AG Prof. Dr. J. Hartung


Oxygen Centered Radicals

A2) Mecanistic Investigation - On Selectivity Control by Polar Substituent Effects

1. Keywords: Alkoxyl radical; Polar effect; Reactive conformer; Stereoselective synthesis; Tetrahydrofuran.


2. Summary: 4-Pentenoxyl radicals cyclize 2,3-cis-selectively, when substituted by an allylic hydroxy, acetyloxy, or benzoyloxy group. Additional substituents increase or decrease the fraction of 2,3-cis-cyclized product, depending on relative configuration, positioning, and their chemical nature. The preference for 3-acceptor-subsituted pentenoxyl radicals to furnish products of 2,3-cis-ring closure arises from a secondary orbital interaction between the allylic oxygen substituent and the alkene entity, kinetically disfavoring the competing 2,3-trans-mode of 5-exo-cyclization. Aligning the β-C,O-bond in anticline orientation to the plane of the alkene, which is the preferred conformation for transition structures for 2,3-trans-cyclization, stabilizes the double bond by delocalizing π-electrons into the σ*(C,O)-orbital. Along with energy decreases the affinity ofπ-electrons for adding the oxygen radical. In 2,3-cis-cyclization, a similar stabilizing effect cannot occur, because the allylic oxygen substituent and the alkene align synperiplanar. The kinetic effect of an allylic oxygen substituent becomes furthermore apparent in cyclization of the 3-hydroxynona-1,8-dien-5-oxyl radical, favoring intramolecular addition to the unsubstituted allylic double bond by a factor three.


3. Introduction and outline: 4-Pentenoxyl radicals cyclize 2,3-trans-selectively when substituted with an allylic alkyl or a phenyl group (Scheme 1). The fraction of 2,3-trans-product increases with the size of the allylic substituent, from 80/20 for methyl to above 99/1 for tert-butyl. Transition state theory explains 2,3-trans-selectivity on the basis of cumulative 1,2- and 1,3-repulsion, progressively disfavoring 2,3-cis-addition as steric demand of the allylic substituent grows.

Scheme 1. Stereoselectivity in 5-exo-cyclization of allyl substituted 4-pentenoxyl radicals.

Figure 1. Structure formulas of bio-inspired 2- and 3-hydroxy-substituted tetrahydrofurans as targets in organic synthesis.

Steric effects controlling selectivity in synthesis of 2,3-trans-substituted heterocycles by intramolecularly adding polar reactands or radicals  to double bonds are well documented in the scientific literature. In the past decades, however, more and more reports appeared describing selectivity not fitting into this stereochemical scheme. Alkenols bearing an allylic oxygen substituent, for example, show a marked propensity for cyclizing 2,3-cis-selectively, when treated with molecular iodine. A theory explaining this phenomenon starts to evolve, but is not yet consistent.

The affinity of the allylic hydroxy group to direct cyclizations 2,3-cis-selectively also extends to oxygen radical additions, as recently outlined in synthesis of allo-isomuscarine (Scheme 1, Figure 1). The alkene in this example poses the nucleophilic component and the radical oxygen the electrophilic, which is exactly opposed to the situation in electrophile-induced alkenol cyclization. A theory explaining 2,3-cis-selectivity in radical cyclization so far does not exist.

For uncovering the principles leading to 2,3-cis-selective ring closures, we investigated in the study summarized below, reactivity and selectivity of seven 4-pentenoxyl radicals, differing in substitution at the allylic carbon and at proximal positions. The results from this effort show that an allylic oxygen substituent reduces the rate of intramolecular 2,3-trans-addition, and leave the rate of the 2,3-cis-pathway largely unaffected. The rate effect of the allylic oxygen substituent is not restricted to stereocontrol but also controls selectivity in intramolecular addition of an oxyl radical to two chemically different C,C-double bonds. The 3-hydroxynona-1,8-dien-5-oxyl radical thus prefers adding to the unsubstituted allylic double bond by a partial rate factor three.


4. Results

Figure 2. Structure formulas of 4-pentenoxyl radicals Iaf conceived for uncovering the origin of 2,3-cis-selectivity in homolytic 5-exo-cyclization.

Scheme 2. Chain reaction for bromomethyltetrahydrofuran synthesis from 3-alkenoxy-4-methylthiazole-2(3H)-thione 1 and BrCCl3 (R1 = H, Ac, Bz; R2 = H, OAc, CH3).

Table 1. Products formed from O-(4-pentenoxy)thiazolethiones 1ac and bromotrichloromethane.

a Stereodescriptors refer to configuration at carbons C2 and C3. b Stereodescriptors refer to configuration at carbons C3 and C4. c 65/35-Mixture of stereoisomers.




