Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jul 26;3(7):692-700.
doi: 10.1021/acscentsci.7b00212. Epub 2017 Jun 12.

Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes

Gregory C Fu  1
Affiliations
Review

Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes

Gregory C Fu. ACS Cent Sci. .

Abstract

Classical methods for achieving nucleophilic substitutions of alkyl electrophiles (SN1 and SN2) have limited scope and are not generally amenable to enantioselective variants that employ readily available racemic electrophiles. Radical-based pathways catalyzed by chiral transition-metal complexes provide an attractive approach to addressing these limitations.

PubMed Disclaimer

Conflict of interest statement

The author declares no competing financial interest.

Figures

Figure 1
Figure 1
Nucleophilic substitution reactions of alkyl electrophiles: SN1 and SN2 reactions.
Figure 2
Figure 2
Limitations of the SN1 reaction.
Figure 3
Figure 3
Limitations of the SN2 reaction.
Figure 4
Figure 4
Attributes of radicals as intermediates in substitution reactions.
Figure 5
Figure 5
Substitution reactions via radical intermediates (without a transition-metal catalyst).
Figure 6
Figure 6
Outline of a mechanism for palladium-catalyzed cross-couplings (nucleophilic substitutions) of aryl electrophiles.
Figure 7
Figure 7
Representative examples of nickel-catalyzed substitution reactions of unactivated secondary alkyl halides by organozinc, -boron, -silicon, and -tin nucleophiles.
Figure 8
Figure 8
Observations consistent with the intermediacy of an alkyl radical.
Figure 9
Figure 9
Nickel-catalyzed substitution reactions of unactivated tertiary alkyl halides by arylboron nucleophiles.
Figure 10
Figure 10
Enantioconvergent substitution reactions of activated electrophiles: Organozinc reagents as nucleophiles.
Figure 11
Figure 11
Applications of nickel-catalyzed enantioconvergent substitution reactions to the synthesis of natural products. The chiral catalyst controls the stereocenters indicated by the green balls and forms the bonds indicated by the wavy red lines.
Figure 12
Figure 12
Enantioconvergent substitution reactions of activated electrophiles: Other families of organometallic nucleophiles.
Figure 13
Figure 13
Enantioconvergent substitution reactions of unactivated electrophiles: Alkylboron reagents as nucleophiles.
Figure 14
Figure 14
Nickel-catalyzed substitution reactions of unactivated secondary and tertiary alkyl halides by boron and silicon nucleophiles.
See this image and copyright information in PMC

References

    1. Hartshorn S. R.Aliphatic Nucleophilic Substitution; Cambridge University Press: London, 1973.
    1. Anslyn E. V.; Dougherty D. A.. Substitutions at Aliphatic Centers and Thermal Isomerizations/Rearrangements. Modern Physical Organic Chemistry; University Science Books: Sausalito, CA, 2006; Chapter 11.
    1. For examples of interesting exceptions (albeit with limited scope with respect to the nucleophile and the electrophile), see:Reisman S. E.; Doyle A. G.; Jacobsen E. N. Enantioselective Thiourea-Catalyzed Additions to Oxocarbenium Ions. J. Am. Chem. Soc. 2008, 130, 7198–7199. 10.1021/ja801514m. - DOI - PMC - PubMed
    1. Lee S.; Kaib P. S. J.; List B. Asymmetric Catalysis via Cyclic, Aliphatic Oxocarbenium Ions. J. Am. Chem. Soc. 2017, 139, 2156–2159. 10.1021/jacs.6b11993. - DOI - PubMed
    1. Encyclopedia of Radicals in Chemistry, Biology and Materials; Chatgilialoglu C., Studer A., Eds.; John Wiley & Sons, Chichester, U.K., 2012; Vols. 1 and 2.