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I have included a synarchive pathway: https://synarchive.com/syn/144 where BuLi favours deprotonation over halogen metal exchange

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    $\begingroup$ No direct answer from me, but Clayden's book on organolithiums is an excellent read for these things, and I suspect may contain an answer for you. I don't mean the general org chem textbook, I mean this: elsevier.com/books/organolithiums-selectivity-for-synthesis/… $\endgroup$ Commented Sep 10, 2021 at 10:48
  • $\begingroup$ I recommend looking for Prof. Hans Reich (RIP) and his work covering a broad range of organolithium chemistry, with lots of NMR kinetic studies. He condensed much of his life's work in his personal webpage, which has since been repurposed as part of organicchemistrydata.org. There are multiple sections on organolithium chemistry, which you can access on the dropdown menu on the left. My suspicion is that deprotonation is generally faster, and only Li/I and Li/Te exchange can compete with deprotonation. $\endgroup$ Commented Sep 10, 2021 at 11:33
  • $\begingroup$ You need to look at the pKas of the protons that can potentially be removed. If there are any below ~50 then you will get deprotonation. $\endgroup$
    – Waylander
    Commented Sep 10, 2021 at 11:48
  • $\begingroup$ The reagents should be written as discreet steps: 1)t-BuLi, 2) 4-iodobutene. $\endgroup$
    – user55119
    Commented Sep 10, 2021 at 15:28

1 Answer 1


According to Bordwell $\mathrm{p}K_\mathrm{a}$ Table, $\mathrm{p}K_\mathrm{a}$ of $\ce{PhCH2COSPh}$ is $16.9$, which is compatible with alcoholic $\ce{OH}$. We all know that Grignard reagents and organolithium reagents are very susceptible to acidic hydrogens because they are strongly basic as well as nucleophilic. Between $\ce{t-BuLi}$ and $\ce{n-BuLi}$, $\ce{t-BuLi}$ is considered to be acting as base than nucleophile compared to $\ce{n-BuLi}$, due to its bulkiness. However, both of them are known for their capability of metal-proton exchange (e.g., see Wikipedia).

On the other hand, lithium-halogen exchange reactions are kinetically controlled. The position of the equilibrium varies with the stabilities of the carbanion intermediates involved $\mathrm{(sp >> sp^2 >> sp^3)}$, rather than whether it is $\ce{n-BuLi}$ or $\ce{t-BuLi}$. Keep in mind that lithium-halogen exchange reactions using alkyl-lithium typically employ two or more equivalents of alkyl-lithium reagent. The first equivalent is used for the exchange and the second equivalent reacts with the alkyl-I produced to form corresponding alkane, alkene, and lithium iodide (e.g., Ref.1). Nevertheless, if acidic hydrogen is available, the reaction goes through metal-proton exchange.

Note that the scheme given in Synthesis of Aplysin, part of which OP has copied is somewhat misleading. When you look at the original reference (Ref.2), it is clear that their intention wasn't halogen-metal exchange. It is clearly to use the lithium reagent as a base:

Scheme 2 of Ref.1

It indicated that $\ce{t-BuLi}$ is added to the compound $\bf{12}$ at $\pu{-78 ^\circ C}$, waited $\pu{10 min}$ before adding 4-iodobutene, and then let the solution warm up to $\pu{0 ^\circ C}$. After $\pu{5 h}$ at room temperature, the yield of the compound $\bf{13}$ was still only $48\%$ (see the red box). The ref.2 did not mention what was the other $52\%$. It may be a combination of nucleophilic addition and halogen exchange. I'm just speculating.

An example for use of $\ce{n-BuLi}$ for halogen-metal exchange is given in Ref.3.


  1. Helmut Neumann, and Dieter Seebach, "Stereospecific preparation of terminal vinyllithium derivatives by Br/Li-exchange with t-butyllithium," Tetrahedron Letters 1976, 17(52), 4839-4842 (DOI: https://doi.org/10.1016/S0040-4039(00)78926-X).
  2. David C. Harrowven, Matthew C. Lucas, and Peter D Howes, "Total syntheses of aplysin and debromoaplysin using a diastereoselective, sulfur mediated radical cyclisation strategy," Tetrahedron Letters 1999, 40(23), 4443-4444 (DOI: https://doi.org/10.1016/S0040-4039(99)00768-6).
  3. Donald F. Hoeg, Donald I. Lusk, and Alvin L. Crumbliss, "Preparation and Chemistry of α-Chloroalkyllithium Compounds. Their Role as Carbenoid Intermediates," J. Am. Chem. Soc. 1965, 87(18), 4147–4155 (DOI: https://doi.org/10.1021/ja01096a025).

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