Andrew Sasser ‘23, Physical Sciences, Fall 2020
Figure 1: Structure of tris(acetylacetonato)iron(III), an airstable iron catalyst commonly used in organic synthesis. Although this catalyst is generally not capable of reducing most inactivated alkenes by itself (alkenes without heteroatom substituents), it is very successful in promoting atom transfer when paired with a second radical trapping catalyst (Source: Wikimedia Commons)
One of the most important reactions in synthetic organic chemistry is the reduction of alkenes (carbon-carbon double bonds) to alkanes (carbon-carbon single bonds). This exothermic process is commonly used in the production of saturated fats from unsaturated fats. It can also be used to increase stability and reduce unwanted side reactions for drug intermediates (Lew, 2020). However, this type of reaction requires the use of a metal catalyst in combination with hydrogen to reduce the activation energy and allow the reaction to occur near room temperatures (Lew, 2020). Most common industrial methods of hydrogenation catalysis rely upon the use of expensive transition metals like palladium, platinum, and silver. Additionally, industrial applications rely upon large reserves of flammable and explosive hydrogen gas, which poses a significant industrial hazard (Rice University, 2020).
To avoid the use of rare transition metals and flammable hydrogen gas, many research efforts have focused on the application of hydrogen atom transfer – a process through which other, more stable reagents are used as hydrogen donors. In this method, a transition metal abstracts a hydrogen radical (a hydrogen atom with one electron). The electron-rich reactive alkene then removes the hydrogen via nucleophilic attack, generating a radical on the more substituted carbon which can then take another hydrogen atom from a donor species (Ma and Herzon, 2015). In addition to opening up new avenues for more stable hydrogen donors, this type of reaction can also make use of more abundant metals like iron, cobalt, and chromium (Kattamuri and West, 2020). However, this reaction requires large stoichiometric amounts of an oxidant like TBHP (tert-butyl hydroperoxide) to return the metal to its original oxidation state, which results in the production of significant amounts of toxic waste products (Ma and Herzon, 2015; Kattamuri and West, 2020).
However, recent work from Kattamuri and West at Rice University demonstrated that the use of a dual-catalytic cycle with two catalysts – one iron, one sulfur – could allow the hydrogen atom transfer reaction to proceed without the need for an oxidant. Nicknamed “cHAT” – cooperative hydrogen atom transfer – the group used a tris(acetylacetonato)iron(III) catalyst with a bench stable phenyl-silane reagent to add the first hydrogen to a target alkene (Kattamuri and West, 2020). After producing a carbon-centered radical on the target substrate, the group proposed that the thiophenol reagent could then donate a second hydrogen to the target; the resulting aryl thiyl radical could then oxidize the radical before being reprotonated by ethanol. The resulting ethoxide ion could then be bound by the iron(III) cation before being exchanged with the hydride in phenylsilane, thus producing the iron hydride needed for the first hydrogen atom transfer (Kattamuri and West, 2020).
In testing with various substrates, the group found that at 23˚C, the alkene 4-phenylbut-1-ene could be reduced to an alkane at 93% yield when both catalysts, two equivalents of phenylsilane, and excess ethanol were used. This reaction was successfully scaled up to reduce one gram of 3-methylbut-2-en-1-yl benzoate at 98% yield (Kattamuri and West, 2020). Control experiments determined that both catalysts play significant roles in the reduction mechanism; without the iron catalyst, no product was formed, and without the sulfur catalyst, the reaction’s yield dropped to 27% (Kattamuri and West, 2020). Furthermore, attempts to swap each catalyst with a slightly modified catalyst also failed – when the iron catalyst was switched with a cobalt equivalent, the yield dropped to 30%. Similarly, dodecanethiol produced a reaction yield of 43% when switched for the thiophenol (Kattamuri and West, 2020). The group also found that while most alkene substrates worked well with cHAT, molecules that contained styrenes (alkenes bonded to aryl groups) and phenols had poor reactivity; the authors suggested that that the benzylic radical produced from styrenes was too stable to undergo the second hydrogen atom transfer, whereas phenols exhibit natural anti-oxidant properties (Kattamuri and West, 2020). Ultimately, the group concluded that cHAT presents a “green” opportunity for pharmaceutical companies and others to reduce alkenes needed for vital materials without using rare metals, flammable hydrogen gas, or producing large amounts of waste (Rice University, 2020).
References
- Kattamuri, P. V., & West, J. G. (2020). Hydrogenation of Alkenes via Cooperative Hydrogen Atom Transfer.Journal of the American Chemical Society, 142(45), 19316- 19326. doi:10.1021/jacs.0c09544
- Lew, J. (2020, September 13). Catalytic Hydrogenation of Alkenes. Retrieved November 18, 2020, from https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_(Organic_Chemistry)/Alkenes/Reactivity_of_Alkenes/Catalytic_Hydrogenation
- Ma, X., & Herzon, S. B. (2015). Non-classical selectivities in the reduction of alkenes by cobalt-mediated hydrogen atom transfer.Chemical Science, 6(11), 6250-6255. doi:10.1039/c5sc02476e
- Rice University. (2020, October 30). ‘Green’ method for making pharmaceutical intermediates. ScienceDaily. Retrieved November 18, 2020 from www.sciencedaily.com/releases/2020/10/201030122547.htm