What is Cross-Electrophile Coupling (XEC)?
Cross-electrophile coupling is a term coined to describe reactions that “cross-couple two electrophiles via a reductive catalytic cycle.”
- “Cross-couple” = Reactions that form C–C/X σ-bonds by reductive elimination. Additions across π-bonds can be part of the reaction, but it should terminate with a reductive elimination.
- This distinguishes the reaction from the better- known (and already-named) reductive Heck reaction and Barbier reactions. This would also rule out reactions that don’t involve organometallic intermediates.
- “Electrophiles” are referring to how these species react. Generally, this aligns with the polarization of the X-FG as defined by
bond polarity and reactivity (C–Br, NO₂).- Actual reactivity is paramount – if they are activated by net reduction (oxidative addition, XAT, single-electron reduction), then they are (mechanistically) electrophiles. This means that an alkyl carboxylic acid can be an electrophile or a nucleophile, depending upon activation mode: if the carboxylate is oxidized to a carboxylic acid radical, then it is a nucleophile; if an N-hydroxyphthalimide ester is reduced to fragment to the same radical, then it is an electrophile.
- “Reductive catalytic cycle” = Addition of electrons and has nothing to do with hydrides. Mechanistically, the catalyst must be reduced during the catalytic cycle.
- If the substrate is reduced to form a nucleophile (e.g., alkyl-I reacting with Zn metal to form alkyl-ZnI), then this is a cross-coupling reaction with in-situ formation of the nucleophilic coupling partner (e.g., a Negishi reaction). Because the mechanism of the reaction is often initially unclear, there will be some confusion in the short term. However, in the long-run, this will be less problematic for the field.
“I want to use XEC in my chemistry but don’t know where to start!”
Our group has tabulated most common conditions for a variety of coupling types reported through mid-2023. They are available as a clickable flowchart pdf at the link below.
If you intend to use this data in your own work, you must consent to cite this Chemical Reviews publication (10.1021/acs.chemrev.4c00524), which contains all of the data tabulated in the following pdf.
Flowchart coming soon!
Why Cross-Electrophile Coupling? Why not other terms?
- Our own initial work (and earlier studies) used some variation of “reductive cross-coupling” or “reductive coupling”. These terms are inadequate, because they are overbroad, and led to a lot of confusion.
- The confusion was due to the fact that “reductive coupling” was an established, contemporary area of chemistry that utilized hydride or even dihydrogen as the “reductant.” These reactions are mechanistically distinct because a hydride is a nucleophile, despite the reaction being reductive (because hydride addition is considered reductive).
- We sought to make a more concise name that better captured to meaning as we were beginning to understand it.
This led to “cross-electrophile coupling”. The term “reductive cross-electrophile coupling” is also in use, but we favor leaving off “reductive” because all cross-electrophile coupling reactions require a reduction step.
Why ‘XEC’ and not ‘CEC’ for abbreviation?
Given our motivation to coin a term that was less ambiguous for this new field, we were also wary of using an acronym that was already in use in chemistry. Searching the literature, the acronym CEC appeared to already be used by several areas of chemistry: in separations for capillary electrophoresis chromatography, in electrochemistry to describe a class of reaction involving an alternating series of chemical and electrochemical steps, and in materials for cation-exchange capacity. There were numerous other, lesser-used, CEC abbreviations in the chemistry literature.
On the other hand, XEC appeared to have little use in English-language chemistry at the time. This is probably because very few English words start with X. Finally, the letter “X” is frequently used in English to denote “crossing” – for example in sport, cross-country = XC. XEC was chosen to simply minimize confusion and, in the long term, simplify literature searching as the field grew.