A Greatly Under-Appreciated Fundamental Principle of Physical Organic Chemistry

Abstract

If a species does not have a finite lifetime in the reaction medium, it cannot be a mechanistic intermediate. This principle was first enunciated by Jencks, as the concept of an enforced mechanism. For instance, neither primary nor secondary carbocations have long enough lifetimes to exist in an aqueous medium, so SN1 reactions involving these substrates are not possible, and an SN2 mechanism is enforced. Only tertiary carbocations and those stabilized by resonance (benzyl cations, acylium ions) are stable enough to be reaction intermediates. More importantly, it is now known that neither H3O+ nor HO− exist as such in dilute aqueous solution. Several recent high-level calculations on large proton clusters are unable to localize the positive charge; it is found to be simply “on the cluster” as a whole. The lifetime of any ionized water species is exceedingly short, a few molecular vibrations at most; the best experimental study, using modern IR instrumentation, has the most probable hydrated proton structure as H13O6+, but only an estimated quarter of the protons are present even in this form at any given instant. Thanks to the Grotthuss mechanism of chain transfer along hydrogen bonds, in reality a proton or a hydroxide ion is simply instantly available anywhere it is needed for reaction. Important mechanistic consequences result. Any charged oxygen species (e.g., a tetrahedral intermediate) is also not going to exist long enough to be a reaction intermediate, unless the charge is stabilized in some way, usually by resonance. General acid catalysis is the rule in reactions in concentrated aqueous acids. The Grotthuss mechanism also means that reactions involving neutral water are favored; the solvent is already highly structured, so the entropy involved in bringing several solvent molecules to the reaction center is unimportant. Examples are given.

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

“…A proposed mechanism 25,26 is depicted in Scheme 6. Initial protonation at the C-terminal amide carbonyl 27 to give 19 is followed by cyclization to the tetrahedral intermediate 20 .…”

Mechanistic investigations of the hydrolysis of amides, oxoesters and thioesters via kinetic isotope effects and positional isotope exchange

“…This last issue has been raised recently in the literature. Cox has argued that in many cases tetrahedral intermediates with full positive or negative charge on an oxygen atom are generally too unstable to exist in aqueous solution [17]. Instead he proposes that charge is spread out through a chain of solvent water molecules (via the Grotthuss mechanism).…”

“…Some controversy exists concerning the stability of fully charged tetrahedral intermediates in aqueous media [17]. It has been proposed that some tetrahedral intermediates do not have a sufficiently long lifetime to be considered as a true intermediate.…”

Biological Water Dynamics and Entropy: A Biophysical Origin of Cancer and Other Diseases

“…The findings reported in this paper support Pollack's conclusions. The therapeutic approach he recommends is consistent with the hope of lessening EIWS by restoring and preserving structural entropy consumption [139][140][141][142][143].…”

“…We propose that dynamical nanomolecular ensembles of water CDs represent structural entropy-consuming [139][140][141][142][143] nano-engines which trap, transduce, and conduct the energy to induce conformational changes in both DNA and proteins. Nanoclusters of magnetized water and DNA, then, may act in concert to provide a supramolecular scaffolding acting to transmit both energy and information over long distances.…”