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
. 2025 Jun 27;90(25):8445-8456.
doi: 10.1021/acs.joc.5c00517. Epub 2025 Jun 16.

Nonradical Reactions of p-Benzyne Diradicals

Charles L Perrin  1
Affiliations
Review

Nonradical Reactions of p-Benzyne Diradicals

Charles L Perrin. J Org Chem. .

Abstract

Enediynes undergo electrocyclization to p-benzyne diradicals. Although such diradicals ordinarily react by radical pathways, they can also be trapped by nucleophilic addition, a pathway supported by computations. The product of that addition is a "naked" aryl anion that is unselective toward protonation. A cyclohexeno-substituted enediyne was synthesized and found to be more amenable to further derivatization and mechanistic study. Moreover, it was shown to undergo automerization, rearrangement to a degenerate form of the original enediyne.

PubMed Disclaimer

Figures

1
1. Proposed Mechanism for Haloaromatic Formation via Halide Addition to a p-Benzyne Diradical 7 Derived from Enediyne 6
1
1
ln­[6] vs time for reaction of 6 with LiBr under various initial conditions (Reproduced from J. Am. Chem. Soc. 2007, 129, 4795. Copyright 2007 American Chemical Society).
2
2. Detailed Mechanism of Halide Addition to p-Benzyne 10
2
2
Calculated energies for reaction of Cl– with p-benzyne diradical 10: (a) UBPW91/6-311G+(d,p) gas phase. (b) UBPW91/6-31+G­(d) in DMSO (Reproduced with permission from J. Phys. Org. Chem., 2013, 26, 206. Copyright 2012 John Wiley & Sons, Ltd).
3
3
Orbital-correlation diagrams for Ar· + X– and for p-benzyne + X– (Reproduced with permission from J. Phys. Org. Chem., 2013, 26, 206. Copyright 2012 John Wiley & Sons, Ltd).
3
3. Formation and Hydronation of a “Naked” Aryl Anion
4
4. Cycloaromatization of 3,4-Cyclohexenocyclodec-3-ene-1,5-diyne (16) and Nucleophilic Capture of Diradical 17 by I– and Acid
5
5. Reaction of Enolates (a–e, 50-fold excess) in DMSO with p-Benzyne Diradicals Derived from Enediynes 6 (RR = HH), 14 (RR = (CH)4), and 16 (RR = (CH2)4)
6
6. Automerization of 3,4-Cyclohexenocyclodec-3-ene-1,5-diyne (16) to 17
7
7. Automerization of cis-l,5-hexadiyn-3-ene (23)
8
8. Cycloaromatization of 3,4-Cyclohexenocyclodec-3-ene-1,5-diyne (16) and Capture by Nucleophile Nu– (Nu = I, Br, CN, SCN) and Acid
4
4
1H NMR spectrum of 3,4-cyclohexenocyclodec-3-ene-1,5-diyne (16) before heating with LiI in DMSO-d 6. Signals appear at δ 10.19 (br s, acetic acid), δ 7.37 (s, benzene), δ 3.229 (m, trace diiodobutane), δ 2.448 (m, CH2 of 16), δ 2.263 (m, CH2 of 16), δ 2.12 (s, acetic acid), δ 2.003 (m, trace diiodobutane), δ 1.757 (m, CH2 of 16), δ 1.601 (m, CH2 of 16), δ 0 (s, TMS). (Reproduced from J. Org. Chem. 2025, 90, 3809. Copyright 2025 American Chemical Society).
5
5
1H NMR spectrum of 3,4-cyclohexenocyclodec-3-ene-1,5-diyne (16) after heating with LiI in DMSO-d 6 at 75 C for 6 h (Reproduced from J. Org. Chem. 2025, 90, 3809. Copyright 2025 American Chemical Society).
6
6
1H NMR spectrum of 3,4-cyclohexenocyclodec-3-ene-1,5-diyne (16) after heating with NaNO3 in DMSO-d 6 at 75 C for 6 h. Signals persist at δ 11.2 (acetic acid), δ 7.274 (benzene), δ 3.229 (trace diiodobutane), δ 2.446 (CH2 of 16), δ 2.158 (CH2 of 16), δ 2.103 (acetic acid), δ 2.008 (trace diiodobutane), δ 1.751 (CH2 of 16), δ 1.602 (CH2 of 16), δ 0 (TMS) (Reproduced from J. Org. Chem. 2025, 90, 3809. Copyright 2025 American Chemical Society).
7
7
Expansions of CH2 regions of 1H NMR spectra of 3,4-cyclohexenocyclodec-3-ene-1,5-diyne (16) before and after heating with NaNO3 in DMSO-d 6 at 75 C for 6 h (adapted from Figures and ).
9
9. Automerization of 3,4-Cyclohexenocyclodec-3-ene-1,5-diyne (16) to 17
See this image and copyright information in PMC

References

    1. Oh D.-C., Williams P. G., Kauffman C. A., Jensen P. R., Fenical W.. Cyanosporasides A and B, Chloro- and Cyano-cyclopenta­[a]­indene Glycosides from the Marine Actinomycete “Salinispora pacifica”. Org. Lett. 2006;8:1021–1024. doi: 10.1021/ol052686b. - DOI - PubMed
    1. Jensen P. R., Moore B. S., Fenical W.. The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery. Nat. Prod. Rep. 2015;32:738–751. doi: 10.1039/C4NP00167B. - DOI - PMC - PubMed
    1. Abe M.. Diradicals. Chem. Rev. 2013;113:7011–7088. doi: 10.1021/cr400056a. - DOI - PubMed
    2. Wenk H. H., Winkler M., Sander W.. One Century of Aryne Chemistry. Angew. Chem., Int. Ed. 2003;42:502–528. doi: 10.1002/anie.200390151. - DOI - PubMed
    3. Clark A. E., Davidson E. R.. Model Studies of Hydrogen Atom Addition and Abstraction Processes Involving ortho-, meta-, and para-Benzyne. J. Am. Chem. Soc. 2001;123:10691–10698. doi: 10.1021/ja0159620. - DOI - PubMed
    1. Perrin C. L., Agranat I., Bagno A., Braslavsky S. E., Fernandes P. A., Gal J.-F., Lloyd-Jones G. C., Mayr H., Murdoch J. R., Nudelman N. S., Radom L., Rappoport Z., Ruasse M.-F., Siehl H.-U., Takeuchi Y., Tidwell T. T., Uggerud E., Williams I. H.. Glossary of Terms Used in Physical Organic Chemistry (IUPAC Recommendations 2021) Pure Appl. Chem. 2022;94:353–534. doi: 10.1515/pac-2018-1010. - DOI
    1. Smith A. L., Nicolaou K. C.. The Enediyne Antibiotics. J. Med. Chem. 1996;39:2103–2117. doi: 10.1021/jm9600398. - DOI - PubMed

LinkOut - more resources