The Effect of Ring Size on Reactivity: The Diagnostic Value of ‘Rate Profiles’

Abstract

Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthdayThe rates of cycloalkyl phenyl sulfide formation of a series of homologous bromocycloalkanes upon treatment with sodium benzenethiolate have been determined to ascertain the effect of ring size on reactivity. The rate profile, i.e., reaction rate vs. ring size, for these nucleophilic substitutions (S N 2) was determined. A linear free-energy relationship could be derived from computed hydride affinities of cycloalkanes and rates of typical S N 1 reactions, whereas rates of S N 2 reactions exhibited a strong discrepancy from the seven-up to the twelve-membered rings. This discrepancy was rationalized by a careful examination of the geometry of the intermediates and transition states involved in these reactions.1. Introduction. ± In the early fifties, Brown et al. [1 ± 3] recognized characteristic effects of ring size on the reactivity of a series of model substrates. They suggested to use plots of rates vs. ring size, so called rate profiles, as tools to diagnose mechanistic details, in particular the geometry of key intermediates or transition states. According to this concept, first-and second-order substitution reactions (S N 1 and S N 2, resp.) should exhibit like ring dependences. As both processes involve a planarized C-atom as a high-energy species, the principal reactivity-controlling factor should be the extra strain (internal strain or I-strain) caused by the change of a tetragonal to a trigonal C-center.This simplified view raised objections by Sicher [4]. When comparing the rate profiles of two archetypical S N 1 reactions (Fig. 1a, b) [3] [5] with intramolecular ( Fig. 1,c) [6] and intermolecular (Fig. 1,d) [5] S N 2 displacements, he spotted significant discrepancies in the C 8 ± C 15 range. This comparison was flawed by two experimental shortcomings, however. On one hand, the kinetic work monitored only the consumption of the substrate, but did not rigorously quantify the products formed. Thus, important side reactions may have remained undetected. On the other hand, the juxtaposition was not continued into the area of the smallest rings, cyclobutyl and cyclopropyl derivatives. Such an extension should be especially meaningful if one considers the coincidence of five-, six-, and seven-membered-ring reactivities (Fig. 1). We, thus, set out to bridge these gaps and to propose a detailed and comprehensive justification of the measured rate constants.

Total Synthesis of Alkaloid 205B

“…Our difficulties in reductively cleaving the excessive ketone carbonyl through radical reduction in a straightforward manner led us to consider different options, and our attention was focused on the preparation of axial alcohol 32b . 42 It was envisioned that studies with a single stereoisomer would simplify the analysis and separations of the reaction mixtures, and furthermore, axial alcohol 32b should be more reactive since it is more sterically accessible. With sufficient amounts of the ketone in hand, the effect of different reducing agents on the stereoselectivity of alcohol formation was investigated (Table 3 ).…”

1,3-Dipolar cycloadditions of diphenyldiazomethane to thioketones: Rate measurements disclose thiones to be superdipolarophiles

“…Superimposed is the change of conformational strain in the conversion of an sp 2 -hybridized center to a tetrahedral C-atom, as exemplified by the reduction rates of cyclic ketones with sodium borohydride: k rel = 38:1:23 for the four-, five-, and six-membered ring, respectively [31]. The I-strain concept of Brown et al [32] served as interpretation for a bulk of rate and equilibrium data [33,34], but in the application to cycloalkyl solvolysis rates [35] some reserve is recommended [36].…”

Reactivity of imidazolidin-4-one derivatives of primaquine: implications for prodrug design

“…7 The higher reactivity of the seven-and five-membered ring derivatives, 4d,k, when compared with the six-membered ring derivative 4g, finds parallel in the solvolysis of cycloalkyl halides and sulfonates and can be explained by Brown's I-strain (internal strain) effect. [26][27][28] Accordingly, seven-and five-membered rings are strained, and reactions involving a change in coordination number of one of the carbon atoms from four to three, as in S N 1-type reactions, will lead to a decrease in internal strain. In contrast, six-membered halides and sulfonates are perfectly staggered and strain-free, and changes in coordination number from four to three will lead to an increase in internal strain and to a decrease in reactivity.…”