Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent

Abstract

Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step. Herein, we explore the modulation of alkene reactivity and halocyclization rates by nucleophile proximity and basicity, through detailed analyses of starting material spectroscopy, addition stereopreferences, isotope effects, and nucleophile-alkene interactions, all obtained in a context directly relevant to synthesis reaction conditions. The findings build on the prior work by highlighting the reactivity spectrum of halocyclizations from stepwise to concerted, and suggest strategies for design of new reactions. Alkene reactivity is seen to span the range from the often overgeneralized "sophomore textbook" image of stepwise electrophilic attack on the alkene and subsequent nucleophilic bond formation, to the nucleophile-assisted alkene activation (NAAA) cases where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack. By highlighting the factors that control reactivity across this range, this study suggests opportunities to explain and control stereo-, regio-, and organocatalytic chemistry in this important class of alkene additions.

Figure 1

Path A and path B represent the rate-determining classically perceived intermediates (I and II) involved in electrophilic addition to alkenes. Path C represents the nucleophile-assisted alkene activation pathway (NAAA).

Figure 2

Rate-determining formation of intermediates (I or II) fails to explain the observed rate ordering, whereas the concerted NAAA pathway predicts the halofunctionalization barriers ^α(B3LYP/6-31G*/SM8-CHCl₃) in accordance with the observed rates (as determined via ¹H NMR and GC–MS analysis).

Figure 3

Computational predictions for possible chlorenium atom transfer (B3LYP/6-31G*/SM8-CHCl₃). (a) A barrierless transition to the chlorocarbenium intermediate proceeds if a naked chlorenium is used. (b) With the chlorenium donor included in the calculations, a transition state for halogen transferred cannot be reached, even with intramolecular hydrogen-bond activation of the donor carbonyl functionality; instead, a resting state complex is achieved. (c) Prepolarization of the olefin raises the HalA(Cl) of the olefin such that it can now compete with the donor for the chlorenium, resulting in a transition state that initiates halogen transfer.

Figure 4

(a,b) ¹³C KIE results predicted at the B3LYP/6-31G*level of theory and its validation by experimental results. For simplicity, the TS only for syn-addition to 1a is shown; see Supporting Information, section F for details. (c,d) Secondary KIE (²H) for halolactonization of 1a and 1d. (e,f) Primary ¹⁸O KIE experimental results for 1a and 1d. Numbers in parentheses represent the standard deviation in the third decimal place; see Supporting Information, section D.

Figure 5

NMR resonances of olefinic C and H (at room temperature in CDCl₃) displaying the interaction of a remotely tethered nucleophile with the π-system upon modulation of the nucleophilic strength. The minor impurities appearing in the NMRs are the corresponding E-isomers.