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Metal-hydride hydrogen atom transfer

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Metal-Hydride Hydrogen Atom Transfer (MHAT) is a process where a metal hydride (M–H) transfers a hydrogen atom (H•) to an alkene, forming a carbon-centered radical. This radical can then undergo diverse transformations.

Pioneering work by Iguchi, Halpern, and Jackman demonstrated that metal hydrides can undergo outer-sphere hydrogenation with activated olefins through a mechanism which is distinct from metal insertion, hydride addition, and protonation.[1][2][3] MHAT has attracted increasing attention in recent years as a useful reaction that can hydrofunctionalize olefins chemoselectively following Markovnikov's rule.[4]

Mechanism

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Metal hydrides involved in MHAT reactions are typically generated in situ from low-valent transition metal precursors upon treatment with silanes or borohydrides as stoichiometric reductants. The thermodynamic driving force for this process arises from the formation of strong Si–O or B–O bonds, particularly under protic conditions that promote solvolysis to reactive monoalkoxysilanes. Alcoholic solvents are thus often essential for efficient activation and turnover. In this context, Ph(i‑PrO)SiH₂ has been identified as a particularly effective silane,[5] offering operational stability and reliable hydride delivery.

The resulting metal–hydride species—typically based on first-row transition metals such as Fe, Co, Mn, or Ni—exhibit redox flexibility, moderate bond strengths, and accessible spin states. These enable hydrogen atom transfer to π-systems, generating carbon-centered radicals and transiently oxidized metal species. The radical pair initially remains in a solvent cage, where it may revert, recombine, or escape to engage in productive downstream reactivity.[6] The use of weak-field ligands promotes high-spin configurations that enhance the radical character of the M–H bond and facilitate efficient HAT. These mechanistic features collectively distinguish MHAT from conventional hydride or proton transfer pathways, supporting its use in mild and chemoselective olefin functionalization.[4][6]

C–O bond formation

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MHAT-mediated C–O bond formation typically proceeds via hydrogen atom transfer from a transition metal hydride to an alkene, generating a carbon-centered radical that is subsequently trapped by oxygen-based electrophiles. These radical-based processes encompass hydration, hydroalkoxylation, and hydroperoxidation, and are exemplified by the Mukaiyama hydration, in which a metal hydride and molecular oxygen effect Markovnikov-selective water addition across unactivated alkenes. Such transformations offer high chemoselectivity under mild conditions and have been increasingly applied in complex molecule synthesis.[4][6][7]

Mukaiyama hydration

Mukaiyama hydration is a formal addition of an equivalent of water across an olefin catalyzed by metal-hydride complex and atmospheric oxygen, to produce an alcohol with Markovnikov selectivity. This reaction is known as a pioneering and representative example of the Metal Hydride Atom Transfer (MHAT) mechanism via a transition metal hydride. In the recent report by Fan and co-workers in 2017, the regioselectivity of Mukaiyama hydration was found to depend on the metal catalyst. While Co(acac)₂ promoted conventional Markovnikov hydration at the C12-position of anhydrolycodoline, Mn(acac)₃ induced hydroxylation at a more remote γ-position, yielding 12-epi-flabelliformine.[8]

Mukaiyama hydroperoxidation

Using typical Mukaiyama conditions, peroxidation can be performed on specific substrates. Maimone and co-workers reported the oxygen-stitching strategy using hydroperoxidation to efficiently construct nortrilobolide using Co(acac)₂.[9] In this strategy, Mukaiyama-hydroperoxidation of olefins followed by reductive workup to produce triols. Iron and manganese based catalysts were almost unreactive.

C–N bond formation

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MHAT-mediated C–N bond formation involves hydrogen atom transfer from a transition metal hydride to an alkene, generating a carbon-centered radical that subsequently reacts with nitrogen-based electrophiles. These reactions include hydroamination, hydrazination, and azidation.[4][6][7]

Hydrohydrazination

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Carreira and co-workers expanded Mukaiyama hydrofunctionalization framework to C-N bond formation.[10] In the report, they demonstrated that cobalt(III) complexes could catalyze the Markovnikov-selective hydrohydrazination of unactivated olefins with azodicarboxylates. These reactions proceed with high chemoselectivity, which is difficult to achieve under traditional protic conditions. This reaction could proceed via cobalt hydride-mediated hydrogen atom transfer, thus contributing to the conceptual foundation of MHAT (metal hydride atom transfer) reactivity.

Hydroazidation

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Boger and co-workers developed an Fe(III)/NaBH₄-mediated hydroazidation of unactivated alkenes using NaN₃ as the azide source.[11] The reaction proceeds via a radical pathway, exhibits exclusive Markovnikov selectivity, and tolerates a broad range of functional groups. This method enables direct alkene azidation, facilitating access to previously inaccessible C20′-vinblastine analogues.

C–X bond formation

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MHAT-mediated C–X bond formation proceeds via radical interception of alkenes with electrophilic halogen or chalcogen sources. In addition to C–F bond formation, MHAT enables hydrohalogenation and hydrochalcogenation under mild, chemoselective conditions, as demonstrated with Cl, Br, I, and S-based reagents.[4][6]

Hydrofluorination

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Boger and co-workers further expanded Fe(III)/NaBH₄ system to free radical hydrofluorination of unactivated alkenes using Selectfluor reagent as a source of fluorine and resulting in exclusive Markovnikov addition.[12] Baran and co-workers applied this to introduce a fluorine atom to an unactivated alkene in a steroid derivative.[13]

C–C bond formation

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MHAT-mediated C–C bond formation involves the generation of carbon-centered radicals from alkenes via metal hydride hydrogen atom transfer, followed by bond formation through conjugate addition, hydroarylation, hydrocyanation, or hydroalkylation. These radical-based processes often proceed under mild, redox-neutral conditions and enable regioselective C–C coupling complementary to polar or pericyclic pathways.[4][6][7]

