chemistry inside molecular containers in the gas phase

5/24/2018 Chemistry Inside Molecular Containers in the Gas Phase

WATER ELECTROLYSISA split in the camp

PREBIOTIC CHEMISTRYMaking the right connections

PHASE TRANSITIONS

Nanocrystals under the microscope

Weighing upchemistryinside containers

MAY 2013 VOL 5 NO 5www.nature.com/naturechemistry


Chemistry inside molecular containers in the

gas phaseTung-Chun Lee1, Elina Kalenius2*, Alexandra I. Lazar3, Khaleel I. Assaf3, Nikolai Kuhnert3,Christian H. Grun4, Janne Janis5, Oren A. Scherman1 and Werner M. Nau3*

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

It is well established that the reversible complexation of guests bysupramolecular hosts affects their chemical reactivity in sol-ution13, and so affords impressive examples of supramolecular

catalysis and, in the case of reactions inside concave hosts,enzyme-mimetic activity410. This situation is different in the gasphase where the supply of thermal energy favours irreversibledissociation of the hostguest complexes rather than chemical reac-tions of the encapsulated guests1113. Although precedents for gas-phase reactivity of hostguest complexes exist1427, inner-phasereactions that involve chemical conversions of guests inside amacrocyclic cavity have, until now, been limited to the solutionphase28. Irreversibly bound guests inside hemicarcerands serve as

particularly instructive examples of inner-phase reactions in sol-ution29,30. For example, studies of diazirines in hemicarcerandsrevealed the importance of dispersion interactions in stabilizingtransition states and accelerating deazatization29,30, although theelimination of SO

2from 3-sulfolene inside an asymmetric carcerand

was slower than that from the non-encapsulated guest15. We havenow investigated hostguest inclusion complexes between cucur-bit[n]urils (CBn, n 68) and the bicyclic azoalkanes 13(Fig. 1) by mass spectrometry, and document here several examplesof thermally activated, selective retro-DielsAlder reactions in thegas phase. We observed an interesting reactivity pattern, in whichthe cycloelimination inside the cavity became dominant when thepacking coefficients (PCs) of the complexes fell within a narrowrange of 3050%. A combination of constrictive binding and voidspace emerged as an important structurereactivity relationship,in which the irreversible dissociation generally prevailed overcycloelimination when the packing was either too loose or too tight.

Among macrocyclic hosts, CBs stand out due to their high rigid-ity, thermal stability and high-affinity binding3134. The structure oftheir inclusion complexes is determined by a hydrophobic innercavity and two tighter portal regions with cation-receptor proper-ties. Complementing examples of solution-phase reactions ofguests encapsulated in cyclodextrins and calixarenes, several

examples of chemoselective and, in part, catalytic reactions insideCBs in water are already available3438. We now describe gas-phasecycloelimination reactions of encapsulated guests, namely water-soluble bicyclic azoalkanes. Their small size allows a completeimmersion inside the cavities of several CBs, which is accompaniedby large binding constants, on the order of 103107 M21, fortheCB7 complexes in water37,39,40. Azoalkanes act as weak bases41

and weak ligands37,41, which facilitates, in combination withthe cation-receptor properties of CBs themselves, the observationof positively charged hostguest complexes by massspectrometric methods.

ResultsAqueous solutions that contained both CB7 and azoalkanes 13showed mass spectrometry peaks of the corresponding[CB7 .azoalkane.H] and [CB7 . azoalkane.Na] complexes.When the latter complexes were isolated and investigated by col-lision-induced dissociation (CID) experiments, thermal activationled to the formation of [CB7 .Na], which indicates the convention-al dissociation of the hostguest complex (Supplementary Fig. S7).Surprisingly, however, CID experiments with the former complexesnot only affected dissociation, but also the formation of new com-plexes that consisted ofCB7 and a reaction product from the azo-alkane (Supplementary Figs S8S13). This provided evidence of afragmentation reaction of the guest inside the cavity while maintain-ing the supramolecular assembly. When the initially produced[CB7 . fragment.H] complexes were further subjected to CID, sec-ondary reactions through multiple reaction intermediates occurredfor the complexes of azoalkane 2, which led to [CB7 .H] only atthe end of a reaction cascade.

