Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Inducing and quantifying forbidden reactivity with single-molecule polymer mechanochemistry


Forbidden reactions, such as those that violate orbital symmetry effects as captured in the Woodward–Hoffmann rules, remain an ongoing challenge for experimental characterization, because when the competing allowed pathway is available the reactions are intrinsically difficult to trigger. Recent developments in covalent mechanochemistry have opened the door to activating otherwise inaccessible reactions. Here we report single-molecule force spectroscopy studies of three mechanically induced reactions along both their symmetry-allowed and symmetry-forbidden pathways, which enables us to quantify just how ‘forbidden’ each reaction is. To induce reactions on the ~0.1 s timescale of the experiments, the forbidden ring-opening reactions of benzocyclobutene, gem-difluorocyclopropane and gem-dichlorocyclopropane require approximately 130 pN less, 560 pN more and 1,000 pN more force, respectively, than their corresponding allowed analogues. The results provide the first experimental benchmarks for mechanically induced forbidden reactions, and in some cases suggest revisions to prior computational predictions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Disrotatory and conrotatory pathways of three mechanically activated reactions studied in this work.
Figure 2: Polymers employed in this work.
Figure 3: Representative plateaus in the force–separation curves of BCB-containing polymers.
Figure 4: Representative plateaus in the force–separation curves of gDHC-containing polymers.


  1. Woodward, R. B. & Hoffmann, R. Conservation of orbital symmetry. Angew. Chem. Int. Ed. Engl. 8, 781–853 (1969).

    Article  CAS  Google Scholar 

  2. Houk, K. N., Li, Y. & Evanseck, J. D. Transition structures of hydrocarbon pericyclic reactions. Angew. Chem. Int. Ed. Engl. 31, 682–708 (1992).

    Article  Google Scholar 

  3. Baldwin, J. E., Andrist, A. H. & Pinschmi, R. K. Orbital-symmetry disallowed energetically concerted reactions. Acc. Chem. Res. 5, 402–406 (1972).

    Article  CAS  Google Scholar 

  4. Brauman, J. I. & Archie, W. C. Energies of alternate electrocyclic pathways—pyrolysis of cis-3,4-dimethylcyclobutene. J. Am. Chem. Soc. 94, 4262–4265 (1972).

    Article  Google Scholar 

  5. Hickenboth, C. R. et al. Biasing reaction pathways with mechanical force. Nature 446, 423–427 (2007).

    Article  CAS  Google Scholar 

  6. Lenhardt, J. M., Black, A. L. & Craig, S. L. gem-dichlorocyclopropanes as abundant and efficient mechanophores in polybutadiene copolymers under mechanical stress. J. Am. Chem. Soc. 131, 10818–10819 (2009).

    Article  CAS  Google Scholar 

  7. Lenhardt, J. M. et al. Trapping a diradical transition state by mechanochemical polymer extension. Science 329, 1057–1060 (2010).

    Article  CAS  Google Scholar 

  8. Klukovich, H. M. et al. Tension trapping of carbonyl ylides facilitated by a change in polymer backbone. J. Am. Chem. Soc. 134, 9577–9580 (2012).

    Article  CAS  Google Scholar 

  9. Ong, M. T., Leiding, J., Tao, H. L., Virshup, A. M. & Martinez, T. J. First principles dynamics and minimum energy pathways for mechanochemical ring opening of cyclobutene. J. Am. Chem. Soc. 131, 6377–6379 (2009).

    Article  CAS  Google Scholar 

  10. Ribas-Arino, J., Shiga, M. & Marx, D. Understanding covalent mechanochemistry. Angew. Chem. Int. Ed. 48, 4190–4193 (2009).

    Article  CAS  Google Scholar 

  11. Kochhar, G. S., Bailey, A. & Mosey, N. J. Competition between orbitals and stress in mechanochemistry. Angew. Chem. Int. Ed. 49, 7452–7455 (2010).

    Article  CAS  Google Scholar 

  12. Wiita, A. P., Ainavarapu, R. K., Huang, H. H. & Fernandez, J. M. Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques. Proc. Natl Acad. Sci. USA 103, 7222–7227 (2006).

    Article  CAS  Google Scholar 

  13. Wu, D., Lenhardt, J. M., Black, A. L., Akhremitchev, B. B. & Craig, S. L. Molecular stress relief through a force-induced irreversible extension in polymer contour length. J. Am. Chem. Soc. 132, 15936–15938 (2010).

    Article  CAS  Google Scholar 

  14. Klukovich, H. M., Kouznetsova, T. B., Kean, Z. S., Lenhardt, J. M. & Craig, S. L. A backbone lever-arm effect enhances polymer mechanochemistry. Nature Chem. 5, 110–114 (2013).

    Article  CAS  Google Scholar 

  15. Roth, W. R., Rekowski, V., Borner, S. & Quast, M. Forbidden reactions. 2. The disrotatory cyclobutene ring opening. Liebigs Ann. 409–430 (1996).

