We have quantum chemically analyzed the ring‐opening reaction of the model non‐symmetrical epoxide 2,2‐dimethyloxirane under basic and acidic conditions using density functional theory at OLYP/TZ2P. For the first time, our combined activation strain and Kohn–Sham molecular orbital analysis approach have revealed the interplay of physical factors that control the regioselectivity of these chemical reactions. Ring‐opening under basic conditions occurs in a regime of strong interaction between the nucleophile (OH–) and the epoxide and the interaction is governed by the steric (Pauli) repulsion. The latter steers the attack preferentially towards the sterically less encumbered Cβ. Under acidic conditions, the interaction between the nucleophile (H2O) and the epoxide is weak and, now, the regioselectivity is governed by the activation strain. Protonation of the epoxide induces elongation of the weaker (CH3)2Cα–O bond, and effectively predistorts the substrate for the attack at the sterically more hindered side, which goes with a less destabilizing overall strain energy. Our quantitative analysis significantly builds on the widely accepted rationales behind the regioselectivity of these ring‐opening reactions and provide a concrete framework for understanding these indispensable textbook reactions.

Proteins possess unique molecular recognition capabilities and enzymatic activities, features that are usually tied to a particular tertiary structure. To make use of proteins for biotechnological and biomedical purposes, it is often required to enforce their tertiary structure in order to ensure sufficient stability under the conditions inherent to the application of interest. The introduc-tion of intramolecular crosslinks has proven efficient in stabilizing native protein folds. Herein, we give an overview of methods that allow the macrocyclization of expressed proteins, discussing involved reaction mechanisms and structural implications.

We investigated the tunability of hydrogen bond strength by altering the charge accumulation around the frontier atoms with remote substituents. For pyridine···H 2 O with NH 2 and CN substituted at different positions on pyridine, we find that the electron-withdrawing CN group decreases the negative charge accumulation around the frontier atom N, resulting in weakening of the hydrogen bond, whereas the electron-donating NH 2 group increases the charge accumulation around N, resulting in strengthening of the hydrogen bond. By applying these design principles on DDAA–AADD, DADA–ADAD, DAA–ADD, and ADA–DAD hydrogen-bonded dimers, we find that the effect of the substituent is delocalized over the whole molecular system. As a consequence, systems with an equal number of hydrogen bond donor (D) and acceptor (A) atoms are not tunable in a predictable way because of cancellation of counteracting strengthening and weakening effects. Furthermore, we show that the position of the substituent and long-range electrostatics can play an important role as well. Overall, the design principles presented in this work are suitable for monomers with an unequal number of donor and acceptor atoms and can be exploited to tune the binding strength of supramolecular building blocks.

The spatial alignment of functional groups is a central aspect of most catalytic processes. Protein scaffolds with their exceptional molecular recognition properties have evolved into powerful biological catalysts. However, the...