On a substituted benzene ring the position that bears the substituent is designated as the ipso position. This Perspective presents the history behind that designation.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This article presents a personal view of the field of physical organic chemistry (broadly construed), its history, its current status, and what it may become in the future.

After many years of unsuccessful attempts, monomeric malonic anhydrides were prepared by ozonolysis of ketene dimers, a procedure validated by model studies. The structure proof relied most heavily on IR absorption at 1820 cm^-1 and a Raman band at 1947 cm^-1. Malonic anhydrides are unstable, decomposing below room temperature to a ketene plus carbon dioxide. Surprisingly, according to kinetic studies, the dimethyl derivative is slightly less unstable than the parent, and the monomethyl is the fastest to decompose, with an enthalpy of activation of only 12.6 kcal/mol. Computations rationalize this behavior in terms of a concerted [2_s + 2_a] cycloreversion that requires a more highly organized transition state, as also manifested by a negative entropy of activation.

The referenced article in PCCP presents calculations of solvent kinetic isotope effects that indicate that the rate-limiting step in base-catalyzed chalcone formation in aqueous solution becomes the second enolization. This disputes our previous conclusion, based on experimental isotope effects in aqueous acetonitrile, that the rate-limiting step is the final loss of hydroxide and formation of the C-C double bond. That conclusion is here affirmed as general for any protic solvent, and it is further concluded that those calculations are flawed.

Although my research has no common theme or defining area, a coherence connects the diverse topics insofar as one project leads logically to another. Thus, studies on mechanisms of hydrogen exchange in amides and amidines led to the influence of hydrogen bonding and to NMR methods for chemical kinetics, including 2D-EXSY spectroscopy. Another connection was the OH^--catalyzed NH exchange in amines that had supported the hypothesis of stereoelectronic control. We therefore analyzed that hypothesis critically, tested it, found counterexamples, and proposed an alternative hypothesis. We next addressed one-bond NMR coupling constants in ethers and the reverse anomeric effect. The latter studies required a highly accurate NMR titration method that we developed to measure the additional steric bulk resulting from protonation of a substituent. This method is also applicable to measuring secondary isotope effects on acidity, and we could demonstrate that they arise from n-σ* delocalization, not from an inductive effect. Other studies included kinetic isotope effects for both dissociation and H exchange of aqueous NH₄⁺, for C-N rotation in amides, and for a hydride transfer. The role of hydrogen bonding led us to the rotation of NH₄⁺ within its solvent cage and then to the symmetry of hydrogen bonds.

A powerful pH-free multicomponent NMR titration method can measure relative acidities, even of closely related compounds, with excellent accuracy. The history of the method is presented, along with details of its implementation and a comparison with earlier NMR titrations using a pH electrode. Many of its areas of applicability are described, especially equilibrium isotope effects. The advantages of the method, some practical considerations, and potential pitfalls are considered.

Short, strong, symmetric, low-barrier hydrogen bonds (H-bonds) are thought to be of special significance. We have been searching for symmetric H-bonds by using the NMR technique of isotopic perturbation. Various dicarboxylate monoanions, aldehyde enols, diamines, enamines, acid-base complexes, and two sterically encumbered enols have been investigated. Among all of these, we have found only one example of a symmetric H-bond, in nitromalonamide enol, and all of the others are equilibrating mixtures of tautomers. The nearly universal lack of symmetry is attributed to the presence of these H-bonded species as a mixture of solvatomers, meaning isomers (or stereoisomers or tautomers) that differ in their solvation environment. The disorder of solvation renders the two donor atoms instantaneously inequivalent, whereupon the hydrogen attaches to the less well solvated donor. We therefore conclude that there is no special significance to short, strong, symmetric, low-barrier H-bonds. Moreover, they have no heightened stability or else they would have been more prevalent.

We reaffirm our conclusion that secondary deuterium isotope effects on acidity are due to n-σ∗ delocalization that decreases vibrational frequencies and zero-point energies. We reject an electrostatic or inductive explanation that arises from the anharmonicity of the C-H bond. We address calculated values of atomic charges, dipole moments, and dipole-moment derivatives dμ/dr, and we show the isotope effect to be a stereoelectronic phenomenon arising from harmonic vibrations.