The combined results for the different azoalkanes13are sum-marized inFig. 2. Evidently, but unexpectedly, in several cases intra-molecular (covalent) bond cleavage competes very efficiently withthe intermolecular (non-covalent) one. For the protonated CB7complex of azoalkane 1, thermal activation led to elimination of

1Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK, 2Department ofChemistry, University of Jyvaskyla, Survontie 9, 40500 Jyvaskyla, Finland, 3School of Engineering and Science, Jacobs University Bremen, Campus Ring 1,D-28759 Bremen, Germany, 4 Unilever R&D Vlaardingen, Olivier van Noortlaan 120, 3133 AT Vlaardingen, The Netherlands, 5Department of Chemistry,University of Eastern Finland, Joensuu Campus, Yliopistokatu 7, 80100 Joensuu, Finland.*e-mail: [email protected];[email protected]

ARTICLESPUBLISHED ONLINE: 7 APRIL 2013 |DOI: 10.1038/NCHEM.1618

NATURE CHEMISTRY| VOL 5 | MAY 2013 | www.nature.com/naturechemistry376
http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1mailto:[email protected]:[email protected]://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/naturechemistryhttp://www.nature.com/naturechemistryhttp://www.nature.com/doifinder/10.1038/nchem.1618mailto:[email protected]:[email protected]://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1


ethylene and subsequent dissociation of the intermediary pyrazolecomplex. This reaction became a minor pathway, however, wheneither a smaller host with a more tight packing (CB6) or a largerone with a more loose packing (CB8) was selected. Specifically,the inner-phase reaction efficiencies at a particular collisionenergy (f

rvalues near centre-of-mass collision energies (E

com) of

5 eV,Table 1) for the complexes of azoalkane 1 with CB6(0.04)and CB8 (0.37) were significantly smaller than that with themedium-sizedCB7 (0.62) (Supplementary Figs S8, S12 and S13).To ease discussion, we assign reaction efficiencies that are largerand smaller than 0.5 to be predominantly inner-phase reactionsand dissociations, respectively. Strictly speaking, the f

rvalues are

lower limits, because a fraction of the observed [CBn .H] stemsfrom dissociation of the product rather than the reactant complexes,even at low collision energies.

For azoalkane2, CID of the protonated CB7 complex led to therichest gas-phase chemistry, namely a sequential elimination of firstethylene and then hydrogen cyanide, the latter presumably after a

1,3-H shift. Following this two-step reaction cascade, the encapsu-lated secondary product (assigned as propenimine) did notfurther fragment, but its complex with CB7 dissociated. Althoughprotonated CB7 was detected as a dissociation product from thecorresponding complex of 2, its abundance was substantially lessthan that of both fragment complexes at low collision energies,which resulted in a large f

r value of 0.69 (Supplementary

Figs S8S11). Azoalkane 2 is too large to form an inclusioncomplex with CB631,39 and no complexes were observed in thiscase, which furbishes an important piece of evidence that the obser-vable complexes are not of the exclusion type (see below). Thecomplex of 2 with the larger CB8 required, however, a muchlarger collision energy (7.5 eV E

com) to afford sizable amounts

of fragmentation and dissociation products (fr 0.63) than that

with CB7 (Supplementary Fig. S13 and Section S5.2).For azoalkane3, no complex was formed with the smallest host,

CB6, either, but the protonatedCB7 complex underwent predomi-nantly direct dissociation, with only a small amount of eliminationof a C

4H

7N fragment (f

r 0.19), which very probably also entailed

an initial ethylene extrusion (Supplementary Section S4). In thecomplex with the largest host, CB8, azoalkane 3 suffered elimin-ation of ethylene only at a larger energy (f

r 0.17 at 7.5 eV

Ecom

), followed by dissociation of the intermediary complex.Numerous control experiments were performed to verify the

reaction pathways presented in Fig. 2. The loss of ethylene asopposed to molecular dinitrogen, which is commonly encounteredin the thermal deazatization of unprotonated azoalkanes42,43, wasverified by Fourier transform ion cyclotron resonance (FT-ICR)mass spectrometry accurate mass determination experiments

(Supplementary Tables S9 and S10). The same method also con-firmed that, on CID, the [CB7 .2 .H] complex did not yield[2 .H] (and neutral CB7) as the alternative dissociation pathway(Supplementary Fig. S8), a result that is fully in line with thelarger calculated proton affinities of CBs versus those of the azoalk-anes (Supplementary Table S11). CID experiments with the com-plexed and free azoalkanes 13 demonstrated further that N

2H

is not a fragmentation product (Supplementary Figs S9 and S16).

