Chemistry inside molecular containers in the gas phase

Journal name:
Nature Chemistry
Year published:
Published online


Inner-phase chemical reactions of guest molecules encapsulated in a macromolecular cavity give fundamental insight into the relative stabilization of transition states by the surrounding walls of the host, thereby modelling the situation of substrates in enzymatic binding pockets. Although in solution several examples of inner-phase reactions are known, the use of cucurbiturils as macrocyclic hosts and bicyclic azoalkanes as guests has now enabled a systematic mass spectrometric investigation of inner-phase reactions in the gas phase, where typically the supply of thermal energy results in dissociation of the supramolecular host–guest assembly. The results reveal a sensitive interplay in which attractive and repulsive van der Waals interactions between the differently sized hosts and guests need to be balanced with a constrictive binding to allow thermally activated chemical reactions to compete with dissociation. The results are important for the understanding of supramolecular reactivity and have implications for catalysis.

At a glance


  1. Chemical structures of the hosts (CBn, n = 6–8) and guests (azoalkanes 1–3) investigated in this study.
    Figure 1: Chemical structures of the hosts (CBn, n = 6–8) and guests (azoalkanes 13) investigated in this study.
  2. Reaction and dissociation pathways of the inclusion complexes of the bicyclic azoalkanes 1–3 with CBn (n = 6–8) in CID experiments.
    Figure 2: Reaction and dissociation pathways of the inclusion complexes of the bicyclic azoalkanes 13 with CBn (n = 6–8) in CID experiments.

    a, For azoalkane 1, the CB7 complex eliminates ethylene as the major pathway, followed by the dissociation of the retro-Diels–Alder reaction product (pyrazole) complex. For the more tightly packed complex with CB6 and the more loosely packed complex with CB8, dissociation becomes the major pathway (dashed arrows indicate the minor of the two competing pathways). b, For azoalkane 2, no complex was observed with CB6. The major pathway for the CB7 complex is elimination of ethylene and then hydrogen cyanide, followed by dissociation of the complex with the secondary product (propenimine). The CB8 complex reacts similarly, with a slightly lower preference for inner-phase reaction than that observed for CB7 (see Table 1). c, For azoalkane 3, no complex was observed with CB6 either, and the CB7 and CB8 complexes predominantly undergo direct dissociation. As a minor pathway, the CB7 complex eliminates a C4H7N fragment and the CB8 complex eliminates ethylene (at a larger collision energy, see Table 1), in both cases followed by dissociation of the product complexes. For CID mass spectra, structural assignments and fragmentation mechanisms, see Supplementary Figs S8–S13, Table S15 and Section S4.

  3. Geometry-optimized molecular structures (HF/6-31G* level of theory) of [CB7 · 2 · H]+ complexes.
    Figure 3: Geometry-optimized molecular structures (HF/6-31G* level of theory) of [CB7 · 2 · H]+ complexes.

    a,b, Side views (top) and top views (bottom) of the inclusion (a) and the exclusion (b) complex between CB7 and the azoalkane 2. Ab initio (for example, HF/6-31G*) and DFT (for example, B3LYP/6-311++G**) calculations predict the exclusion complex to be up to 18 kcal mol−1 more stable than the inclusion one. However, advanced methods, which consider dispersion interactions as well, namely wB97XD/6-31++G** and MP2/6-31G*, predict the inclusion complex to be more stable by 1–2 kcal mol−1 (Supplementary Table S3). The two types of complexes can be discriminated experimentally through their cross-sections. As becomes obvious from the side view of (a), the [CB7 · 2 · H]+ inclusion complex should have a cross-section comparable to that of [CB7 · H]+, which is observed by ion-mobility measurements (see text and Fig. 4). In contrast, the exclusion complex has a significantly larger cross-section (side view of (b)) and no experimental evidence was obtained for its existence in the course of this study.

  4. Ion mobilograms.
    Figure 4: Ion mobilograms.

    a, [CB7 · H]+. b, [CB7 · 2 · H]+. ce, Product ions after CID of the [CB7 · 2 · H]+ complex. The corresponding chemical structures are shown on the right. The cross-section scale (top) was approximated from the calculated cross-sections for regular and inverted CB7, assuming a linear correlation with drift time (Supplementary Information). The relative differences in drift times (maxima) are experimentally significant within ± 0.07 ms. The peak with a 9.84 ms drift time in (a) and (e) was identified as being caused by inverted CB7, which forms under the CID conditions from (regular) protonated CB7 in the absence of an included guest. The propensity for inversion of CBs in the gas phase will be investigated separately.

  5. Model potentials for the interaction of a spherical guest positioned centrosymmetrically inside a host cavity versus guest volume.
    Figure 5: Model potentials for the interaction of a spherical guest positioned centrosymmetrically inside a host cavity versus guest volume.

    a, Illustration of the hypothetical expansion of a spherical guest inside a CBn cavity, as a mimic of a chemical reaction with a positive volume of activation. b, Relative potential energies (Erelpot) of the CB6 (solid), CB7 (dashed) and CB8 (dotted) complexes versus guest volume, modelled with a 12-6 Lennard-Jones function (Supplementary Section S2). c, Magnified area of (b) with interval bars for the volumes that correspond to guests 1 (red), 2 (blue) and 3 (orange) as they expand to the corresponding fragment and ethylene; the arrows indicate the change in intermolecular potential energy as the intramolecular reaction proceeds.


6 compounds View all compounds
  1. 2,3-Diazabicyclo[2.2.1]hept-2-ene
    Compound 1 2,3-Diazabicyclo[2.2.1]hept-2-ene
  2. 2,3-Diazabicyclo[2.2.2]oct-2-ene
    Compound 2 2,3-Diazabicyclo[2.2.2]oct-2-ene
  3. 6,7-Diazabicyclo[3.2.2]non-6-ene
    Compound 3 6,7-Diazabicyclo[3.2.2]non-6-ene
  4. Cucurbit[6]uril
    Compound CB6 Cucurbit[6]uril
  5. Cucurbit[7]uril
    Compound CB7 Cucurbit[7]uril
  6. Cucurbit[8]uril
    Compound CB8 Cucurbit[8]uril


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Author information


  1. Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK

    • Tung-Chun Lee &
    • Oren A. Scherman
  2. Department of Chemistry, University of Jyväskylä, Survontie 9, 40500 Jyväskylä, Finland

    • Elina Kalenius
  3. School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany

    • Alexandra I. Lazar,
    • Khaleel I. Assaf,
    • Nikolai Kuhnert &
    • Werner M. Nau
  4. Unilever R&D Vlaardingen, Olivier van Noortlaan 120, 3133 AT Vlaardingen, The Netherlands

    • Christian H. Grün
  5. Department of Chemistry, University of Eastern Finland, Joensuu Campus, Yliopistokatu 7, 80100 Joensuu, Finland

    • Janne Jänis


T-C.L. initiated this project with E.K., O.A.S. and W.M.N. The manuscript was co-written by T-C.L., A.I.L. and W.M.N. and commented on by all the authors. All mass spectrometry experiments were conducted by E.K. and A.I.L. in the laboratories of J.J. and N.K., and C.H.G. conducted the ion-mobility experiments. K.I.A. performed the quantum-chemical and cross-section calculations. W.M.N. and A.I.L. analysed the data in terms of the model potentials. The student authors T-C.L. and A.I.L. contributed equally.

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