Skip to main content
Chemistry LibreTexts

V. Internal Hydrogen-atom abstraction in Acetals and Ethers

  • Page ID
    24025
    \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \) \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)\(\newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\) \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\) \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\) \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\) \( \newcommand{\Span}{\mathrm{span}}\) \(\newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\) \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\) \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\) \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\) \( \newcommand{\Span}{\mathrm{span}}\)\(\newcommand{\AA}{\unicode[.8,0]{x212B}}\)

    A. Abstraction by Alkoxy Radicals

    Hydrogen-atom abstraction by alkoxy radicals from acetals and ethers is described in the next sev­eral sections. More information about the formation and reactions of alkoxy radicals is found in Chap­ter 6.

    1. Abstraction From an Acetal

    Intramolecular hydrogen-atom abstraction by an oxygen-centered radical from the central carbon atom in an acetal linkage is the “key” step in the orthoester formation pictured in Scheme 10.19 The radical phase of this reaction begins with photochemically initiated fragmentation of the hypo­io­dite 29. Internal hydrogen-atom abstraction followed by carbon–iodine bond formation completes the radical phase of the reaction. Formation of the orthoester 31 from the iodide 30 then occurs by an ionic process.

    II5s10.png

    2. Abstraction From an Ether

    Internal hydrogen-atom abstraction from a benzyloxy group produces a highly stabilized radical (32) that can be an intermediate in the formation of a benzyl­idene acetal (Scheme 11). This type of reaction takes place in good yield when the substrate contains adjacent O-benzyl and hydroxyl groups (Scheme 11).20 The reaction in Scheme 12 illustrates the type of transfor­mation possible. In this reaction the hypo­iodite 33 is not just assumed to exist but is actually observed by 13C NMR spectroscopy. Such direct observation of a hypoiodite is rare.

    II5s11.png

    II5s12.png

    It is not essential to have aromatic stabilization in the developing radical for internal hydrogen-atom abstraction to take place.21–23 In the alkoxy radical 35 abstraction from a nearby methoxy group begins a process that ultimately unites the interacting groups as an acetal (Scheme 13).21 This reaction consti­tutes a regioselective transformation of a methoxy group that is in close prox­imity to an oxygen-centered radical.

    II5s13.png

    3. Abstraction From an α-Aminoether

    Internal hydrogen-atom abstraction by an alkoxy radical from an α‑amino­ether linkage can lead to the same type of ring formation observed in reac­tions of acetals and other ethers. For example, 1,6-hydrogen-atom abstraction converts the alkoxy radical 36 into the α-amino radical 37. Combination of 37 with an iodine atom or reaction of 37 with I2 then produces a reactive iodide that cyclizes to give the spiro nucleoside 38 (Scheme 14).24,25

    II5s14.png

    B. Abstraction by Carbon-Centered Radicals

    Although internal hydrogen-atom abstraction usually involves an alkoxy radical, some car­bon-cen­tered radicals are capable of such reaction. One ele­ment associated with successful hydrogen-atom abstraction is that ring strain in the transition state be minimal. (Ring strain usually is min­imized when hydrogen-atom abstraction involves a six-membered-ring transition state.26 Such a reaction can be described as a 1,5-hydrogen-atom transfer or 1,5-HAT.) A second characteristic of successful abstraction is that stabil­i­zation of the devel­oping radical contribute to lowering the transition-state barrier.26 The need for radical stabil­ization means that primary27 and vinylic28,29 radi­cals are prime candi­dates for hydrogen-atom abstraction because their reactions typically lead to much more stable radicals; how­ever, even a secondary radical will abstract a hydrogen atom internally if the devel­oping radical is sufficiently stabilized.30 In the reaction shown in Scheme 15, the vinylic radical 39 abstracts a hydro­gen atom from the adja­cent O-benzyl group in route to the major products 41 and 42 (80% com­bined yield). The product 40, formed when 39 abstracts a hydrogen atom from (C6H5)3SnH, is produced in only 8% yield, demonstrating that inter­mo­lecular reaction from this tin hydride has difficulty competing with internal hydrogen-atom abstraction.29

    II5s15.png

    It is often difficult to predict the extent of internal hydrogen-atom abstraction when a reactive, car­bon-centered radical is formed in the presence of an effec­tive hydrogen-atom transfer. For example, generating the radical 39 with (C6H5)3SnH present in solution still results primarily in internal reaction (Scheme 15);29 in contrast, in the reaction shown in eq 12 deuterium incorporation dem­on­strates that even though a primary radical is formed, abstraction from Bu3SnH is more rapid than internal 1,4- or 1,5-HAT.31

    II5(12).png