Most of the observed reactions in Fig. 2 are retro-DielsAlderreactions, which are common fragmentation pathways in mass spec-trometry44. DielsAlder reactions to produce or revert bicyclicazoalkanes are known to require the protonation of the azogroup42,43. The importance of the proton to catalyse the observedcycloelimination reactions could be deduced from CID experimentswith the corresponding sodium adducts of the azoalkane complexes(see above), which did not afford any evidence for inner-phase reac-tions. We therefore assign the chemical reactions of the complexesbetween CBn and 13 to the encapsulated protonated azoalkaneinside the CBn rather than to the encapsulated azoalkane insidethe protonated CBn. Indeed, although the proton affinities of freeCBs are higher than those of free azoalkanes 13, the complexeswith the protonated azoalkanes are energetically much morefavoured (for example, 283.1 kcal mol21 for CB7 . [2 .H] versus

232.6 kcal mol21 for [CB7 .H] .2, Supplementary Table S4)

because of additional iondipole interactions with the CBnportals and the protonated guest. The gas-phase reactions deter-mined for the protonated CBncomplexes of azoalkanes 13werealso observed for the uncomplexed protonated azoalkanes(Supplementary Information), which demonstrates that the samereactive molecular species are involved.

To conclude rigorously that the reactions took place in the innerphase, we needed to rule out the involvement of exclusion com-plexes, in which the protonated azo group could be associated elec-trostatically with one carbonyl rim and the bicyclic organic residuewould remain outside the inner cavity (Fig. 3b)45. Althoughinclusion complexes of azoalkanes 13 with CBs were establishedrigorously in aqueous solution, for example, by characteristic

upfield 1

H NMR shifts37,39

, the hydrophobic driving force forinclusion31,32,40 is absent in the gas phase. The relative complex stab-ility, inclusion versus exclusion, in the gas phase would conse-quently need to derive from differential dispersion interactions,which, although much smaller than those for hemicarcerands2931,would be maximized for the inclusion complex. Indeed, when thegeometries of the protonated inclusion and exclusion complexeswere optimized at the HF/6-31G* level of theory (Fig. 3), energy cal-culations withab initio(for example, HF/6-31G*) or density func-tional theory (DFT, for example, B3LYP/6-311G**) methods

O

N

N

N

N

O

O

N

N

N

N

O

O

N

N

N

N

O

O

N

N

N

N

N

N

O

O

N

N

N

N

O

N

N

O

On

Cucurbit[n]uril

CB6(n= 1)CB7(n= 2)CB8(n= 3)

NN

NN

NN

1 2 3

Figure 1 | Chemical structures of the hosts (CBn, n 5 68) and guests

(azoalkanes13) investigated in this study.

Table 1 | Packing coefficients (PCs), calculated activationenergies and inner-phase reaction efficiencies for theuncomplexed protonated guests.

Guest EA(kcalmol21)

HostCB6 CB7 CB8

PC (%) fr

PC (%) fr

PC (%) fr

1 27.6 68% 0.04 40% 0.62 26% 0.372 35.8 78% n/a 46% 0.69 30% 0.03 38.1 89% n/a 52% 0.19 34% 0.0

PCs were obtained by dividing the volume of the neutral guests (Supplementary Table S10) by theinner cavity volume of the host cavity (142 3 for CB6, 242 3 for CB7 and 367 3 for CB8),neglecting the minor influence (+1 3) of the proton. The frvalues (at approximately 5 eV Ecom(Supplementary Section S5.2)) were calculated as the ratio of the sum of the m/z peakintensities of all fragmented complexes and the sum of the m/z peak intensities of both thefragmented and dissociated complexes observed. The activation energies of the uncomplexedguests (EA) were determined at the B3LYP/6-311G** level of theory. For the [CB8.2 .H]

and[CB8.3 .H] complexes, fr could not be determined at 5 eV because of negligible fragmentabundances. The fr values of [CB8. 2 .H]

and [CB8.3 .H] near 7.5 eV Ecom were 0.63 and0.17, respectively. n/a, not applicable.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1618 ARTICLES