Table2. Carbon-13 NMR-chemical shifts for cis/trans-isomers of 2,3-substituted tetrahydrofurans 3ac (in CDCl3, ambient temperature)

Scheme 3. Products formed from radical reactions between bromotrichloromethane and 3-[erythro-2,3-bis-(acetyloxy)pent-4-enoxy]thiazolethione erythro-1d [top; yields for experiment conducted via photochemical activation (l = 350 nm, 22 °C, 30 minutes) on a 196-millimolar scale of 1d in C6D6 containing 9.6 equivalents of BrCCl3: 77% of 2, 68% of erythro-3d and erythro-11d taken together] and stereoisomer threo-1d [bottom; yields for experiment conducted via photochemical activation (l = 350 nm, 22 °C, 30 minutes) on a 196-millimolar scale in C6D6, containing 9.0 equivalents of BrCCl3: 53% of 2, 72% of threo-3d and threo-11d taken together]; MW = microwave.

Scheme 4. Products formed from 3-[arabino-3,4-bis-(acetyloxy)hex-5-enoxy]-1,3-thiazole-2(3H)-thione 1e and bromotrichloromethane.

Scheme 5. Products formed from 3-[rel-(3R,5S)-3-hydroxynona-1,8-dien-5-oxy]-4-methyl-1,3-thiazole-2(3H)-thione 1f and tributylstannane.

Scheme 6. Scheme of elementary reactions, kinetic equations (eqs. 1–2) and approximation (app. 1) set up for identifying thermochemical contributions to 2,3-cis-selectivity in 5-exo-cyclization of 3-acetyloxypentenoxyl radical Ib.

Scheme 7. Elementary reactions (top) and differential equation (bottom) for comparing rates and life-time of alkyl radical trapping under reductive conditions (eq. is short for equation).

Scheme 8. Reducing 2-bromomethyltetrahydrofurans cis/trans-3b with tributylstannane (diastereomeric purity of all products >98:2, according to information from GC-MS in combination with proton NMR-spectroscopy; for reactand concentrations, refer to the text).

Figure 3. Twist-models for transition structures leading to 2,3-cis- (left; pa = pseudo-axial) or 2,3-trans-5-exo-cyclized products (right; pe = pseudo-equatorial) from 4-pentenoxyl radicals.

Figure 4. Correlation diagram describing angle dependency of frontier molecular orbital (FMO)-interactions in acceptor-substituted butenes used for explaining the kinetic origin of 2,3-cis-selectivity in oxygen radical additions (right; R = e.g. CH3 or CH2CH2O•, R' = e.g. primary, secondary, and tertiary alkyl; X = e.g. OH, OAc, OBz).

Figure 5. Transition structure models for explaining stereoselectivity in 5-exo-trig-cyclization on the basis of cumulative polar and steric substituent effects in 2,3-diacetyloxy-4-pentenoxyl radicals erythro-Id and threo-Id (a = axial, pa = pseudo-axial, pe = pseudo-equatorial, e = equatorial).

Figure 6. Transition structure models for explaining 2,5-trans-selectivity in 5-exo-trig-cyclisation of arabino-configured 3,4-bis(acetyloxy)-5-hex-2-oxyl radical Ie (a = axial, pa = pseudo-axial, pe = pseudo-equatorial, e = equatorial; arcs symbolize steric repulsion between interconnected substituents).


5. Concluding remarks: 2,3-cis-Selectivity arises from electrophilicity at oxygen in homolytic addition to non-activated double bonds on one side and a stereoelectronic effect exerted by an allylic hydroxy, acetyloxy or benzoyloxy substituent on the other. This combination kinetically disfavors 2,3-trans-ring closures of 3-acceptor-subsituted 4-pentenoxyl radicals, allowing to become a 2,3-cis-stereoisomer of a substituted tetrahydrofuran to become principal cyclization product.

According to theory, 2,3-cis-selectivity should extend to other acceptor groups X in allylic position and to other electrophilic radicals. The stronger X withdraws p-electrons toward the s*(C,X)-orbital, the more pronounced 2,3-cis-stereocontrol shall be. At some point, we expect steric repulsion between the vinyl group and X to counteract the polar 2,3-cis-directing effect. Using Winstein-Holness A-parameters and electronegativity of atoms, we expect allylic halogens to be potential 2,3-cis-directing substituents. Nitrogen and sulfur groups, on the other hand possibly are borderline cases.

Addressing questions of this kind will help to expand our knowledge about polar effects in oxygen radical chemistry and the role such effects play for controlling selectivity in homolytic carbon-oxygen bond formation. This is particularly interesting because 2,3-cis-selectivity adds a component to synthesis of tetrahydrofurans in pH-neutral non-oxidative environment, not available so far from carbon substitution. The key for refining the existing reaction model, as far as we understand the mechanism, lies in the interplay between steric and polar substituent effects acting on transition structures. We will report in an upcoming article on this topic.


6. Leading References:

2,3-cis-Cyclization of 4-Pentenoxyl Radicals. I. Kempter, C. Schur, K. Huttenlocher, R. M. Bergsträßer, J. Bachmann, B. Wolff, T. Kopf, J. Hartung, Tetrahedron, 2016, DOI: 10.1016/j.tet.2016.07.001.

For a review on alkoxyl radical chemistry, see: J. Hartung, T. Gottwald, K. Špehar, Synthesis2002, 1469–1498, DOI: 10.1055/s-2002-33335