Bond length and reactivity: the gauche effect. A combined crystallographic and theoretical investigation of the effects of β-substituents on C–OX bond length

Abstract

The 'variable oxygen probe' is applied t o systems with the general structure Y-C-C-OX (Y = F, H, SiR,), using both crystal structure correlations (including 25 n e w structures) and ab initio calculations (SCF[DZP]), for 20 structures, Y-CH,-CH,-OX: Y = H, F and SiH, (gauche and trans); X = CH3, CHO ( E and Z) and NO,. The calculations reproduce conformational preferences well (all our 2-fluoroethyl derivatives crystallise with F gauche to OX). Both crystal and calculated structures give linear bond-length/pK,,, correlations. From the crystal structures: definitive correlations are derived for primary and secondary alcohol derivatives; no significant difference is observed between axial and equatorial cyclohexyl systems; p-fluorine has a small bond-shortening effect on the C-OX bond, which is greatest for the best leaving groups OX; and data for two systems with p-silicon are consistent with a bond-lengthening effect. The inductive effect of p-fluorine, observed as its effect o n the C-OX bond length, shows no significant dependence on geometry. Calculated bond lengths give similar results, but show the different sensitivities to varying OX expected from frontier orbital considerations (G,,-~ -o*c-ox for Y = Si > H > F). The length of the C-OX bond in Y-CH,-CH,-OX is a linear function of the electronegativity of Y. 1,3-lnteraction energies calculated (at the MP2[DZP] level) for the isodesmic reaction Y-CH,-CH,-OX + CH,-CH,+ CH,-CH,-OX + Y-CH,-CH,give a measure of the destablising effect of p-fluorine and the stabilising effect of p-silicon in these systems. In three different systems which react with participation of adjacent o-bonds, the lengthening of the C-OX bond, observed in the ground state using the variable oxygen probe, is not accompanied b y significant involvement of the adjacent orbitals. It is suggested that C-OX bond breaking, and the further structural reorganisation, are not closely coupled in such reactions.Unique mechanistic insight is available from the systematic study of ground-state structures of suitable organic compounds. '.' We have identified a simple relationshipthe longer the bond the faster it breaks-between the length of the bond to oxygen in systems R-OX and the rate at which the same bond is broken in ionic reactions in s ~l u t i o n . ~ R-OX-R+ Paper 1 106 109G

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

“…The gauche effect has also been investigated for systems involving fluorine. 44 The neurotransmitter acetylcholine (ACh, Figure 5) is a compelling example of the gauche effect in a bioactive molecule. On the basis of considerable steric crowding between the trimethylammonium terminus and the acetyl group, one may presume that a gauche conformation is disfavored.To the contrary, the small molecule structures in the CSD overwhelmingly adopt a gauche conformation, though the torsion distribution is broad and centered closer to 80°.…”

Anomeric and Gauche Effects

“…We have looked at a large series of compounds having the general structure Y-C-C-OX, using the method of crystal structure correlation (15). We established earlier (2 ) that the length of the C-OX bond is a criterion of its ease of cleavage.…”

Solid state and theoretical evaluation of β-fluoroethyl esters indicate a fluorine-ester gauche effect

“…This is a relatively large value in the context of other accepted gauche preferences, for example, 1,2-difluoroethane [4,5]. Amos et al have carried out ab initio calculations on the ester of fluoroethyl formate 5 and determined a gauche preference of 0.66 kcal mol À1 [2]. In order to examine further the fluorine-gauche effect in esters, we have prepared three crystalline O-b-fluoroethylesters 4c-e and examined the solid state conformations of these molecules by X-ray crystallographic analyses.…”

“…The preference of 1,2-difluoroethane 1 to adopt a gauche in favour of an anti conformation has been widely reported and is acknowledged as the classical example of the fluorinegauche effect [1][2][3]. The magnitude of this preference (anti-gauche) has been calculated in the range of 0.5-1.0 kcal mol À1 [4,5].…”