NATURE CHEMISTRY| VOL 5 | MAY 2013 | www.nature.com/naturechemistry 377
http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/naturechemistryhttp://www.nature.com/naturechemistryhttp://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature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predicted the exclusion complex betweenCB7and [2 .H] (selectedas a representative case) to be 18 kcal mol21 more stable than theinclusion complex; only advanced methods that encode empirically(wB97XD/6-31G**) or explicitly (MP2/6-31G*) for dispersioninteractions predict theCB7inclusion complex of2to be distinctlymore stable than the exclusion counterpart (by 12 kcal mol21, seeSupplementary Table S3).

Experimentally, exclusion complexes, as they would need to bepostulated for azoalkanes2and3with CB6 on the basis of size argu-ments31,39, did not afford any detectable mass spectrometry signals,which suggests that these are too labile to be observable under our

electrospray ionization (ESI) conditions. More definitively, ion-mobility experiments (Fig. 4) revealed that the [CB7 .2 .H]

complex has the same drift time (11.25+0.07 ms) and consequentlythe same collision cross-section (185 2) asCB7itself. This resultcan only be accounted for by assuming a deep immersion of2insidethe cavity. Exclusion complexes between guests and CBs woulddisplay larger collision cross-sections with significantly longerdrift times (for example, 195 2 for [CB7 .2 .H])22. Gratifyingto observe, on dissociation of the final fragment (propenimine),the emptyCB7 cage recovered back to its original collision cross-section, as expected (Fig. 4e).

C2H

4

[CB73H]+

[CB83H]+

CB6 [3H]+

Complex notobserved

C4H

7N

NNH

1,3H-shift

C2H

4

CB6 [2H]+

Complex notobserved

HCN

1,3H-shift

NNH

Dissociation Direct

dissociation

Direct

dissociation

C2H

4

C2H

4 Dissociation

C2H

4

[CB61H]+

[CB71H]+

[CB81H]+

c

b

a

Dissociation

Dissociation

HCN Dissociation

Dissociation

Dissociation

Direct

dissociation

C2H

4 Direct

dissociation

Direct

dissociation

Direct

dissociation

Direct

dissociation

+

+

[CB72H]+

[CB82H]+

Figure 2 | Reaction and dissociation pathways of the inclusion complexes of the bicyclic azoalkanes 13with CBn (n5 68) in CID experiments. a, For

azoalkane 1, the CB7complex eliminates ethylene as the major pathway, followed by the dissociation of the retro-DielsAlder reaction product (pyrazole)

complex. For the more tightly packed complex with CB6and the more loosely packed complex with CB8, dissociation becomes the major pathway (dashed

arrows indicate the minor of the two competing pathways). b, For azoalkane2, no complex was observed with CB6. The major pathway for the CB7complex

is elimination of ethylene and then hydrogen cyanide, followed by dissociation of the complex with the secondary product (propenimine). The CB8complex

reacts similarly, with a slightly lower preference for inner-phase reaction than that observed for CB7(seeTable 1).c, For azoalkane 3, no complex was

observed withCB6either, and theCB7and CB8complexes predominantly undergo direct dissociation. As a minor pathway, the CB7complex eliminates a

C4H7N fragment and theCB8complex eliminates ethylene (at a larger collision energy, see Table 1), in both cases followed by dissociation of the productcomplexes. For CID mass spectra, structural assignments and fragmentation mechanisms, see Supplementary Figs S8S13, Table S15 and Section S4.

ARTICLES NATURE CHEMISTRY DOI: 10.1038/NCHEM.1618

http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/naturechemistryhttp://www.nature.com/naturechemistryhttp://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7