  16. Getty, S. J., Hrovat, D. A. & Borden, W. T. Ab-initio calculations on the stereomutation of 1,1-difluorocyclopropane—prediction of a substantial preference for coupled disrotation of the methylene groups. J. Am. Chem. Soc. 116, 1521–1527 (1994).

    Article  CAS  Google Scholar 

  17. Tian, F., Lewis, S. B., Bartberger, M. D., Dolbier, W. R. & Borden, W. T. Experimental study of the stereomutation of 1,1-difluoro-2-ethyl-3-methylcyclopropane confirms the predicted preference for disrotatory ring opening and closure. J. Am. Chem. Soc. 120, 6187–6188 (1998).

    Article  CAS  Google Scholar 

  18. Dopieralski, P., Ribas-Arino, J. & Marx, D. Force-transformed free-energy surfaces and trajectory-shooting simulations reveal the mechano-stereochemistry of cyclopropane ring-opening reactions. Angew. Chem. Int. Ed. 50, 7105–7108 (2011).

    Article  CAS  Google Scholar 

  19. Parham, W. E. & Yong, K. S. Steric effects in the solvolysis of cis- and trans-1,1-dichloro-2,3-dipropylcyclopropane. J. Org. Chem. 33, 3947–3948 (1968).

    Article  CAS  Google Scholar 

  20. Marszalek, P. E., Oberhauser, A. F., Pang, Y-P. & Fernandez, J. M. Polysaccharide elasticity governed by chair-boat transitions of the glucopyranose ring. Nature 396, 661–664 (1998).

    Article  CAS  Google Scholar 

  21. Ribas-Arino, J., Shiga, M. & Marx, D. Unravelling the mechanism of force-induced ring-opening of benzocyclobutenes. Chem. Eur. J. 15, 13331–13335 (2009).

    Article  CAS  Google Scholar 

  22. Roth, W. R. et al. Energy profile of ortho-quinodimethane–benzocyclobutene equilibrium. Chem. Ber. 111, 3892–3903 (1978).

    Article  CAS  Google Scholar 

  23. Lenhardt, J. M. et al. Reactive cross-talk between adjacent tension-trapped transition states. J. Am. Chem. Soc. 133, 3222–3225 (2011).

    Article  CAS  Google Scholar 

  24. Hummer, G. & Szabo, A. Kinetics from nonequilibrium single-molecule pulling experiments. Biophys. J. 85, 5–15 (2003).

    Article  CAS  Google Scholar 

  25. Getty, S. J., Hrovat, D. A., Xu, J. D., Barker, S. A. & Borden, W. T. Potential surfaces for cyclopropane stereomutations—what a difference geminal fluorines make. J. Chem. Soc. Faraday Trans. 90, 1689–1701 (1994).

    Article  CAS  Google Scholar 

  26. Liang, J. & Fernandez, J. M. Mechanochemistry: one bond at a time. ACS Nano 3, 1628–1645 (2009).

    Article  CAS  Google Scholar 

  27. Tian, Y. C., Kucharski, T. J., Yang, Q. Z. & Boulatov, R. Model studies of force-dependent kinetics of multi-barrier reactions. Nature Commun. 4, 2538 (2013).

    Article  Google Scholar 

  28. Yang, Q-Z. et al. A molecular force probe. Nature Nanotech. 4, 302–306 (2009).

    Article  CAS  Google Scholar 

  29. Boulatov, R. Reaction dynamics in the formidable gap. Pure Appl. Chem. 83, 25–41 (2011).

    Article  CAS  Google Scholar 

  30. Grandbois, M., Beyer, M., Rief, M., Clausen-Schaumann, H. & Gaub, H. E. How strong is a covalent bond? Science 283, 1727–1730 (1999).

    Article  CAS  Google Scholar 

Download references


This material is based on work supported by the US Army Research Laboratory and the US Army Research Office under grant W911NF-12-1-0337. S.L.C. acknowledges partial support from the National Science Foundation Materials Interdisciplinary Research Teams (DMR-1122483). Part of this work was performed under the auspices of the US Department of Energy by the Lawrence Livermore National Laboratory under Contract DE-ACS2-07NA27344. The authors thank B. Akhremitchev for providing the original force-extension modelling code.

Author information

Authors and Affiliations



J.W. and S.L.C. conceived and designed the experiments. J.W. and H.M.K. performed the synthesis. T.B.K. collected the AFM data. Z.N. and A.L.R. performed the crystallography. M.T.O. and T.J.M. performed the calculations of the transition states. J.W. and S.L.C. analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Stephen L. Craig.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 2995 kb)

Supplementary information

Crystallographic data for compound 4. (CIF 18 kb)

Supplementary information

Crystallographic data for compound 7. (CIF 898 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Kouznetsova, T., Niu, Z. et al. Inducing and quantifying forbidden reactivity with single-molecule polymer mechanochemistry. Nature Chem 7, 323–327 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing