK groups and isoforms thereof using chemometrics. The score plots show excellent classification and accuracy, while support vector machine analysis leads to the quantification of ERK and an ERK inhibitor concentration in kinase mixtures. Examination of the loading plots reveals cross-reactivity among the peptides, and some unexpected surprises.

Benzalcyanoacetamides were designed and synthesized as reversible thiol conjugate addition acceptors. These thia-conjugate additions can rapidly and reversibly achieve equilibrium under aqueous conditions at neutral pH. Kinetic studies show that electron-withdrawing groups at the 4-position of the phenyl ring of the benzalcyanoacetamides promote the conjugate addition at equilibrium. Dynamic thiol exchange of these conjugate acceptors is faster than singly activated α,β-unsaturated carbonyl compounds. These thia-conjugate additions can be assembled as potentially useful components in dynamic combinatorial chemistry.

The association between an achiral copper(II)-containing host 1 and chiral carboxylates has been expanded beyond previous studies to new chiral carboxylate guests, both α-amino acids and β-homoamino acids. The observed exciton-coupled circular dichroism (ECCD) signals for the enantiomers of each carboxylate were equal and opposite, and these signals differed in size and shape between the individual amino acids. Linear discriminant analysis (LDA) was applied as a statistical analysis technique to differentiate the amino acids, both enantioselectively and chemoselectively, giving the absolute configuration and identity of the amino acid. The identity of each of the α-amino acids and β-homoamino acids were determined independently by LDA, and then the two were considered together. Each of these analyses showed good differentiation of the amino acid guests with the use of only one host molecule.

Ginsenosides are complex natural products with a diverse array of biological activities, but their molecular recognition and sensing is challenging. A library of simple bis-boronic acid-based receptors with various spacers was synthesized for the sensing of ginsenosides. The incorporation of two boronic acids allowed the pairing of two indicators, which can simultaneously bind the receptors or two saccharides within the ginsenosides. A cross-reactive sensing array was therefore constructed using the receptors in conjunction with different pairs of indicators. LDA plots created from the colorimetric response of the hosts and indicator pairs reveal excellent classification of the ginsenosides, and the corresponding loading plots reveal the cross-reactivity of the receptors. In addition, several commercial ginseng extracts were unambiguously classified using the same sensing array. The assay reported here should be applicable to the analysis of other large saccharide-based natural products.

A simple approach to generating in situ metal-templated tris-(2-picolyl)amine-like multicomponent assemblies with potential applications in molecular recognition and sensing is reported. The assembly is based on the reversible covalent association between di-(2-picolyl)amine and aldehydes. Zinc ion is best for inducing assembly among the metal salts investigated, whereas 2-picolinaldehyde is the best among the heterocyclic aldehydes studied. Although an equilibrium constant of 6.6×10³ M⁻¹ was measured for the assembly formed by 2-picolinaldehdye, di-(2-picolyl)amine, and zinc triflate, the equilibrium constants for other systems are in the 10² M⁻¹ range. X-ray structural analysis revealed that zinc adopts trigonal-bipyramidal geometry within the assembled ligand. The diversity and equilibrium of the assemblies are readily altered by simply changing concentrations, varying components, or adding counteranions.

A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of α-chiral primary amines with potential applications in asymmetric reaction discovery has been developed. The protocol requires derivatization of α-chiral primary amines through condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The Cu^I complex with 2,2′-bis (diphenylphosphino)-1,1′-dinaphthyl (BINAPCu^I) with the imine yields a metal-to-ligand charge-transfer (MLCT) band in the visible region of the circular dichroism (CD) spectrum upon binding. Diastereomeric host–guest complexes give CD signals of the same signs but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP-ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal-catalyzed reaction are determined. The potential of the application of this protocol in high-throughput screening (HTS) of ee is discussed.