DiscussionThe observation of efficient inner-phase reactions for some (but notfor all) homologous hostguest complexes discloses fundamentalinsights into the factors that govern chemical reactivity in isolatedconfined environments. Although unprecedented reaction pathwaysobserved in mass spectrometry for macromolecules are frequentlyattributed to the rate and efficiency by which internal energy is dis-tributed4648, such RiceRamspergerKasselMarcus effects cannotaccount comprehensively for the non-systematic trends of the reac-tion efficiencies in Table 1. We interpret the observed trends interms of a balance between three contributing factors: (1) the intrin-sic activation energies for chemical reactions of the guest, (2) theconstrictive binding displayed by the particular host and (3) thevoid space inside the hostguest complex. For example, based onthe results obtained by DFT calculations, the experimentallyobserved elimination of ethylene from the protonated azoalkanes13shows a typical ring-strain effect in the sense that the activationbarrier increases significantly from the smallest to the largest bicycle(seeTable 1). Some trends of the reaction efficiencies for the hostguest complexes, such as that azoalkane 3 shows invariably lowerreaction efficiencies than those of the smaller homologues, are unques-tionably related to its intrinsically lower retro-DielsAlder reactivity.

When the reaction efficiencies for the same azoalkane are com-pared at the same low collision energy (f

rvalues at 5 eV E

com,

Table 1) for the differently sized hosts another trend becomesapparent, namely that the largest host, CB8, shows smaller f

r

values thanCB7does. This can be rationalized in terms of a different

degree of constrictive binding. Constrictive binding, that is, theobservation of an activation barrier towards dissociation of encapsu-lated guests, is a phenomenon originally described for hemicarcer-ands1,29,30. For CBs, the constrictive binding originates from thecarbonyl portals, which are significantly tighter than the innercavity (for example, 3.9 versus 5.8 for CB6)38, such thatguests need to squeeze through the portals to ingress oregress37,39. Accordingly, the degree of constrictive binding increases

as the portal diameter of the host becomes narrower (from 6.9 forCB8, to 5.4 for CB7, to 3.9 for CB6)38. This peculiarity retardsboth the association of guests and the dissociation of their CBninclusion complexes, and may render them sufficiently kineticallystable to undergo (in the gas phase) chemical reactions in compe-tition with dissociation. The idea that constrictive binding is animportant factor in triggering inner-phase reactions receivestwofold experimental support. First, fragmentation reactions occuronly for the inclusion complexes, but exclusion complexes ofazoalkanes13may be too unstable because they are not observedunder our conditions (see Results). Second, the protonated hostguest complex of azoalkane2withb-cyclodextrin, a flexible macro-cycle that does not exhibit constrictive binding, did not undergo anydetectable inner-phase reactions (Supplementary Fig. S19). Theconstrictive binding in the inclusion complexes ofCB8is apparentlysufficient to allow chemical reactions to compete, but to a signifi-cantly smaller extent than for CB7, or only at a higher collisionenergy (7.5 eVE

com).

Strikingly, the reaction efficiency for the inclusion complex of theintrinsically most-reactive azoalkane 1 with the most constrictiveCB6 fell below expectation; indeed, only trace amounts ofretro-DielsAlder product complexes were detected (Table 1).This reveals the importance of the third factor in determining

a b

Figure 3 | Geometry-optimized molecular structures (HF/6-31G* level of

theory) of [CB7.2. H]1 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/6-311G**) calculations predict the exclusion complex to

be up to 18 kcal mol21 more stable than the inclusion one. However,

advanced methods, which consider dispersion interactions as well, namely

wB97XD/6-31G** and MP2/6-31G*, predict the inclusion complex to be

more stable by 12 kcal mol21 (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 andFig. 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.

Abundance

Drift time (ms)

8.0 9.0 10.0 11.0 12.0 13.0

[CB72H2]+

[CB72HC2H4HCN]+

[CB72HC2H4]+

[CB72H]+

[CB7H]+

Cross-section (2)

170 180 190

11.29

11.29

11.18

11.04

11.29

9.84e

d

c

b

a

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 CB7in the

absence of an included guest. The propensity for inversion of CBs in the gas

phase will be investigated separately.