Conjugate addition

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In 2014, Baran and co-workers discovered a functionalized olefin cross-coupling reaction, that is initiated by MHAT followed by the conjugate addition to the electron-deficient olefin.[14] Pronin and co-workers applied this method to radical cyclization process in the synthesis of (±)-Emindole SB.[15]

Hydroarylation

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Hydroarylation was first established by Gui and Shenvi as a MHAT-enabled transformation wherein carbon-centered radicals, generated from alkenes, undergo intramolecular addition to arenes.[4][6][7] In 2019, Gao and co-workers applied this strategy to the construction of the tetracyclic core of viridin-type aromatic steroids, highly oxygenated furanosteroids that function as potent PI3K inhibitors, demonstrating the method's utility in assembling biologically active, densely functionalized polycyclic frameworks.[16]

Reductive coupling

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Carbon-centered radicals have also been known to undergo reductive coupling with carbonyl functionalities represented in the seminal work by Krische and co-workers.[17] In 2018, Ma and co-workers expanded the scope of reductive coupling to nitrile functionalities in the report of the synthesis of navirine C. The observed regioselectivity is attributed to steric hindrance around the nitrile acceptor, which directs radical addition to the less hindered site.[18]

Hydrogenation

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MHAT-based hydrogenation represents a mechanistically distinct alternative to classical hydrogenation via metal dihydrides. Foundational studies by Halpern proposed hydrogen atom transfer from transition metal hydrides to olefins, establishing a conceptual basis. Mukaiyama demonstrated the synthetic potential of this mechanism under mild conditions using cobalt catalysts.[4][6][7] Shenvi and co-workers expanded these principles to develop general and chemoselective hydrogenation. A key feature of the systems is the thermodynamic control, enabled by reversible hydrogen atom transfer between radical intermediates.[19] Krische applied this method for the synthesis of Andrographolide and 14-Hydroxy-Colladonin.[20]

Isomerization

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MHAT-based isomerization operates through a distinct mechanistic route. Co-mediated MHAT has been employed to isomerize terminal alkenes to internal ones, for example, in the synthesis of (−)-Humulene oxide II.[19]

See also

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References

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  1. ^ J. T. Hynes, J. P. Klinman, H.-H. Limbach, R. L. Schowen (eds.), Hydrogen‐Transfer Reactions, Wiley‐VCH, 2007.
  2. ^ Shenvi Research Group, "Short Course in MHAT".
  3. ^ Shenvi Research Group, "Hydrogen Atom Transfer".
  4. ^ a b c d e f g h R. A. Shenvi, D. P. Curran, T. R. Newhouse, Chem. Rev. 2016, 116, 8912–9000.https://doi.org/10.1021/acs.chemrev.5b00715
  5. ^ R. A. Shenvi, The Journal of the American Chemical Society 2016, 138, 4962–4971. https://doi.org/10.1021/jacs.6b00957 [dead link]
  6. ^ a b c d e f g h S. L. Shevick, C. Obradors, R. A. Shenvi, Chemical Science 2020, 11, 12401–12422. https://doi.org/10.1039/D0SC04112B
  7. ^ a b c d e Z. Ma, Y. Wang, S. Wang, Z. Shen, J. Li, W. Liu, Organic Chemistry Frontiers 2021, 8, 7050–7060. https://doi.org/10.1039/D1QO01139A
  8. ^ C. A. Fan, Y. Li, L. Zhou, et al., Journal of the American Chemical Society 2017, 139, 7095–7098. https://doi.org/10.1021/jacs.7b03280
  9. ^ T. J. Maimone, J. R. Coombs, K. A. Margrey, et al., Journal of the American Chemical Society 2019, 141, 14904–14911. https://doi.org/10.1021/jacs.9b08001
  10. ^ E. M. Carreira, A. G. Rychnovsky, Journal of the American Chemical Society 2004, 126, 5676–5677. https://doi.org/10.1021/ja048698u
  11. ^ D. L. Boger, H. Jin, Organic Letters 2012, 14, 1428–1431. https://doi.org/10.1021/ol300173
  12. ^ D. L. Boger, H. Jin, Journal of the American Chemical Society 2012, 134, 13588–13591. https://doi.org/10.1021/ja3063716
  13. ^ P. S. Baran, J. B. Ellis, et al., Journal of the American Chemical Society 2015, 137, 1330–1335. https://doi.org/10.1021/ja512022r
  14. ^ P. S. Baran, K. M. Engle, et al., Nature 2014, 516, 343–348. https://doi.org/10.1038/nature14006
  15. ^ S. V. Pronin, J. M. Bauer, R. A. Shenvi, Journal of the American Chemical Society 2015, 137, 15410–15413. https://doi.org/10.1021/jacs.5b11129
  16. ^ S. H. Gao, X. Li, et al., Journal of the American Chemical Society 2019, 141, 16208–16215. https://doi.org/10.1021/jacs.9b08577
  17. ^ M. J. Krische, Y. Yoon, B. M. Trost, Accounts of Chemical Research 2004, 37, 653–661. https://doi.org/10.1021/ar020108e
  18. ^ D. Ma, H. Chen, et al., Angewandte Chemie International Edition 2018, 57, 6676–6680. https://doi.org/10.1002/anie.201803018
  19. ^ a b R. A. Shenvi, T. A. Davis, B. J. Simmons, Journal of the American Chemical Society 2014, 136, 16788–16791. https://doi.org/10.1021/ja5105602
  20. ^ M. J. Krische, M. Holmes, et al., Angewandte Chemie International Edition 2020, 59, 23169–23175. https://doi.org/10.1002/anie.202011363
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