The Role of Ring Strain on the Ease of Ring Closure of Bifunctional Chain Molecules

Abstract

The role of ring strain on the ease of ring formation over a wide range of ring sizes is discussed on the basis of a comparison of transition state versus product‐ring strain energies. A general procedure is illustrated for the assessment of transition‐state strain energies, based on experimental effective molarities (EMs) and an extra‐thermodynamic treatment of entropy data for ring closure. It is found that the ring product is a good model of the transition state of cyclisation for all but the shortest chains. Our earlier interpretation of this remarkable lack of correspondence between transition state and product‐ring strain energies in intramolecular nucleophilic substitutions of the very short chains, is compared with the results of recent theoretical calculations.

Why is RCM Favoured Over Dimerisation? Predicting and Estimating Thermodynamic Effective Molarities by Solution Experiments and Electronic Structure Calculations

“…For most systems, EM T can be predicted using the strain energy of the cyclic products, the number of rotatable bonds and the treatment of Mandolini et al. [9] The use of electronic structure calculations to predict RCM outcomes based on free-energy differences has also been explored. Due to entropic discrepancies, free energies obtained from electronic structure calculations cannot be used directly but a straightforward correction delivers predictively useful free energies.…”

“…Galli and Mandolini reviewed a large body of experimental work in solution dealing predominantly with lactone and cyclic ether-forming reactions and analysed how EM T partitions into enthalpic and entropic components, [9] drawing on the fundamental contributions of Page and Jencks. [11] The entropic component (EM S ) can be calculated for short chains of up to about 7 single bonds, from the number of rotatable s bonds (rotors, r) ([Eq.…”

“…Burt and co-workers have explored RCM reactions of butenoate esters to form lactones by electronic structure calculation methods, and used reac- Table 1. Thermodynamic effective molarities calculated using Mandolini s approach [9] and literature strain energies for cycloalkenes. www.chemeurj.org tion yields from the synthetic literature to test their predictions.…”

Functionalized Azamacrocycles and Large-Ring α-Amino Esters by One-Pot Syntheses from Methyl 2-Siloxy-2-vinylcyclopropanecarboxylates

“…Many spacer units may be incorporated between the protected enone unit provided by the siloxycyclopropane part derived from 1 and the nucleophilic terminus. Taking into account the difficulties involved in the generation of large-membered heterocycles, due to unfavourable enthalpic and entropic effects, [42] our method could be very useful.…”

Seven-membered ring scaffolds for drug discovery: Access to functionalised azepanes and oxepanes through diazocarbonyl chemistry

“…13,14 Relative to five-and six-membered oxygen containing heterocycles, oxepanes are synthetically more challenging due to enthalpic and entropic constraints. [15][16][17] Methods towards oxepanes are diverse, 5,6,18 Seven-membered rings are often flanked by aromatic ring systems and these bi-and tricyclic systems have interesting activity on the central nervous system. 1 However, this type of scaffold adds significant sp 2 character to the overall compound.…”