http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/naturechemistryhttp://www.nature.com/naturechemistryhttp://www.nature.com/doifinder/10.1038/nchem.1618http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp2http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_compCB6http://www.nature.com/compfinder/10.1038/nchem.1618_compCB7http://www.nature.com/compfinder/10.1038/nchem.1618_compCB8http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp3http://www.nature.com/compfinder/10.1038/nchem.1618_comp1


inner-phase reactivity of the hostguest complexes in the gas phase:the necessity of void space. We have assessed void-space effects bybuilding on first principles of intermolecular interactions and con-sidering empirical observations on the preferential binding of guestsinside concave hosts. The chemical reaction, that is, the extrusion ofethylene, was modelled by constructing a Lennard-Jones 12-6potential of a spherical guest expanding inside a rigid host cavitythat matches the cavity size of the different CBs (Fig. 5a andSupplementary Section S2). This potential, which includes attractive(dispersion) and repulsive van der Waals interactions, neglectssolvent effects, and thereby provides a good comparison with theobserved gas-phase results. It also neglects electrostatic interactionsof the cationic sites with the carbonyl rim; the latter were assumedto remain constant in the course of the ethylene extrusion. Thepotentials were plotted against the guest volume and adjusted (byvarying the effective collision diameter) to display their minimumat a 55% PC to match Rebeks empirical solution for ideal hostguest inclusion31,32,49.

The model potential (energy versus guest volume,Fig. 5b) nicelyreveals an initially increasing stabilization of the hostguest complexas the guest volume increases, followed by the expected minimum,and a steep increase as the volume of the guest becomes too large.Evidently, the synchronous rupture of two bonds and the incipientformation of two fragments require a positive volume of activation.As reference points, we inserted inFig. 5c interval bars that bracketthe volumes of the reactant azoalkane and the sum of the volumes ofthe products (fragment and ethylene). The volumes of the transition

states must fall in between; for example, calculations suggestan increase from the reactant volumes by 56 3 or 5%(Supplementary Table S10). The propensity towards cycloelimina-tion inside a molecular container depends critically on whetherthe intermolecular forces between the host walls and the guest arevan der Waals attractive or repulsive in nature, as indicated by theslopes of the arrows in Fig. 5c. These reflect the assistance (byincreasing dispersion interactions with the host) or resistance (by

increasing Pauli repulsion against the host) as the guest expandsduring cycloelimination. As can be approximated from the DFT-calculated differential binding energies of the reactants versus pro-ducts (Supplementary Fig. S1) as well as those of the differentguests (these are also caused by dispersion or repulsion, seeSupplementary Tables S4 and S5), the additional supramolecularstabilization or destabilization energy amounts to several kilocal-ories per mole, which presents a highly significant modulation ofthe intrinsic activation energies (Table 1).

Arguing in terms of the potentials (Fig. 5c) and focusing on thevariations in host size, the very smallf

rvalue of1 in CB6 reflects

that the reaction occurs in the repulsive region of the associatedpotential (uphill arrow). In contrast, the reactions of 1 in CB7and CB8 are efficient, because the cycloelimination occurs in theattractive region of the potential, that is, at volumes smaller thanthe minimum on the potential energy surface. Interestingly, accord-ing toFig. 5c, the elimination of3 insideCB7 occurs very close tothe minimum (ideal packing (almost horizontal arrow)), whichcould contribute to the lower f

rvalue of the largest guest. The

increase in frfor CB7 on going from 1 to 2 cannot be explained

with the potentials nor with the intrinsic activation energies, suchthat the lower degree of constrictive binding for the CB7 .1complex (facilitating dissociation) must be the important factor inthis case. Similarly, the lower f

rvalues of all guests in CB8 versus

CB7 most probably result from a lower degree of constrictivebinding and cannot be judged with this simplistic Lennard-Jonesapproach, which would predict similar (for 1 and 2) or more effi-cient (for3) reactions, as judged by the slopes of the arrows.

Arguing in terms of PC values (Table 1) and focusing on the

variation in guest size, the PC values of the CB7 complexes with1and 2 are sufficiently small (4046%)31,32 to accommodate com-fortably for the required volume of activation, and for thecomplex between the largest guest homologue 3and CB7 the PCis essentially ideal (52%) and gives little incentive for the guest toreact. In the latter case, dissociation predominates over the chemicalreaction. The complex between azoalkane 1 and the smaller hosthomologueCB6(PC 68%) is the most tightly packed, but, neverthe-less, mainly dissociation is detected on CID. This emphasizes that aconfinement of the guest is a necessary, but not a sufficient criterionto observe predominant inner-phase reactions in hostguest com-plexes. The competitive dissociation observed for the CB8 com-plexes reveals, vice versa, that a sufficient amount of void spacealone is also insufficient to promote predominant inner-phase reac-tions, but that a sufficiently large confinement of the guest isanother prerequisite, which must be met in parallel. Fully in linewith our train of thought, experiments in which the void spacein CB7 is artificially reduced by blocking and tightening thesecond portal of CB7 with either a proton or a sodium ion(Supplementary Figs S4 and S14) show that the inner-phase reactionpathway can be effectively shut down for azoalkanes 2 and 3 andthat dissociation then prevails. Only for the smallest azoalkane 1does there appear to remain sufficient void space to allow the reac-tion to occur even from doubly chargedCB7complexes. An alterna-tive, consistent, line of argumentation involves the effect of internalpressure on the reactions (Supplementary Section S3)50.

