I-Strain as a Factor in the Chemistry of Ring Compounds^1,2

Structure and absolute configuration of (E)-(–)-2-cyclododecenyl camphanate

“…In contrast with the recent study of a similar 11-membered ring by Ito et al (1988) where only one atom had highly anisotropic temperature factors, there is apparently highly anisotropic thermal motion for C5 through C11 and, correspondingly, there is a larger number of unusual bond lengths. This observation is in accord with the established classification of organic rings by V. Prelog and H. C. Brown (Brown, Fletcher & Johannesen, 1951) as modified by Eliel (1962) where the boundary between 'medium' and 'large' rings is assigned between 11-and 12-membered rings on a basis of heat of combustion data. Large rings have properties, such as lack of rigidity, similar to long-chain compounds.…”

Structure and Properties of Cyclic Compounds: Xi. Dissociation Constants of the Cyanohydrins of Some Methylcyclohexanones

“…The effect for which the term "equatorial interference" is suggested has not previously been noted. However, Brown, Fletcher, and Johannesen (14) found that in the hydrolysis of methylsubstituted 1-methyl-1-chlorocyclohexanes the order was 2-methyl > 3-methyl > 4-methyl, the reverse to that observed in the present work, and this would be expected since the reverse process of a change in co-ordination number from 4 to 3 is being measured. This distortion effect would be expected to be transferred into a second ring, and cholestan-3-one and coprostan-3-one have been found (15) to be slightly more reactive than cyclohexano~~e.…”

“…This brings the atoms on the equatorial bonds a t positions 3 and 5 nearer to the equatorial bond of atom 4 and the axial bonds of atoms 2 and 6. This results in a general strain in the ring which is relieved when the co-ordination number of the carbony1 carbon atom is changed from 3 to 4 (7,14) as in cyanohydrin formation. A substituent on carbon atom 4 will increase this strain relative to cyclohexanone itself ancl thus 4-methylcyclohexanone should be more reactive since the additional strain is relieved when the cyanohydrin is formed.…”

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.…”