In conclusion, gas-phase reactions of guests included in molecu-lar containers can become efficient when the hostguest complexesfulfil stringent boundary conditions. First, the host must display a

50 75 100 125 150

0.3

0.2

0.1

0.0

Guest volume (3)

1 2 3c

0 50 100 150 200 250

0.4

0.2

0.00.2

0.4

Guest volume (3)

CB8

CB7

CB6

a

b

CB8

CB7

CB6

Epot

rel

Epot

rel

Figure 5 | Model potentials for the interaction of a spherical guest

positioned centrosymmetrically inside a host cavity versus guest volume.

a, I llustration 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.


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constrictive binding of the guest. Second, the intermolecular forcesbetween the guest and the cavity walls of the host must match thevolume of activation of the chemical reaction of interest. For thecycloeliminations examined here, which have a positive volume ofactivation, there must be sufficient void space in the cavity; forcycloadditions with a negative volume of activation, tight packingis favourable. If any of the conditions are not met, the chemical reac-tion of the guest inside the host is readily switched off. For CBs as

macrocycles, the void space can be reduced by selecting a smallerhost (CB6) or by docking of cations to the portals, and the constric-tive binding can be alleviated via the selection of a host with largeportals (CB8). The two supramolecular effects should directly mani-fest themselves on the pre-exponential factors and activation ener-gies of inner-phase reactions and, therefore, be transferable tocatalysis and biocatalysis inside confined reaction space.

MethodsMass spectrometry.Mass spectrometric experiments were performed using ESI FT-ICR, quadrupole time-of-flight and quadrupole ion trap mass spectrometers for theaccurate mass measurements, profile spectra measurements, and the CID andenergy-resolved CID experiments. Ion-mobility measurements were done by directinfusion on a Waters Synapt G2 HDMS mass spectrometer equipped with anion-mobility cell (see Supplementary Section S5.1 for further details, includingcomputational details for the analysis of the cross-sections).

Model potential function.The model potential function for the interaction of aspherical guest positioned centrosymmetrically inside a host cavity with the guestvolume was derived by setting up a 12-6 Lennard-Jones potential and consideringdispersion as the only attractive interaction. The polarizability of the guest wasassumed to increase linearly with its size, and dispersion interactions wereassumed to arise mainly from atoms in the host interacting with atoms near theperiphery of the guest. The final functional relationship (Supplementary SectionS2, equation (S4)) allows one to construct the potential as a function of thevolume of the guest (see Supplementary Information for further details, includingcomputational details for the analysis of the packing coefficients).

Received 24 September 2012; accepted 27 February 2013;

published online 7 April 2013

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AcknowledgementsA.I.L., W.M.N. and K.I.A. thank the Deutsche Forschungsgemeinschaft (DFG, grantnumber NA-686/5), the Deutsche Akademische Austauschdienst (DAAD) and the Centerfor Functional Materials and Nanomolecular Science (NanoFun) for financial support,including graduate fellowships for A.I.L. and K.I.A. The Academy of Finland isacknowledged by E.K. for financial support (project number 127941). The FT-ICR facilityis supported by Biocenter Finland. The authors thank L. Isaacs for making a referencesample of inverted CB7 available, M. Olivucci for donating computing time andD. V. Dearden for helpful comments on the results.

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

Additional informationSupplementary information and chemical compound information are available in theonline versionof the paper.Reprints and permissions information is available online atwww.nature.com/reprints. Correspondence and requests for materials should be addressed to

E.K. and W.M.N.

Competing financial interestsThe authors declare no competing financial interests.


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